Reagents and methods for detecting or modulating CBL and / or CBL-b in patients

Abstract

Systemic lupus erythematosus (SLE) is an autoimmune disease with multisystem involvement and is associated with significant morbidity and mortality. The diagnosis of SLE is challenging because signs and symptoms vary considerably from person to person, may change over time, and may overlap with those of many other disorders. There is thus a need for better tools and assays for the diagnosis and assessment of SLE. The present application discloses novel methods for the diagnosis and follow-up of SLE based on the detection of the levels of Casitas B-lineage lymphoma (CBL) and / or CBL-B in T lymphocytes from a subject, as well as novel methods for treating a subject suffering from SLE or preventing the development of SLE in an at-risk subject through the administration of an agent that increases the expression or activity of CBL and / or CBL-B in T lymphocytes from the subject, and / or the depletion of ICOS+ T cells.

Description

[0001]G12810-00883 1 REAGENTS AND METHODS FOR DETECTING OR MODULATING CBL AND / OR CBL-B IN PATIENTS CROSS REFERENCE TO RELATED APPLICATIONS The present application claims the benefit of U.S. provisional patent application No. 63 / 636,174, filed on April 19, 2024. The entire content of this application is incorporated herein by reference. SEQUENCE LISTING A sequence listing is submitted herewith as an XML file named G12810-00883-AD_Seq listing.xml, that was created on April 11, 2025, and having a size of ~41927 bytes. The content of the aforementioned file is hereby incorporated by reference in its entirety. TECHNICAL FIELD The present invention generally relates to autoimmune diseases, and more specifically to the diagnosis and treatment of systemic lupus erythematosus (SLE). BACKGROUND ART Systemic lupus erythematosus (SLE) is an autoimmune disease involving both innate and adaptive arms of the immune cells1. The disease is initiated by autoantibodies produced by plasma cells (PCs) of either the germinal center (GC) or extrafollicular origin2. While past studies have made significant discoveries about the role of lupus causing factors controlling B cell activation and survival2−4, emerging evidence reveals that the increased blood circulating Tfh (cTfh) cells is closely linked to SLE pathogenesis5-8. The role of Tfh cells in developing SLE-like disease has also been established in Roquin (san / san) and T cell specific Est1 mutant mice, as in the former case Roquin has been shown to control Tfh cell homeostasis by regulating Icos mRNA stability9-11, despite similar mutations have not yet been observed in human SLE. Under normal circumstances, Tfh cell development is controlled by signaling pathways of the TCR, ICOS, and cytokine receptors IL-6 and IL-21, which collectively induce the expression of the master transcription factor BCL-6 for Tfh cell development and function12,13. Expression of BCL-6 in activated T cells leads to the commitment of Tfh cell fate and subsequent cognate T-B cell interaction in GCs promotes Tfh cell maturation and expansion14-16. At the molecular level, it is known that BCL-6 expression is controlled by transcription factors TCF-1 and LEF1 in coordination with STAT3 and STAT117-20. The level of BCL-6 protein can also be post- transcriptionally regulated by ICOS signaling which inactivates the FOXO1 mediated suppression of the initial BCL-6 transcription21. However, the molecular mechanism leading to the excessive G12810-00883 2 Tfh cell development in SLE patients and whether it contributes to the manifestation of SLE remain elusive. The diagnosis of SLE is challenging because signs and symptoms vary considerably from person to person, may change over time, and overlap with those of many other disorders. Currently, no single test can be used to diagnose SLE, and thus the diagnosis is typically based on the combination of blood and urine tests, imaging, signs and symptoms, and physical examination. There is thus a need for better tools and assays for the diagnosis and assessment of SLE. The present description refers to a number of documents, the content of which is herein incorporated by reference in their entirety. SUMMARY OF THE INVENTION In various aspects and embodiments, the present disclosure provides the following items 1 to 64: 1. A method for determining whether a subject suffers from systemic lupus erythematosus (SLE) comprising: (a) measuring the protein level of Casitas B-lineage lymphoma (CBL) and / or CBL-B in T lymphocytes from the subject; (b) comparing the protein level of CBL and / or CBL-B in the T lymphocytes from the subject with a reference protein level of CBL and / or CBL-B or predetermined reference value, and (c) determining whether the subject suffers from systemic lupus erythematosus (SLE) based on said comparing. 2. The method of claim 1, wherein (i) the reference protein level or predetermined reference value is a level in a control population not having SLE, and wherein a lower protein level of CBL and / or CBL-B are indicative that the subject suffers from SLE; or (ii) the reference protein level or predetermined reference value is a level in a control population having SLE, and wherein a lower or similar protein level of CBL and / or CBL-B is indicative that the subject suffers from SLE. 3. The method of claim 1 or 2, wherein the method comprises measuring the protein level of CBL protein. 4. The method of any one of claims 1 to 3, wherein the method comprises measuring the protein level of CBL-B. 5. The method of any one of claims 1 to 4, wherein the method comprises measuring the protein level of CBL and CBL-B. 6. The method of any one of claims 1 to 5, wherein the method further comprises (d) measuring the protein level of ICOS and / or BCL-6 in T lymphocytes from the subject; and (e) comparing the protein level of ICOS and / or BCL-6 in the T lymphocytes from the subject with a reference protein level of ICOS and / or BCL-6 or predetermined reference value. G12810-00883 3 7. The method of claim 6, wherein (i) the reference protein level or predetermined reference value is a level in a control population not having SLE, and wherein a higher protein level of ICOS and / or BCL-6 are indicative that the subject suffers from SLE; or (ii) the reference protein level or predetermined reference value is a level in a control population having SLE, and wherein a higher or similar protein level of ICOS and / or BCL-6 is indicative that the subject suffers from SLE. 8. The method of any one of claims 1 to 7, wherein the biological sample is a blood sample, a peripheral blood mononuclear cell (PBMC) sample, or a tissue sample. 9. The method of any one of claims 1 to 8, wherein the T lymphocytes are naïve T lymphocytes. 10. The method of any one of claims 1 to 9, wherein the T lymphocytes are CD4+ T lymphocytes. 11. The method of any one of claims 1 to 10, wherein the measuring the protein level of CBL and / or CBL-B is performed using one or more ligands that specifically bind to CBL and / or CBL- B. 12. The method of claim 11, wherein the one or more ligands are one or more antibodies. 13. The method of any one of claims 1 to 12, wherein the measuring is performed by an immunoassay. 14. The method of claim 13, wherein the immunoassay is flow cytometry, enzyme-linked immunosorbent assay (ELISA), radioimmunoassay (RIA), Western blotting, or immunofluorescence. 15. The method of claim 14, wherein the immunoassay is flow cytometry. 16. The method of any one of claims 1 to 15, further comprising administering a treatment for SLE to the patient identified as suffering from SLE using the method defined in any one of claims 1 to 15. 17. The method of claim 16, wherein the treatment comprises an anti-inflammatory agent, corticosteroid, an antimalarial drug, an immunosuppressant, a soluble human B lymphocyte stimulator protein (BLyS) inhibitor, a CD20 binding agent, or any combination thereof. 18. The method of claim 17, wherein the anti-inflammatory agent comprises a corticosteroid (e.g., prednisone), the antimalarial drug comprises hydroxychloroquine, the immunosuppressant comprises azathioprine, mycophenolate, methotrexate, cyclosporine, or leflunomide, the BLyS inhibitor comprises belimumab, and / or the CD20 binding agent comprises rituximab. 19. The method of any one of claims 16 to 18, further comprising monitoring the patient's response to the treatment by: a) periodically measuring the level of CBL protein, CBL-B protein, or both, in subsequent biological samples from the subject; and b) comparing the levels from the subsequent biological samples to the levels measured prior to treatment or to subsequent predetermined reference values, wherein an increase in the level of CBL protein, CBL-B protein, G12810-00883 4 or both, relative to the level measured prior to treatment, is indicative of a positive response to the treatment. 20. A method for treating a patient suffering from systemic lupus erythematosus (SLE) comprising: identifying the patient suffering from SLE using the method of any one of claims 1 to 15; and administering a treatment for SLE to the patient. 21. The method of claim 20, wherein the treatment comprises an anti-inflammatory agent, corticosteroid, an antimalarial drug, an immunosuppressant, a soluble human B lymphocyte stimulator protein (BLyS) inhibitor, a CD20 binding agent, or any combination thereof. 22. The method of claim 21, wherein the anti-inflammatory agent comprises a corticosteroid (e.g., prednisone), the antimalarial drug comprises hydroxychloroquine, the immunosuppressant comprises azathioprine, mycophenolate, methotrexate, cyclosporine, or leflunomide, the BLyS inhibitor comprises belimumab, and / or the CD20 binding agent comprises rituximab. 23. A method for assessing the evolution of systemic lupus erythematosus (SLE) in a patient comprising: (a) measuring the protein level of Casitas B-lineage lymphoma (CBL) and / or CBL-B in T lymphocytes from the subject at a first time point; (b) measuring the protein level of CBL and / or CBL-B in T lymphocytes from the subject at a second, later time point; (c) comparing the protein level of CBL and / or CBL-B at the first and second time points, wherein: (i) a lower protein level of CBL and / or CBL-B at the second time point relative to the first time point is indicative that the patient’s disease has worsened; (ii) a similar protein level of CBL and / or CBL-B at the first and second time points is indicative that the patient’s disease is stable; or (iii) a higher protein level of CBL and / or CBL-B at the second time point relative to the first time point is indicative that the patient’s disease has improved. 24. The method of claim 23, wherein the method comprises measuring the protein level of CBL. 25. The method of claim 23 or 24, wherein the method comprises measuring the protein level of CBL-B. 26. The method of any one of claims 23 to 25, wherein the method comprises measuring the protein level of CBL and CBL-B. 27. The method of any one of claims 23 to 26, wherein the method further comprises (d) measuring the protein level of ICOS and / or BCL-6 in T lymphocytes from the subject at said first and second time points; and (e) comparing the protein level of ICOS and / or BCL-6 at the first and second time points, wherein: (i) a higher protein level of ICOS and / or BCL-6 at the second time point relative to the first time point is indicative that the patient’s disease has worsened; (ii) a similar protein level of ICOS and / or BCL-6 at the first and second time points is indicative that the patient’s disease is stable; or (iii) a lower protein level of ICOS and / or BCL-6 at the second time point relative to the first time point is indicative that the patient’s disease has improved. G12810-00883 5 28. The method of any one of claims 23 to 27, wherein the biological sample is a blood sample, a peripheral blood mononuclear cell (PBMC) sample, or a tissue sample. 29. The method of any one of claims 23 to 28, wherein the T lymphocytes are naïve T lymphocytes. 30. The method of any one of claims 23 to 29, wherein the T lymphocytes are CD4+ T lymphocytes. 31. The method of any one of claims 23 to 30, wherein the measuring the protein level of CBL and / or CBL-B is performed using one or more ligands that specifically bind to CBL and / or CBL- B. 32. The method of claim 31, wherein the one or more ligands are one or more antibodies. 33. The method of any one of claims 23 to 32, wherein the measuring is performed by an immunoassay. 34. The method of claim 33, wherein the immunoassay is flow cytometry, enzyme-linked immunosorbent assay (ELISA), radioimmunoassay (RIA), Western blotting, or immunofluorescence. 35. The method of claim 34, wherein the immunoassay is flow cytometry. 36. The method of any one of claims 23 to 35, wherein the patient is undergoing treatment for SLE between the first and second time points, and wherein the method permits to assess the patient’s response to the treatment. 37. A kit for diagnosing or assessing the evolution of systemic lupus erythematosus (SLE) in a subject, the kit comprising: a) one or more reagents for detecting CBL protein, CBL-B protein, or both, in a biological sample; and b) instructions for comparing the level of CBL protein, CBL-B protein, or both, in the biological sample with a predetermined reference value to diagnose or assess the evolution of SLE. 38. The kit of claim 37, wherein the one or more reagents comprise antibodies specific to CBL protein, CBL-B protein, or both. 39. The kit of claim 37 or 38, wherein the kit further comprises one or more reagents for detecting ICOS, BCL-6 and / or CD4 in a biological sample. 40. The kit of any one of claims 37 to 39, further comprising one or more standards comprising known quantities of CBL protein, CBL-B protein, or both, for generating a standard curve. 41. The kit of any one of claims 37 to 40, wherein the kit is configured for use in an immunoassay. 42. The kit of claim 41, wherein the immunoassay is flow cytometry, enzyme-linked immunosorbent assay (ELISA), radioimmunoassay (RIA), Western blotting, or immunofluorescence. 43. The kit of claim 42, wherein the immunoassay is flow cytometry. G12810-00883 6 44. Use of one or more reagents for the detection of CBL protein, CBL-B protein, or both, in the manufacture of a diagnostic kit for systemic lupus erythematosus (SLE). 45. The use of claim 44, further comprising one or more reagents for the detection of ICOS and / or BCL-6. 46. The use of claim 44 or 45, wherein the one or more reagents are one or more antibodies. 47. A method for treating a subject suffering from systemic lupus erythematosus (SLE) or preventing the development of SLE in an at-risk subject, the method comprising administering to the patient an agent that increases the expression or activity of Casitas B-lineage lymphoma (CBL) and / or CBL-B in T lymphocytes from the subject. 48. The method of claim 47, wherein the agent that increases the activity of CBL and / or CBL- B is a compound that stabilizes CBL and / or CBL-B. 49. The method of claim 47, wherein the agent that increases the expression or activity of CBL is a CBL polypeptide having at least 70% sequence identity with the amino acid sequence of human CBL (FIG.17A), or a nucleic acid encoding the CBL polypeptide. 50. The method of claim 47, wherein the agent that increases the expression or activity of CBL is a CBL polypeptide having at least 90% sequence identity with the amino acid sequence of human CBL (FIG.17A), or a nucleic acid encoding the CBL polypeptide. 51. The method of claim 50, wherein the agent that increases the expression or activity of CBL is a CBL polypeptide comprising the amino acid sequence of human CBL (FIG.17A), or a nucleic acid encoding the CBL polypeptide. 52. The method of any one of claims 47-51, wherein the agent that increases the expression or activity of CBL-B is a CBL-B polypeptide having at least 70% sequence identity with the amino acid sequence of human CBL-B (FIG.17B), or a nucleic acid encoding the CBL-B polypeptide. 53. The method of claim 52, wherein the agent that increases the expression or activity of CBL-B is a CBL-B polypeptide having at least 90% sequence identity with the amino acid sequence of human CBL-B (FIG.17B), or a nucleic acid encoding the CBL-B polypeptide. 54. The method of claim 53, wherein the agent that increases the expression or activity of CBL-B is a CBL-B polypeptide comprising the amino acid sequence of human CBL-B (FIG.17B), or a nucleic acid encoding the CBL-B polypeptide. 55. Use of an agent that increases the expression or activity of Casitas B-lineage lymphoma (CBL) and / or CBL-B in T lymphocytes for treating a patient suffering from systemic lupus erythematosus (SLE). 56. Use of an agent that increases the expression or activity of Casitas B-lineage lymphoma (CBL) and / or CBL-B in T lymphocytes for the manufacture of a medicament for treating a patient suffering from systemic lupus erythematosus (SLE). 57. The use of claim 55 or 56, wherein the agent that increases the activity of CBL and / or CBL-B is a compound that stabilizes CBL and / or CBL-B. G12810-00883 7 58. The use of claim 55 or 56, wherein the agent that increases the expression or activity of CBL is a CBL polypeptide having at least 70% sequence identity with the amino acid sequence of human CBL (FIG.17A), or a nucleic acid encoding the CBL polypeptide. 59. The use of claim 55 or 56, wherein the agent that increases the expression or activity of CBL is a CBL polypeptide having at least 90% sequence identity with the amino acid sequence of human CBL (FIG.17A), or a nucleic acid encoding the CBL polypeptide. 60. The use of claim 55 or 56, wherein the agent that increases the expression or activity of CBL is a CBL polypeptide comprising the amino acid sequence of human CBL (FIG.17A), or a nucleic acid encoding the CBL polypeptide. 61. The use of any one of claims 55-60, wherein the agent that increases the expression or activity of CBL-B is a CBL-b polypeptide having at least 70% sequence identity with the amino acid sequence of human CBL-b (FIG.17B), or a nucleic acid encoding the CBL-B polypeptide. 62. The use of claim 61, wherein the agent that increases the expression or activity of CBL-B is a CBL-B polypeptide having at least 90% sequence identity with the amino acid sequence of human CBL-B (FIG.17B), or a nucleic acid encoding the CBL-B polypeptide. 63. The use of claim 62, wherein the agent that increases the expression or activity of CBL-B is a CBL-B polypeptide comprising the amino acid sequence of human CBL-B (FIG.17B), or a nucleic acid encoding the CBL-B polypeptide. 64. The method of claim 47 or the use of claim 55 or 56, wherein the agent is a dual binding molecule that increases the interaction between (i) ICOS and (ii) CBL and / or CBL-B. Other objects, advantages and features of the present invention will become more apparent upon reading of the following non-restrictive description of specific embodiments thereof, given by way of example only with reference to the accompanying drawings. BRIEF DESCRIPTION OF DRAWINGS In the appended drawings: FIGs.1A-G show that SLE patients have impaired CBL and CBL-B expression and hyper Tfh cell responses. FIG. 1A: Flow cytometric analysis (left) and statistics (right) of blood CD4+CD45RO+CXCR5hiPD-1+cTfh cells from healthy control (HC) donors and SLE patients (SLE). (n=10). FIG.1B: Histogram comparison (left) and statistics (right) of ICOS expression on gated cTfh cells from healthy donors (HC) and SLE patients. (n=8). FIG. 1C: Histogram comparison (left) and statistics (right) of BCL-6 expression in gated cTfh cells from healthy donors (HC) and SLE patients. (n=8). FIG.1D: Flow cytometric analysis (top) and statistic (bottom) of CD40L mobilization in cTfh cells from healthy control, RA and SLE patients. (n=10-26). FIG.1E: qPCR analyses of Tfh cell and immune tolerance related gene expression in blood CD4+T cells from heathy donors (HC) and SLE patients. (n=4). FIG. 1F: Western blot (top) and statistical G12810-00883 8 (bottom) analyses of CBL and CBL-B expression in blood CD4+T cells from healthy donors (HC, n=13) and SLE (n=15) patients. FIG.1G: Correlation between the relative expression of CBL and CBL-B proteins and SLEDAI-2X scores from SLE patients from FIG.1F. (n=15) Data are means ± SEM (FIGs.1A-E) and are pooled results of at least two to three experiments (FIGs.1A-F). *p<0.05, **p<0.01, ***p<0.001, ns stands for not significant, unpaired student-t test (FIGs.1A-C and F), one-way ANOVA (FIGs.1D-E), Pearson’s correlation (FIG.1G). FIGs.2A-P show that T cell-specific ablation of CBLs causes hyper Tfh cell and GC responses and the manifestation of SLE-like syndrome in mice. FIGs. 2A-B: Flow cytometric analyses (left) and statistics (right) of the cell number and ratio of splenic Tfh (FIG.2A) and GC B (FIG. 2B) cells in 10- to 12-week-old Ctrl (Cd-4 cre tg C57BL / 6 and Cd4-cre-Cblf / fCbl-b+ / -littermate) and Cbl- / -Cbl-b- / -mice without immunization. (n=7-8) FIG.2C: Histogram analyses (up) and statistics (bottom) of cell surface ICOS, OX40, and CD5 expression on Tfh cells from Ctrl and Cbl- / -Cbl-b- / -mice. (n=5-6). FIG. 2D: ELISA analysis of serum anti-dsDNA antibodies of IgG isotypes. (n=7-8) FIG.2E: Immunofluorescent analysis of serum IgG ANA antibodies. Serum samples are from Ctrl and sicken Cbl- / -Cbl-b- / -mice. (n=5). FIG.2F: Kidney antibody deposits. Shown are immunofluorescent staining of IgG deposits in kidney sections of Ctrl and sicken Cbl- / -Cbl-b- / -mice. (n=5). FIGs 2G and H: Flow cytometric analyses (left) and statistics (right) of Tfh (FIG.2G) and GC B (FIG.2H) cells in Ctrl and Cbl- / -Cbl-b- / -OT-II TCR tg T cell chimeric mice at day 10 post NP-OVA immunization. (n=5-6). FIG.2I: Flow cytometric analyses (left) and statistics(right) of IL-4 and IL-21 production in Tfh cells from Ctrl OT-II and Cbl- / -Cbl-b- / -OT-II TCR tg T cellchimeric mice at day 14 post NP-OVA immunization (n=6). FIG.2J: Histogram analyses of cell surface ICOS and OX40 expression on Tfh cells from Ctrland Cbl- / -Cbl-b- / -OT-II TCR tg T cell chimeric mice. (n=5-6). FIG.2K: Flow cytometric analyses (left) and statistics (right) of CD40L mobilization in Tfh cells from Ctrl OT-II and Cbl- / -Cbl-b- / -OT-II TCR tg T cell chimeric mice at day 10 post NP-OVA immunization (n=6). FIGs. 2L and M: Flow cytometric analyses (left) and statistics (right) of Tfh (FIG.2L) and GC B cells (FIG.2M) from isotype or anti-ICOS antibody treated Cbl- / -Cbl-b- / -mice. (n=5). FIG.2N: Serum anti-dsDNA antibodies of IgG isotypes in isotype or anti-ICOSL antibody treated Cbl- / -Cbl-b- / -mice. (n=5). FIG.2O: IgG ANA antibodies in serum samples from isotype or anti-ICOSL antibody treated Cbl- / -Cbl-b- / -mice. (n=5). FIG.2P: Kidney antibody deposits. Shown are immunofluorescent staining of IgG deposits in kidney sections of isotype or anti-ICOSL antibody treated Cbl- / -Cbl-b- / -mice. (n=5) Data are means ± SEM (FIGs. 2A-D, G-I, K-N) and are pooled results from two or three independent experiments. **p<0.01, ***p<0.001, unpaired student-t test (FIGs.2A-D, G, H, K-N), one-way ANOVA (FIG.2I). FIGs. 3A-I show that CBLs control Tfh cell differentiation and survival by restraining ICOS signaling. FIG.3A: In vivo tracking of OT-II TCR tg CD4+T cell proliferation. Shown are dot plots of CTV labelled OT-II TCR tg T cells at day 5 after NP-OVA immunization. (n=6). FIG.3B: Flow cytometric analyses (top) and statistics (bottom) of the ratio and cell number of in vivo Tfh G12810-00883 9 cell differentiation. Shown are CXCR5 vs. PD-1 expression in each division of proliferating Ctrl or Cbl- / -Cbl-b- / -OT-II TCR tg T cells at day 5 after immunization. (n=6). FIG.3C: Flow cytometric analyses (top) and statistics (bottom) of the Tfh cell development in each division of proliferating OT-II TCR tg T cells influenced by anti-ICOSL treatment. (n=6). FIG. 3D: Flow cytometric analyses (left) and statistics (right) of Cbl- / -Cbl-b- / C373ATfh cells at day 10 after NP-CGG immunization. (n=6-7). FIG.3E: Flow cytometric analyses (left) and statistics (right) of Cbl- / -Cbl- b- / C373AGC B cells mice at day 10 after NP-CGG immunization. (n=6-7). FIG.3F: Western blot analysis of ICOS ubiquitination in 293T cells. (n=2). FIG.3G: Flow cytometric analysis (left) and statistics (right) of the Tfh cell development in ICOS mutant T cell chimeric mice at day 10 after immunization. (n=5). FIG. 3H: Flow cytometric analysis (left) and statistics (right) of BCL-6 expression in WT and mutant ICOS expressing Tfh cells. (n=5). FIG. 3I: Cell surface ICOS expression on WT and mutants ICOS expressing Tfh cells. (n=3). Data are means ± SEM (FIGs. 3B-E and G-I) and are pooled results from two or three independent experiments. *p<0.05, **p<0.01, ***p<0.001, ns stands for not significant, unpaired student t-test (H), one-way ANOVA (FIGs.3B-E and G-I). FIGs.4A-I show that the ICOS-CBLs axis regulates BCL-6 degradation via CMA. FIG. 4A: Flow cytometric analyses of BCL-6 expression in Ctrl and Cbl- / -Cbl-b- / -Tfh cells. (n=6). FIG. 4B: Flow cytometric analyses of BCL-6 in Tfh cells treated with CMA activity inhibitor leupeptin. (n=6). FIG.4C: Confocal microscope (left) and statistical (right) analyses of BCL-6-mCherry andLAMP-2A-Dendra co-localization in in vitro generated Ctrl or Cbl- / -Cbl-b- / -Tfh cells. Each dotrepresents one cell. FIG.4D: confocal microscope (left) and statistical (right) analyses of Tfh cell endogenous BCL-6 and LAMP-2A-Dendra co-localization in in vivo generated Ctrl or Cbl- / -Cbl-b- / -Tfh cells. Each dot represents one cell. FIG. 4E: Confocal microscope (left) and statistical analyses (right) of endogenous BCL-6 and LAMP-2A+lysosomes with or without 30 min ICOS stimulation. Each dot represents one cell. FIG.4F: Western blot analysis of BCL-6 and HSC70 association in Ctrl and Cbl- / -Cbl-b- / -Tfh cells with or without 30 min TCR and ICOS co-stimulation. (n=3). FIGs.4G-H: The Cbl- / -Cbl-b- / -mutation enhances the phosphorylation of AKT (FIG.4G) and of GFAP (FIG.4H), with or without 15 min TCR and ICOS co-stimulation. (n=2). FIG.4I: Western blot analysis of GFAP and LAMP-2A association in Ctrl and Cbl- / -Cbl-b- / -Tfh cells upon TCR and ICOS co-stimulation. (n=2). Data are means ± SEM (FIGs.4A-E), and data (FIGs.4G- J) are representative results from two or three independent experiments. *p<0.05, **p<0.01, ***p<0.001, unpaired student-t test (FIGs.4A-D), one-way ANOVA (FIG.4E). FIGs.5A-E show that mutation of BCL-6 KFERQ-like motifs enhances BCL-6 expression and Tfh cell responses. FIG. 5A: Schematical presentation of three KFERQ-like motifs and mutations in BCL-6. Motif1WT, NRLRS (SEQ ID NO:22); Motif2 / 3WT, KKYKFI (SEQ ID NO:23), Motif1Mutant, NRLRA (SEQ ID NO:32) or Motif2 / 3Mutant, KKARFI (SEQ ID NO:33). PKAC = SEQ ID NO:25. FIG.5B: Confocal microscopic (top) and statistical (bottom) analyses of co-localization of G12810-00883 10 WT and mutant motif1 and motif2 / 3 BCL-6-mCherry with LAMP-2A+lysosomes. Each dot represents one cell. FIGs.5C-D: Flow cytometric (left) and statistical (right) analyses of Tfh (FIG. 5C) and GC B (FIG. 5D) cells in T cell chimeric mice receiving OT-II TCR tg CD4+T cells expressing either WT (BCL-6WT) or mutant BCL-6 (BCL-6Mut) carrying compounded KFERQ mutations after OVA immunization. (n=5). FIG.5E: Histogram comparison (left) and statistical (right) analysis of BCL-6 expression in BCL-6WTand BCL-6Mutexpressing Tfh cells. (n=5). Data are means ± SEM (FIGs. 5B-E); Data (FIG. 5B) are pooled results from two independent experiments; Data (FIGs. 5B-E) are representative results from two or three independent experiments. *p<0.05, **p<0.01, ***p<0.001, unpaired student-t test (FIGs. 5C-E), one-way ANOVA (FIG.5B). FIGs.6A-E show that ablation of CBLs enhances human Tfh cell lineage development and attenuates BCL-6 degradation via CMA. FIG.6A: Ablation of CBLs in human CD4+T cells promotes Tfh cell differentiation. Shown are flow cytometric (left) and statistics (right) analyses of in vitro generated Tfh cells from WT (Ctrl) and CBL- / -CBL-B- / -CD4+T cells. (n=6). FIG.6B: Ablation of CBLs in human CD4+T cells facilitates Tfh cell fate commitment. Shown are flow cytometric (top) and statistics (bottom) analyses of WT and CBL- / -CBL-B- / -Tfh cells generated under either Th0 (left) or Tfh (right) polarization conditions. (n=4). FIG.6C: Human CBL- / -CBL-B- / -Tfh cells exhibit enhanced ICOS expression. Shown are histogram comparison of ICOS expression on WT (Ctrl) and CBL- / -CBL-B- / -Tfh cells. (n=6). FIG. 6D: Histogram comparison of ICOS-induced phosphorylation of S6 and AKT kinases in human WT (Ctrl) and CBL- / -CBL-B- / -Tfh cells. (n=3). FIG.6E: Confocal microscope (top) and statistical (bottom) analyses of BCL-6 and LAMP-2A+lysosomes co-localization in human WT or CBL- / -CBL-B- / -CD4+Tfh cells. Each dot represents one cell. Data are means ± SEM (FIG.6E); Data (FIGs.6A-C and E) are pooled results from two independent experiments; Data (FIG. 6D) are representative results from two independent experiments. *p<0.05, **p<0.01, ***p<0.001, paired student-t test (FIGs.6A, C), one-way ANOVA (FIG.6B), unpaired student-t test (FIG.6E). FIGs.7A-D show analyses of Tfh cell development and autoimmune regulators in SLE and RA patients. FIG.7A: Western blot (top) and statistics (bottom) analyses of CBL-B and CBL expression in blood B cells from healthy (HC) donors and SLE patients. (n=5). FIG.7B: Single cell RNA-seq analysis of Tfh cell development and immune tolerance related gene expression in CD4+T cells from healthy (HC) and SLE patients. FIG.7C: Flow cytometry (left) and statistical (right) analyses of blood CD4+CXCR5+PD-1+cTfh cells from healthy donors (HC) and RA patients (RA). (n=10). FIG.7D: Western blot (top) and statistical (bottom) analyses of CBL-B and CBL expression in blood CD4+T cells from healthy donors (HC) and RA patients. (n=3). Data are means ± SEM (FIG.7C) or means ± SD (FIGs.7A and D) and each dot represents a single patient. ns stands for not significant, unpaired student-t test (FIGs.7A, C and D). G12810-00883 11 FIGs.8A-M show analyses of CBLs expression and T cell development in Ctrl and Cbl- / -Cbl-b- / -mice. FIG.8A: Western blot analysis of CBL and CBL-B deletion in CD4+T cells from Cbl- / -Cbl-b- / -mice. FIGs.8B-C: Flow cytometric (left) and statistical (right) analyses of thymic (FIG. 8B) and splenic (FIG.8C) T cell development in Ctrl and Cbl- / -Cbl-b- / -mice. (n=6). FIG.8D: Flow cytometric (left) and statistics (right) analyses of splenic CD4+and CD8+T cell activation in Ctrl and Cbl- / -Cbl-b- / -mice. (n=5). FIGs. 8E, F and G: Flow cytometric (left) and statistics (right) analyses of Th1 (FIG.8E), Th2 (FIG.8F) and Th17 (FIG.8G) cells in Ctrl and Cbl- / -Cbl-b- / -mice. (n=5). FIG.8H: Flow cytometric (left) and statistical (right) analyses of ABC-like GC B cells from ten-weeks old Ctrl and Cbl- / -Cbl-b- / -mice. (n=6). FIG.8I: Flow cytometric (left) and statistical (right) analyses of splenic ABC B cells from ten-weeks old Ctrl and Cbl- / -Cbl-b- / -mice. (n=6). FIG.8J: Representative H / E staining of kidney sections from Ctrl (Cd4-cre tg C57BL / 6) and Cbl- / -Cbl-b- / -mice. FIG.8K: Kaplan-Meier survival curve of Ctrl (Cd-4 cre C57BL / 6) and Cbl- / -Cbl-b- / -mice. (n=10). FIGs.8L-M: Flow cytometric (left) and statistical (right) analyses of Tfh (FIG.8L) and GC B (FIG.8M) cells from NP-CGG immunized Ctrl, Cbl- / -, Cbl-b- / -and Cbl- / -Cbl-b- / -mice 10 days post immunization. (n=5-6). Data are means ± SEM (FIGs.8B-I, L and M) and are pooled results from two or three independent experiments. These results (FIGs.8A and J) are representative of three to five different mice. ***p<0.001, ns stands for not significant, unpaired student-t test (FIGs.8E- I), one-way ANOVA (FIGs.8B-D, L and M). Log-rank survival curve test (FIG.8K). FIGs.9A-F show analyses of Tfh function in vivo and in T-B cell co-culture and Cbl- / -Cbl- b- / -Tregmice. FIGs.9A-B: Flow cytometric (left) and statistics (right) analyses of total (NP38-binding) (FIG.9A) and high affinity (NIP5-binding) (FIG.9B) NP-specific GC B cells from WT and Cbl- / -Cbl- b- / -OT-II TCR tg T cell chimeric mice at day 10 days post NP-OVA immunization. (n=6). FIG.9C: Flow cytometric (left) and statistic (right) analyses of AID-GFP+IgG1+B cells from in vivo generated Ctrl OT-II or Cbl- / -Cbl-b- / -OT-II Tfh cells co-cultured with naïve B cells from AID-GFP mice. (n=5). FIGs.9D-F: Flow cytometric (left) and statistical (right) analyses of GC B (FIG.9D), Tfh (FIG.9E) and Tfr (FIG.9F) cells from NP-CGG immunized Ctrl and Cbl- / -Cbl-b- / -Tregmice 10 days post immunization. (n=5). Data are means ± SEM (FIGs.9A-F) and are pooled results from two independent experiments. **p<0.01, ***p<0.001, ns stands for not significant, unpaired student-t test (FIGs.9A-F). FIGs.10A-J show analyses of Tfh cell development in Cbl- / -Cbl-b- / -mice. FIG.10A: In vivo tracking of OT-II TCR tg CD4+T cell proliferation. Shown are histograms of CTV labelled OT- II TCR tg Tfh cells at day 5 after NP-OVA immunization. (n=6). FIG.10B: Flow cytometric (left) and statistical (right) analyses of Ki67 expression in Tfh cells. (n=5). FIG.10C: Flow cytometric (left) and statistical (right) analyses of Annexin V+naïve T and Tfh cells. (n=6). FIG.10D: Flow cytometric (top) and statistical (bottom) analyses of BCL-6+Tfh cells in each division of doner OT- II TCR tg T cells in T cell chimeric mice. (n=6). FIGs.10E-G: Statistics analyses of Th1 (FIG. 10E), Th2 (FIG.10F) and Th17 (FIG.10G) cells from Ctrl OT-II and Cbl- / -Cbl-b- / -OT-II TCR tg T G12810-00883 12 cell chimeric mice at day 5 after NP-OVA immunization. (n=5). FIG.10H: Flow cytometric (top) and statistical (bottom) analyses of the Tfh cell development in each division of OT-II TCR tg T cells in anti-OX40L treated T cell chimeric mice. (n=6). FIGs. 10I-J: Histogram analyses of proliferation of OT-II TCR tg CD4+T cells in anti-OX40L (FIG. 10I) or anti-ICOSL (FIG. 10J) antibody treated T cell chimeric mice. (n=6). Data are means ± SEM (FIGs. 10B-H) and are pooled results from two or three independent experiments. ***p<0.001, ns stands for not significant, unpaired student-t test (FIGs.10B, E, F and G), one-way ANOVA (FIGs.10C, D and H). FIGs.11A-G show that the ubiquitination, expression, and signaling of ICOS is regulated by CBLs. FIG.11A: Flow cytometric (left) and statistical (right) analyses of cell surface ICOS internalization in activated WT (Ctrl) and Cbl- / -Cbl-b- / -OT-II TCR tg CD4+T cells (n=3). FIG.11B: Flow cytometric analysis of ICOS expression on WT (Ctrl) and Cbl- / -Cbl-b- / C373ATfh cells. (n=3). FIG.11C: Schematic presentation of WT ICOS protein with five putative ubiquitination lysine (K) residues of the cytoplasmic tail, and three mutant ICOS proteins carrying site specific mutations from lysine (K) to arginine (R). SKKKY = SEQ ID NO:28; SRRRY = SEQ ID NO:29; NKKSRLAGVTS = SEQ ID NO:30; NRRSRLAGVTS = SEQ ID NO:31. FIG.11D: Flow cytometric (left) and statistical (right) analyses of the GC B cell development in ICOS mutant T cell chimeric mice at day 10 after immunization. (n=5). FIG.11E: Flow cytometric (top) and kinetical analyses of the ICOS internalization in activated WT-ICOS, 2K2R-ICOS, 3K2R-ICOS, or 5K2R-ICOSexpressing OT-II TCR tg CD4+T cells. Cells were stimulated with anti-ICOS for 10 min. (n=2).FIG. 11F: Histogram comparison of AKT (S473) phosphorylation in WT-ICOS, 2K2R-ICOS, 3K2R-ICOS or 5K2R-ICOS expressing OT-II TCR tg CD4+T cells after ICOS stimulation. (n=4). FIG.11G: Flow cytometric analyses of Ca2+influx in WT-ICOS and 5K2R-ICOS expressing OT-II TCR tg CD4+T cells elicited by ICOS stimulation. (n=3). Data are means ± SEM (FIGs.11A and D) and are pool results from two or three independent experiments. These results (FIGs.11B, and E-G) are representative from 2-4 different mice. **p<0.01, ***p<0.001, ns stands for not significant, one-way ANOVA (FIGs.11A and D). FIGs.12A-E show targeting BCL-6 to CMA. FIG.12A: Heat map comparison of Tfh cell development related genes in WT (Ctrl) and Cbl- / -Cbl-b- / -Tfh cells. FIG.12B: Western blot analysis of BCL-6 ubiquitination in 293T cells (n=2). FIG. 12C: KFERQ-like motifs in BCL-6 protein identified by KFERQ motif finder. Motif1, NRLRS (SEQ ID NO:22); Motif2 / 3, KKYKFI (SEQ ID NO:23), KKYKF (SEQ ID NO:26) or KYKFI (SEQ ID NO:27). PKAC = SEQ ID NO:25. FIG.12D: Schematic design of tracking BCL-6 protein translocation to LAMP-2A+lysosomes. BCL-6 protein or truncated BCL-6 proteins with either WT or mutated KFERQ-like motifs are fused to mCherry protein (Red), respectively. The LAMP-2A-KEFRQ motif is fused to Dendra2 (Green). In CMA activated cells, LAMP-2A-Dendra2 reporter is targeted to CMA+lysosomes and forms multimers which can be visualized as lysosome puncta. BCL-6 (red) targeted to CMA+lysosomes can be G12810-00883 13 quantified based on the co-localization with LAMP-2A puncta (orange). FIG. 12E: Confocal microscopic (left) and statistical (right) analyses of LAMP-2A-Dendra2 and BCL-6-mCherry co- localization in NIH3T3 cells under normal (top) or starvation (bottom) condition. Each dot represents one cell. Data are means ± SEM (FIG.12E) and are pool results from two independent experiments. **p<0.01, unpaired student-t test (FIG.12E). FIGs.13A-B show that KFERQ-like motif1 and motif2 / 3 in BCL-6 are required for CMA- mediated BCL-6 degradation. FIG.13A: Confocal microscopic (left) and statistical (right) analyses the co-localization of WT or mutant KFERQ BCL-6-mCherry and LAMP-2A-Dendra2 in NIH3T3 cells upon CMA activation. Each dot represents one cell. FIG.13B: Flow cytometric (left) and statistical (right) analyses of WT or mutant BCL-6 mCherry expression upon CMA activation. (n=3). Data are means ± SEM (FIGs.13A-B) and are pool results from two or three independent experiments. *p<0.05, **p<0.01, ***p<0.001, one-way ANOVA (FIGs.13A-B). FIGs.14A-B show the expression of CBL, CBL-B, ICOS, and BCL-6 protein in human CD4+T cells. FIG.14A: Western blot analyses of CBL and CBL-B proteins in human primary CD4+T cells with or without deletion of CBL and CBL-B by CRISPR. FIG. 14B: Sequence comparison of human and mouse ICOS and BCL-6 proteins. Top: both human and mouse ICOS contain five lysine residues that may serve as putative ubiquitination sites in their cytoplasmic tails (SKKKY = SEQ ID NO:18; NKKSRLAGVT = SEQ ID NO:19; TKKKY = SEQ ID NO:20; AKKSRLTDVT = SEQ ID NO:21). Bottom: both human and mouse BCL-6 contain the conserved KFERQ-like motif1 (NRLRS, SEQ ID NO:22) and motif2 / 3 (KKYKFI, SEQ ID NO:23). MASP = SEQ ID NO:24; PKAC = SEQ ID NO:25). FIG.15A shows the nucleotide sequence encoding wild-type (WT) murine ICOS (SEQ ID NO:1). FIG.15B shows the nucleotide sequence encoding the 2K2R murine ICOS mutant (SEQ ID NO:2). FIG.15C shows the nucleotide sequence encoding the 3K2R murine ICOS mutant (SEQ ID NO:3). FIG.15D shows the nucleotide sequence encoding the 5K2R murine ICOS mutant (SEQ ID NO:4). FIG. 16A shows the amino acid sequence of murine BCL-6 with the KFERQ motifs identified using the KFERQ finder software (after asparagine or acetyl and phos modification) highlighted in italics (SEQ ID NO:5). FIG.16B shows the nucleotide sequence encoding wild-type (SEQ ID NO:6) and mutant (SEQ ID NO:7) KFERQ motif1 from BCL-6. FIG.16C shows the nucleotide sequence encoding wild-type (SEQ ID NO:8) and mutant (SEQ ID NO:9) KFERQ motif2 / 3 from BCL-6. G12810-00883 14 FIG.16D shows the nucleotide sequence encoding the Motif1WT-mCherry fusion protein (SEQ ID NO:10). FIG. 16E shows the nucleotide sequence encoding the Motif2 / 3WT-mCherry fusion protein (SEQ ID NO:11). FIG. 16F shows the nucleotide sequence encoding the Motif1Mutant-mCherry fusion protein (SEQ ID NO:12). FIG. 16G shows the nucleotide sequence encoding the Motif2 / 3Mutant-mCherry fusion protein (SEQ ID NO:13). FIG.16H shows the nucleotide sequence encoding wild-type murine BCL-6 (SEQ ID NO:14). FIG. 16I shows the nucleotide sequence encoding mutant murine BCL-6 (SEQ ID NO:15). FIG.17A shows the amino acid sequence of human CBL (UniProt accession P22681, (SEQ ID NO:16). FIG.17B shows the amino acid sequence of human CBL-B (UniProt accession Q13191, (SEQ ID NO:17). DISCLOSURE OF INVENTION The use of the terms "a" and "an" and "the" and similar referents in the context of describing the technology (especially in the context of the following claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. The terms "comprising", "having", "including", and "containing" are to be construed as open-ended terms (i.e., meaning "including, but not limited to") unless otherwise noted. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (“e.g.”, "such as") provided herein, is intended merely to better illustrate embodiments of the claimed technology and does not pose a limitation on the scope unless otherwise claimed. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of embodiments of the claimed technology. Herein, the term "about" has its ordinary meaning. The term “about” is used to indicate that a value includes an inherent variation of error for the device or the method being employed to determine the value, or encompass values close to the recited values, for example within 10% of the recited values (or range of values). Recitation of ranges of values herein are merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise G12810-00883 15 indicated herein, and each separate value is incorporated into the specification as if it were individually recited herein. All subsets of values within the ranges are also incorporated into the specification as if they were individually recited herein. Where features or aspects of the disclosure are described in terms of Markush groups or list of alternatives, those skilled in the art will recognize that the disclosure is also thereby described in terms of any individual member, or subgroup of members, of the Markush group or list of alternatives. Unless specifically defined otherwise, all technical and scientific terms used herein shall be taken to have the same meaning as commonly understood by one of ordinary skill in the art (e.g., in stem cell biology, cell culture, molecular genetics, immunology, immunohistochemistry, protein chemistry, and biochemistry). Unless otherwise indicated, the recombinant protein, cell culture, and immunological techniques utilized in the present disclosure are standard procedures, well known to those skilled in the art. Such techniques are described and explained throughout the literature in sources such as, J. Perbal, A Practical Guide to Molecular Cloning, John Wiley and Sons (1984), J. Sambrook et al., Molecular Cloning: A Laboratory Manual, Cold Spring Harbour Laboratory Press (1989), T. A. Brown (editor), Essential Molecular Biology: A Practical Approach, Volumes 1 and 2, IRL Press (1991), D. M. Glover and B. D. Hames (editors), DNA Cloning: A Practical Approach, Volumes 1- 4, IRL Press (1995 and 1996), and F. M. Ausubel et al. (editors), Current Protocols in Molecular Biology, Greene Pub. Associates and Wiley-Interscience (1988, including all updates until present), Ed Harlow and David Lane (editors) Antibodies: A Laboratory Manual, Cold Spring Harbour Laboratory, (1988), and J. E. Coligan et al. (editors) Current Protocols in Immunology, John Wiley & Sons (including all updates until present). In the studies described herein, the present inventors have demonstrated that CD4+T cells from SLE patients exhibit downregulated or decreased levels of both CBL and CBL-B (CBLs) proteins (but not transcripts) relative to healthy subjects or rheumatoid arthritis (RA) patients, and that ablation of CBLs in mouse T cells leads to hyper T follicular helper (Tfh) cell responses and display a phenotype similar to SLE. They have also demonstrated that CBLs induce the ubiquitination of lysine residue(s) at the distal cytoplasmic tail of ICOS and downregulate ICOS expression and ICOS signaling, which in turn prevents hyper Tfh cell responses. Finally, the studies described herein show that ICOS is upregulated in SLE Tfh cells and ICOS signaling increases the level of BCL-6 protein by attenuating BCL-6 degradation via chaperone-mediated autophagy (CMA) and CBLs restrain BCL-6 expression by ubiquitinating ICOS. These results provide evidence that CBL and / or CBL-B protein levels in T lymphocytes may be used for the diagnosis and monitoring of disease progression in SLE patients, and that modulating the ICOS- CBLs pathway in T lymphocytes from SLE patients, for example by increasing the level and / or activity of CBL and / or CBL-B, is a suitable approach for the treatment of SLE. G12810-00883 16 Accordingly, in a first aspect, the present disclosure provides a method for determining whether a subject suffers from systemic lupus erythematosus (SLE) comprising: (a) measuring the protein level of Casitas B-lineage lymphoma (CBL) and / or CBL-B in T lymphocytes from the subject; (b) comparing the protein level of CBL and / or CBL-B in the T lymphocytes from the subject with a reference protein level of CBL and / or CBL-b or predetermined reference value, and (c) determining whether the subject suffers from systemic lupus erythematosus (SLE) based on said comparing. In another aspect, the present disclosure provides a method for monitoring the progression of systemic lupus erythematosus in a subject undergoing treatment, the method comprising: periodically measuring the level of CBL and / or CBL-B protein in T lymphocytes from the subject; and comparing the measured levels to previous measurements to assess changes in the disease state, wherein a decrease in the levels indicates progression of the disease. In another aspect, the present disclosure provides a method for assessing the evolution of systemic lupus erythematosus (SLE) in a patient comprising: (a) measuring the protein level of CBL and / or CBL-B in T lymphocytes from the subject at a first time point; (b) measuring the protein level of CBL and / or CBL-B in T lymphocytes from the subject at a second, later time point; (c) comparing the protein level of CBL and / or CBL-B at the first and second time points, wherein: (i) a lower protein level of CBL and / or CBL-B at the second time point relative to the first time point is indicative that the patient’s disease has worsened; (ii) a similar protein level of CBL and / or CBL- B at the first and second time points is indicative that the patient’s disease is stable; or (iii) a higher protein level of CBL and / or CBL-B at the second time point relative to the first time point is indicative that the patient’s disease has improved. In another aspect, the present invention provides a method for detecting CBL and / or CBL-B in T lymphocytes from a subject, the method comprising contacting the T lymphocytes with an agent that binds to CBL and / or CBL-B, and detecting complexes comprising the agent and CBL and / or CBL-B. In another aspect, the present disclosure provides a computer-implemented method for diagnosing SLE, the method comprising: receiving data representative of the protein level of CBL and / or CBL-B in T lymphocytes; determining that the protein level of CBL and / or CBL-B is below a predetermined reference value; and outputting a diagnostic result based on the determination. Human CBL (UniProt KB accession No. P22681, RefSeq accession No. NP_005179.2) is an E3 ubiquitin-protein ligase of 906 amino acids (FIG.17A). The N-terminus is composed of the phosphotyrosine binding (PTB) domain (residues 47-351), a short linker region (residues 352- 380) and the RING-type zinc finger (residues 381-420). The PTB domain, which is also called TKB (tyrosine kinase binding) domain, is composed of three different subdomains: a four-helix bundle (4H, residues 47-175), a calcium-binding EF hand (residues 176-248) and a divergent SH2 domain (residues 249-351). The RING-type zinc finger domain mediates binding to an E2 G12810-00883 17 ubiquitin-conjugating enzyme. A ubiquitin-associated (UBA) domain that interacts with poly- ubiquitinated proteins is present at the C-terminus (residues 856-895). Human CBL-B (UniProt KB accession No. Q13191, RefSeq accession No. NP_001308717.1) is an E3 ubiquitin-protein ligase of 982 amino acids (canonical sequence, FIG. 17B). The N-terminus is composed of the phosphotyrosine binding (PTB) domain (residues 35- 343), a short linker region (residues 344-372) and the RING-type zinc finger (residues 373-412). The PTB domain, which is also called TKB (tyrosine kinase binding) domain, is composed of three different subdomains: a four-helix bundle (4H, residues 35-167), a calcium-binding EF hand (residues 168-240) and a divergent SH2 domain (residues 241-343). The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme. A UBA domain that interacts with poly-ubiquitinated proteins is present at the C-terminus (residues 931-970). Methods to measure the amount / level of proteins are well known in the art. Protein levels of CBL and / or CBL-B may be detected directly using a ligand binding specifically to the protein, such as an antibody or a fragment thereof, an aptamer, a natural binding partner of CBL and / or CBL-B (or a fragment thereof comprising the binding domain), or a synthetic ligand. In embodiments, such a binding molecule or reagent (e.g., antibody) is labeled / conjugated, e.g., radio-labeled, chromophore-labeled, fluorophore-labeled, or enzyme-labeled to facilitate detection and quantification of the complex (direct detection). Alternatively, protein levels may be detected indirectly, using a binding molecule or reagent, followed by the detection of the [protein / binding molecule or reagent] complex using a second ligand (or second binding molecule) specifically recognizing the binding molecule or reagent (indirect detection). Such a second ligand may be radio-labeled, chromophore-labeled, fluorophore-labeled, or enzyme-labeled to facilitate detection and quantification of the complex. Enzymes used for labeling antibodies for immunoassays are known in the art, and the most widely used are horseradish peroxidase (HRP) and alkaline phosphatase (AP). Examples of methods to measure the amount / level of protein in a sample include, but are not limited to: Western blot, immunoblot, enzyme-linked immunosorbent assay (ELISA), "sandwich" immunoassays, radioimmunoassay (RIA), immunoprecipitation, surface plasmon resonance (SPR), chemiluminescence, fluorescent polarization, phosphorescence, immunohistochemical (IHC) analysis, matrix-assisted laser desorption / ionization time-of-flight (MALDI-TOF) mass spectrometry, microcytometry, microarray, antibody array, microscopy (e.g., electron microscopy), flow cytometry, proteomic-based assays, and assays based on a property or activity of the protein including, but not limited to ligand binding or interaction with other protein partners and enzymatic activity. In an embodiment, the amount / level of CBL and / or CBL-B is measured by flow cytometry. In an embodiment, protein levels of CBL and / or CBL-B are measured using one or more antibodies or antigen-binding fragments thereof. G12810-00883 18 The one or more antibodies may be monoclonal or polyclonal antibodies. Anti-CBL antibodies are commercially available from various providers including ThermoFisher Scientific (catalog Nos. PA5-17453, MA5-14955, PA1-9022, PA5-82992, PA5-54107, 66576-1-IG, 25818- 1-AP, MA5-15885, MA5-47701, PA5-87495, MA5-37728, PA5-99517, PA5-20299, PA5-119725, PA5-27394, H00000867, TA890105, and PA5-97545). Anti-CBL-B antibodies are also commercially available from various providers including ThermoFisher Scientific (PA5-102547, PA5-116918, PA5-76651, PA5-27692, A302-902A). Of course, with the knowledge of the amino acid sequences of CBL and CBL-B (FIGs.17A and 17B), the skilled person would be able to easily generate antibodies specifically binding to CBL and / or CBL-B using commonly used methods. In an embodiment, the methods described herein comprise detecting the protein level of both CBL and CBL-B, and the one or more antibodies may be (a) an antibody capable of specifically binding to both human CBL and CBL-B, e.g., an antibody that binds to a region that is conserved between human CBL and CBL-B, or a bispecific antibody comprising a first binding portion specifically binding to human CBL and a second binding portion specifically binding to CBL-B; or (b) a first antibody specifically binding to human CBL and a second antibody specifically binding to CBL-B. In an embodiment, the methods described herein comprise detecting the protein level of both CBL and CBL-B with an antibody capable of specifically binding to both human CBL and CBL-B. In an embodiment, the antibody binds to a conserved region in human CBL and CBL-B, preferably a conserved region in the C-terminal portion of human CBL and CBL- B. In an embodiment, the methods described herein further comprise detecting the protein levels of ICOS and / or BCL-6 in T cells, wherein higher levels of ICOS and / or BCL-6 is indicative of a higher risk of suffering from SLE, or of a deterioration of the disease (or more severe disease). In an embodiment, the methods described herein include a step of normalizing the protein levels with a housekeeping protein. Commonly used housekeeping proteins include β- tubulin, cyclophilin B, glyceraldehyde-3-phosphate dehydrogenase (GAPDH), β-actin, and heat shock protein 90α (HSP90α)). The term "reference level" or “predetermined reference value” are used interchangeably herein and broadly refers to a separate baseline level measured in one or more comparable “control” samples, which, for example, may be from subjects not suffering from SLE. The corresponding "reference level" or “predetermined reference value” may be a level corresponding to an average / mean or median protein level calculated based of the levels measured in several reference or control subjects (e.g., a pre-determined or established standard level). The "reference level" or “predetermined reference value” may be a pre-determined “cut-off” value recognized in the art or established based on levels measured in samples from one or a group of control subjects. For example, the "reference level" or “predetermined reference value” may be a G12810-00883 19 level corresponding to the maximal protein level of CBL and / or CBL-B (cut-off) that permits to distinguish in a statistically significant manner SLE patients from those not having SLE, which may be determined using T lymphocyte samples from SLE patients and “healthy” subjects (subjects not suffering from SLE), for example. Alternatively, the "reference level" or “predetermined reference value” may be a level corresponding to the protein level of CBL and / or CBL-B (cut-off) that permits to best or optimally distinguish, in a statistically significant manner, SLE patients from those not having SLE. The corresponding "reference level" or “predetermined reference value” may be adjusted or normalized for age, gender, race, or other parameters. The "reference level" or “predetermined reference value” can thus be a single number / value, equally applicable to every patient individually, or the control level can vary according to specific subpopulations of patients. Thus, for example, older men might have a different "reference level" or “predetermined reference value” than younger men, and women might have a different "reference level" or “predetermined reference value” than men. The "reference level" or “predetermined reference value” can be arranged, for example, where a tested population is divided equally (or unequally) into groups, such as a low-risk group, a medium-risk group and a high-risk group or into quadrants or quintiles, the lowest quadrant or quintile being individuals with the lowest risk (i.e., highest level of expression of CBL and / or CBL-B, e.g., in combination with the highest levels of ICOS and BCL-6) and the highest quadrant or quintile being individuals with the highest risk (i.e., lowest level of expression of CBL and / or CBL-B). It will also be understood that the "reference level" or “predetermined reference value” according to the disclosure may be, in addition to predetermined levels or standards, levels measured in other samples (e.g. from healthy / normal subjects, or SLE patients) tested in parallel with the experimental sample. The "reference level" or “predetermined reference value” may correspond to normalized levels, i.e., reference or control values subjected to normalization based on the level of a housekeeping protein. “Lower level” as used herein refers to (i) lower level of CBL and / or CBL-B in one or more given T lymphocytes present in the sample (relative to the control) and / or (ii) lower amount / proportion of T lymphocytes expressing CBL and / or CBL-B in the sample (relative to the control). In an embodiment, lower refers to a level that is below the "reference level" or “predetermined reference value” measured in healthy / normal subjects. In another embodiment, lower refers to a level that is at least one standard deviation below the "reference level" or “predetermined reference value” measured in healthy / normal subjects (e.g., that is statistically significant as determined using a suitable statistical analysis). In another embodiment, the method described herein further comprises obtaining or collecting a biological sample comprising T lymphocytes from a subject. In various embodiments, the sample can be from any source that contains T lymphocytes, for example a tissue or cell sample from the subject (blood sample, lymph node sample, tonsil sample, etc.) that comprises G12810-00883 20 T lymphocytes. The sample may be subjected to cell purification / enrichment techniques to obtain a cell population enriched in T lymphocytes, and / or a specific T lymphocyte subpopulation, such as CD4+T lymphocytes. The sample may be subjected to commonly used isolation and / or purification techniques for enrichment in proteins. Accordingly, in an embodiment, the method may be performed on an isolated protein sample. The biological sample may be collected using any methods for collection of biological fluid, tissue, or cell sample, such as venous puncture for collection of blood cell samples (e.g., peripheral blood mononuclear cells, PBMCs). Thus, the term “biological sample comprising T lymphocytes” as used herein refers to a crude blood sample, a PBMC sample, or a sample enriched in T lymphocytes such as CD4+T lymphocytes (i.e., that has been subjected to cell purification / enrichment techniques), or isolated proteins from T lymphocytes (e.g., CD4+T lymphocytes). Methods for purification / enrichment of T lymphocytes (e.g., CD4+T lymphocytes) are well known in the art (see, e.g., Fuss, Curr Protoc Immunol.2020 Mar; 128(1): e94), and kits for purification / enrichment of human T lymphocytes (e.g., CD4+T lymphocytes) are commercially available (Dynabeads®CD4, Dynabeads®FlowComp™ Human CD4, Dynabeads®CD4 Positive Isolation Kit, and Dynabeads®Untouched™ Human CD4 Cells from ThermoFisher Scientific, EasySep™ Human T Cell Isolation Kit and RoboSep™-C Human CD4+ T Cell Isolation Kit from Stemcell Technologies, CD4+T Cell Isolation Kit from Miltenyi Biotec, and MagCellect™ Human CD4+ T Cell Isolation Kit from R&D Systems). Additional enrichment steps for specific cell subsets, e.g., naïve T lymphocytes, memory T lymphocytes, T follicular helper cells (Tfh), etc., may optionally be performed. In an embodiment, the methods described herein are performed on a protein sample obtained from T lymphocytes, in a further embodiment from CD4+T lymphocytes. Such protein sample may be obtained by lysing the T lymphocytes (e.g., CD4+T lymphocytes) to isolate the proteins, and may include one or more steps of purification (for example to eliminate cell debris). Thus, in an embodiment, the sample is a T lymphocyte (e.g., CD4+T lymphocyte) lysate. In another embodiment, the method may include a step of permeabilization of the lymphocyte to perform an intracellular staining of CBL and / or CBL-B, e.g., to detect CBL- and / or CBL-B-expressing T lymphocytes (e.g., CD4+T lymphocytes) by flow cytometry or any other suitable methods. In certain embodiments, methods described herein may be at least partly, or wholly, performed in vitro. In a further embodiment, the method is wholly performed in vitro. In an embodiment, the above-mentioned method further comprises selecting and / or administering a course of therapy or prophylaxis to said subject / patient, in accordance with the diagnostic results obtained by the methods described herein. For example, if it is determined that the subject suffers from SLE and / or has a high risk of suffering from SLE based on the diagnostic results obtained by the methods described herein, a suitable therapy for SLE may be administered to the subject. G12810-00883 21 Thus, in another aspect, the present disclosure provides a method for treating a patient identified as suffering from SLE and / or being at high risk of suffering from SLE using the methods described herein (based on low protein level of CBL and / or CBL-B in his / her T lymphocytes) comprising treating said patient with a suitable treatment regimen for SLE (e.g., administrating an effective amount of a composition or medicament to treat SLE). In an embodiment, the above method comprises identifying said subject suffering from SLE and / or being at high risk of suffering from SLE using the methods described herein. In another aspect, the present disclosure provides a method for treating a patient suffering from SLE and / or at high risk of suffering from SLE comprising (i) identifying the patient suffering from SLE and / or at high risk of suffering from SLE patient using the methods described herein; and (ii) treating said patient with a suitable treatment regimen. The treatment of SLE may include the administration of an anti-inflammatory agent (e.g., a corticosteroid such as prednisone), an antimalarial drug (e.g., hydroxychloroquine), an immunosuppressant (e.g., azathioprine, mycophenolate, methotrexate, cyclosporine, or leflunomide), a soluble human B lymphocyte stimulator protein (BLyS) inhibitor (e.g., an anti-BLys antibody such as belimumab), a CD20 binding agent (e.g., rituximab), IFN blockade agent, CAR- T cells, or any combination thereof. In another aspect, the present disclosure provides an assay mixture for the assessment of SLE (e.g., for the diagnosis of SLE), the assay mixture comprising: (i) a biological samplecomprising T lymphocytes (e.g., CD4+T lymphocytes) from a subject suspected from or at risk ofsuffering from SLE and (ii) one or more reagents for determining / measuring the protein level of CBL and / or CBL-B in the sample. In another aspect, the present disclosure provides a method for detecting CBL and / or CBL-B in T lymphocytes from a subject suspected from or at risk of suffering from SLE comprising contacting a biological sample comprising T lymphocytes (e.g., CD4+T lymphocytes) with one or more ligands that specifically bind to CBL and / or CBL-B; and detecting the presence of complexes between (i) CBL and / or CBL-B and (ii) the one or more ligands. In another aspect, the present disclosure provides a system for the assessment of SLE (e.g., for the diagnosis of SLE), a biological sample comprising T lymphocytes (e.g., CD4+T lymphocytes) from a subject suspected from or at risk of suffering from SLE; and one or more assays to determine the protein level of CBL and / or CBL-B in the sample. The present disclosure provide for a system for the assessment of SLE (e.g., for the diagnosis of SLE) in a subject in need thereof, comprising: a sample analyzer configured to produce a signal corresponding to the protein level of CBL and / or CBL-B in a biological sample comprising T lymphocytes (e.g., CD4+T lymphocytes) from the subject; and a computer sub- system programmed to calculate, based on the protein level of CBL and / or CBL-B, whether the G12810-00883 22 signal is lower than a reference value. In various embodiments, the system further comprises the biological sample. In another aspect, the present disclosure provides a kit for the assessment of SLE (e.g., for the diagnosis of SLE), the kit comprising: (i) one or more reagents for determining / measuring the protein level of CBL and / or CBL-B in a biological sample comprising T lymphocytes (e.g., CD4+T lymphocytes). In an embodiment, the one or more reagents comprise, for example, antibody(ies) or antigen-binding fragment(s) thereof, solution(s), buffer(s), and / or reagents for detecting antigen- antibody complexes, etc. In an embodiment, the assay mixture or kit further comprises one or more reagents for determining / measuring the level of at least one normalization / housekeeping protein (e.g., β-actin) in the sample. In another embodiment, the kit further comprises antibodies or antigen-binding fragments thereof specific for CD4, ICOS, and / or BCL-6. Furthermore, in an embodiment, the kit may be divided into separate packages or compartments containing the respective reagent components explained above. In addition, such a kit may optionally comprise one or more of the following: (1) instructions for using the reagents for the diagnosis of SLE according to the methods described herein; (2) one or more containers; and / or (3) appropriate controls / standards. Such a kit can include instructions and / or reagents for collecting a biological sample from a patient and reagents for processing the biological sample. The kits featured herein can also include an instruction sheet describing how to perform the assays for measuring the protein level of CBL and / or CBL-B (e.g., in combination with protein levels of ICOS and / or BCL-6) in a biological sample comprising T lymphocytes (e.g., CD4+T lymphocytes). The instruction sheet can also include instructions for how to determine a reference cohort (control patient population), including how to determine the protein level of CBL and / or CBL-B in a biological sample comprising T lymphocytes (e.g., CD4+T lymphocytes) in the reference cohort and how to assemble the expression data to establish a reference for comparison to a test patient. The instruction sheet can also include instructions for assaying the protein level of CBL and / or CBL-B in a biological sample comprising T lymphocytes (e.g., CD4+T lymphocytes) in a test patient and for comparing the level with the level in the reference cohort to subsequently determine the appropriate treatment regimen for the test patient. Informational material included in the kits can be descriptive, instructional, marketing, or other material that relates to the methods described herein and / or the use of the reagents for the methods described herein. For example, the informational material of the kit can contain contact information, e.g., a physical address, email address, website, or telephone number, where a user of the kit can obtain substantive information about performing the methods described herein and interpreting the results, particularly as they apply to a subject’s likelihood / risk of having SLE. The kits featured herein can also contain software necessary to infer the likelihood of a patient of having SLE from the CBL and / or CBL-B level data. G12810-00883 23 In an embodiment, the methods described herein are performed on a biological sample from a subject suspected of suffering from SLE. In an embodiment, the subject is suspected from suffering from SLE according to certain symptoms and / or results from other tests. Symptoms of SLE may include fatigue, skin rashes, fevers, pain or swelling in the joints, sun sensitivity, oral ulcers, arthritis, lung problems, heart problems, kidney problems, seizures, psychosis, and blood cell and immunological abnormalities. In an embodiment, the methods described herein are performed in combination with other methods for the diagnosis of SLE, blood and urine tests, imaging, signs and symptoms, and physical examination, e.g., detection of anti-nuclear antibodies (ANA). Thus, in another aspect, the present disclosure provides a method for treating a subject suffering from SLE or preventing the development of SLE in an at-risk subject, the method comprising administering to the patient an agent that increases the expression or activity of CBL and / or CBL-B in T lymphocytes (e.g., CD4+T lymphocytes) from the subject. The present disclosure also provides the use of an agent that increases the expression or activity of CBL and / or CBL-B in T lymphocytes (e.g., CD4+T lymphocytes) for treating a patient suffering from SLE. The present disclosure also provides the use of an agent that increases the expression or activity of CBL and / or CBL-B in T lymphocytes (e.g., CD4+T lymphocytes) for the manufacture of a medicament for treating a patient suffering from SLE. The present disclosure also an agent that increases the expression or activity of CBL and / or CBL-B in T lymphocytes (e.g., CD4+T lymphocytes) for use in the treatment of a patient suffering from SLE. Agents that increase the expression or activity of CBL and / or CBL-B include CBL and CBL-B agonist such as DPH (5-[3-(4-fluorophenyl)-1-phenyl-1H-pyrazol-4-yl]-2,4- imidazolidinedione or 5-(1,3-diaryl-1H-pyrazol-4-yl)hydantoin) (Yang et al., Chem Biol.2011 Feb 25;18(2):177-86. doi: 10.1016 / j.chembiol.2010.12.013) as well as CBL and / or CBL-B, biologically active fragments or variants thereof, as well as nucleic acids encoding CBL and / or CBL-B, and biologically active fragments or variants thereof. In an embodiment, the agent that increases the activity of CBL and / or CBL-B is an agent that stabilizes CBL and / or CBL-B, i.e. that inhibits the degradation of CBL and / or CBL-B. The agent that increases the biological activity of CBL and / or CBL-B in T lymphocytes may include a dual binding molecule that binds to both ICOS and CBL or CBL-B, consequently enhancing ICOS degradation. The dual binding molecule can be a small molecular compound, a polypeptide, an antibody or an antigen-binding fragment thereof, such as a bispecific antibody or antigen-binding fragment thereof. In an embodiment, the agent that increases the expression or activity of CBL is a biologically active fragment of CBL comprising at least 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, or 900 amino acids from the amino acid sequence of human CBL (FIG.17A). In an embodiment, the agent that increase the expression or activity of CBL is a biologically active G12810-00883 24 variant of CBL comprising an amino acid sequence having at least 70, 75, 80, 85, 90, 95, 96, 97, 98, or 99% identity with the amino acid sequence of human CBL (FIG.17A). In an embodiment, the agent that increases the expression or activity of CBL-B is a biologically active fragment of CBL-B comprising at least 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, or 950 amino acids from the amino acid sequence of human CBL-B (FIG.17B). In an embodiment, the agent that increase the expression or activity of CBL-B is a biologically active variant of CBL-B comprising an amino acid sequence having at least 70, 75, 80, 85, 90, 95, 96, 97, 98, or 99% identity with the amino acid sequence of human CBL-B (FIG. 17B). "Identity" refers to sequence identity between two polypeptides. Percent (%) sequence identity with respect to a reference polypeptide sequence is the percentage of amino acid residues in a candidate sequence that are identical with the amino acid residues in the reference polypeptide sequence, after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence identity, and not considering any conservative substitutions as part of the sequence identity. Alignment for purposes of determining percent amino acid sequence identity can be achieved in various ways that are known for instance, using publicly available computer software such as BLAST, BLAST-2, ALIGN, or Megalign (DNASTAR) software. Appropriate parameters for aligning sequences are able to be determined, including algorithms needed to achieve maximal alignment over the full length of the sequences being compared. For purposes herein, however, % amino acid sequence identity values are generated using the sequence comparison computer program ALIGN-2. The ALIGN-2 sequence comparison computer program was authored by Genentech, Inc., and the source code has been filed with user documentation in the U.S. Copyright Office, Washington D.C., 20559, where it is registered under U.S. Copyright Registration No. TXU510087. The ALIGN-2 program is publicly available from Genentech, Inc., South San Francisco, Calif., or may be compiled from the source code. The ALIGN-2 program should be compiled for use on a UNIX operating system, including digital UNIX V4.0D. All sequence comparison parameters are set by the ALIGN-2 program and do not vary. In situations where ALIGN-2 is employed for amino acid sequence comparisons, the % amino acid sequence identity of a given amino acid sequence A to, with, or against a given amino acid sequence B (which can alternatively be phrased as a given amino acid sequence A that has or comprises a certain % amino acid sequence identity to, with, or against a given amino acid sequence B) is calculated as follows: 100 times the fraction X / Y, where X is the number of amino acid residues scored as identical matches by the sequence alignment program ALIGN-2 in that program's alignment of A and B, and where Y is the total number of amino acid residues in B. It will be appreciated that where the length of amino acid sequence A is not equal to the length of amino acid sequence B, the % amino acid sequence identity of A to B will not equal the % amino G12810-00883 25 acid sequence identity of B to A. Unless specifically stated otherwise, all % amino acid sequence identity values used herein are obtained as described in the immediately preceding paragraph using the ALIGN-2 computer program. The term “biologically active fragments” and “biologically active variants” of CBL and CBL-B means fragments and variants maintaining the ubiquitin ligase activity of native human CBL and CBL-B, and more specifically the ability to induce ICOS ubiquitination. The N-terminal portion of CBL and CBL-B (e.g., residues 1-420 of CBL and residues 1-412 of CBL-B) is primarily involved in the ubiquitination activity. More specifically, the RING-type zinc finger domain (residues 381-420 of CBL and residues 373-412 of CBL-B) mediates binding to an E2 ubiquitin- conjugating enzyme. Thus, in an embodiment, the biologically active fragment or variant of CBL and CBL-B comprises the RING-type zinc finger domain of CBL or CBL-B. In another embodiment, the biologically active fragment or variant of CBL and CBL-B comprises residues 1- 420 of CBL or residues 1-412 of CBL-B. The increase of CBL and / or CBL-B expression in T lymphocytes may be achieved by contacting the T lymphocytes with a nucleic acid (e.g., mRNA) encoding CBL and / or CBL-B, or a functional fragment or variant thereof. In an embodiment, the agent that increases the expression or activity of CBL and / or CBL- B in T lymphocytes may be conjugated or fused to a targeting moiety / agent for T lymphocytes (e.g., CD4+T lymphocytes). Examples of such targeting moieties / agents include peptides, polypeptides, antibodies or antigen-binding fragments thereof, or aptamers that bind to a receptor expressed by T lymphocytes (e.g., CD4+T lymphocytes), e.g., anti-CD3 or anti-CD4 antibodies, antibody fragments or aptamers, IL-2, IL-7, etc. In another embodiment, the agent that increases the expression or activity of CBL and / or CBL-B in T lymphocytes may be conjugated or fused to a cell penetrating peptide (CPP). CPPs are typically basic peptides with a positive charge at physiological pH and are able to translocate membranes and gain entry to the cell interior (see, e.g., Ruseska and Zimmer, Beilstein J Nanotechnol.2020; 11: 101-123). Examples of CPPs include TAT (YGRKKRRQRRR), penetratin (RQIKIWFQNRRMKWKK), R9 (RRRRRRRRR), MPG (GALFLGWLGAAGSTMGAPKKKRKV) Pep-1 (KETWWETWWTEWSQPKKRKV), transportan-10 (AGYLLGKINLKALAALAKKIL-amide), PepFect6 (stearyl-AGYLLGK(ε-TMQ)INLKALAALAKKIL) and Bac7 (RRIRPRPPRLPRPRPRPLPFPRPG). The agent that increases the expression or activity of CBL and / or CBL-B in T lymphocytes may be formulated into a pharmaceutical composition with a pharmaceutically acceptable carrier or excipient. Such compositions may be prepared in a manner well known in the pharmaceutical art by mixing the agent having a suitable degree of purity with one or more optional pharmaceutically acceptable carriers or excipients (see Remington: The Science and Practice of Pharmacy, by Loyd V Allen, Jr, 2012, 22ndedition, Pharmaceutical Press; Handbook G12810-00883 26 of Pharmaceutical Excipients, by Rowe et al., 2012, 7thedition, Pharmaceutical Press). The carrier / excipient can be suitable for administration of the agent by any conventional administration route, for example, for oral, intravenous, parenteral, subcutaneous, intramuscular, intracranial, intraorbital, ophthalmic, intraventricular, intracapsular, intraspinal, intrathecal, epidural, intracisternal, intraperitoneal, intranasal, or pulmonary (e.g., aerosol) administration. An "excipient" as used herein has its normal meaning in the art and is any ingredient that is not an active ingredient (drug) itself. Excipients include for example binders, lubricants, diluents, fillers, thickening agents, disintegrants, plasticizers, coatings, barrier layer formulations, lubricants, stabilizing agent, release-delaying agents, and other components. "Pharmaceutically acceptable excipient" as used herein refers to any excipient that does not interfere with effectiveness of the biological activity of the active ingredients and that is not toxic to the subject, i.e., is a type of excipient and / or is for use in an amount which is not toxic to the subject. Excipients are well known in the art, and the present system is not limited in these respects. In certain embodiments, one or more formulations of the dosage form include excipients, including for example and without limitation, one or more binders (binding agents), thickening agents, surfactants, diluents, release-delaying agents, colorants, flavoring agents, fillers, disintegrants / dissolution promoting agents, lubricants, plasticizers, silica flow conditioners, glidants, anti-caking agents, anti-tacking agents, stabilizing agents, anti-static agents, swelling agents, and any combinations thereof. As those of skill would recognize, a single excipient can fulfill more than two functions at once, e.g., can act as both a binding agent and a thickening agent. As those of skill will also recognize, these terms are not necessarily mutually exclusive. Examples of commonly used excipient include water, saline, phosphate buffered saline, dextrose, glycerol, ethanol, and the like, as well as combinations thereof. In many cases, it will be preferable to include isotonic agents, for example, sugars, polyalcohols such as mannitol and sorbitol, or sodium chloride in the composition. Additional examples of pharmaceutically acceptable substances are wetting agents or auxiliary substances, such as emulsifying agents, preservatives, or buffers, which increase the shelf life or effectiveness. MODE(S) FOR CARRYING OUT THE INVENTION The present invention is illustrated in further details by the following non-limiting examples. Example 1: Materials and Methods Animals: C57BL / 6 mice, B6.SJL mice, TCRb- / -mice, OT-II TCR Tg mice, and Rag1- / -mice were purchased from The Jackson Laboratory. Cblf / fand Cbl-b- / -mice were described previously45. To obtain T cell specific deletion of Cbl and Cbl-b genes, Cblf / fand Cbl-b- / -mice were crossed to Cd4- cre tg mice (termed Cbl- / -Cbl-b- / -mice). Control mice are either Cd-4 cre tg C57BL / 7 or Cd4-cre- G12810-00883 27 Cblf / fCbl-b+ / -littermate. To generate Treg-specific deficient of Cbl and Cbl-b genes, Cblf / fand Cbl- b- / -mice were crossed to Foxp3-cre mice (termed Cbl- / -Cbl-b- / -Tregmice). ICOS- / -mice were gifted by Woong-Kyung Suh. IL-4GFPIL-21KATmice were obtained from J. Craft. In-house generated mouse strains, such as Cbl- / -Cbl-b- / -and Cbl- / -Cbl-b- / C375Awere on C57BL / 6 background. All animal experiments were done in accordance with the Canadian Council of Animal Care approved by the Montreal Clinical Research Institute and conformed to the guidelines outlined in the Guide for the Care and Use of Laboratory Animals, South China University of Technology. Human samples: SLE patients fulfilling the 1997 American College of Rheumatology (ACR) revised criteria with mild-to-severe disease activity assessed by the SLE disease activity index 2000 (SLEDAI- 2K score of ≥4) were recruited from the Department of Rheumatology and Immunology, Guangdong Provincial People's Hospital. Exclusion criteria included those using the high-dose corticosteroids pulse therapy in the last 4 weeks, or with other coexisting connective tissue diseases, active infection or history of chronic infection, malignancy, female pregnancy or breastfeeding. SLE patient samples included 32 females and 2 males, at ages ranging from 19 to 45. Samples for the control group, included 30 females and 4 males at ages ranging from 25 to 55, were obtained from health blood donors. Informed consents were obtained from all subjects. This study was conducted in accordance with the Declaration of Helsinki and approved by the medical ethics committees of Guangdong Provincial People's Hospital (KY-Q-2022-330- 02). Additional information about study subjects is available at Table 1. Table 1: Subject demographics and baseline characteristics C s D L p , , C4 level, mg / L, median (range) 177 (1.05-440) ND RA patients attending the Department of Rheumatology and Immunology, Guangdong Provincial People's Hospital and fulfilling the American College of Rheumatology criteria for the G12810-00883 28 diagnosis of RA were included in the study. Informed consent was obtained from all patients in accordance with the Declaration of Helsinki and approved by the medical ethics committees of Guangdong Provincial People's Hospital. PBMCs samples from 15 patients (13 females and 2 males) with a median age of 40 years-old (range 32-55) were included. Samples for healthy controls were obtained from health blood doners, including 16 females and 4 males at ages ranging from 25-48, and informed consents were obtained from all subjects. Plasmids, Cell lines, and Culture: cDNA encoding wildtype ICOS (termed as ICOSWT) was amplified by RT-PCR from activated CD4+T cells and cloned into a MSCV-MIGR-GFP retroviral vector. Five putative the cytoplasmic tail of ICOS, including K167, K168, K169, K191, and K192, were replaced with arginines by PCR-assisted mutagenesis to block the ubiquitination of ICOS protein. These included all five lysine mutations (termed as 5K2R-ICOS), the membrane proximal three lysine mutations (termed as 3K2R-ICOS) and distal two lysine mutations (termed as 2K2R-ICOS). These mutants were cloned into a MSCV-MIGR-GFP, respectively. Retroviruses were prepared according to our previous publication45. For CBLs and ICOS co-expression and ubiquitination experiments, cDNA encoding WT-ICOS or 5K2R-ICOS was cloned into the expression vector pcDNA-Flag. To monitor BCL-6 translocation to lysosomes for CMA-mediated degradation, cDNAs encoding WT, KFERQ-like motif mutants BCL-6-mCherry fusion proteins or LAMP-2A KFERQ-dendra2 fusion protein were synthesized and subcloned into a MSCV vector, respectively. To verify whether KFERQ-like motifs were responsible for CMA-mediated degradation, constructs expressing a WT KFERQ-like motif1 (motif1WT) or motif2 / 3 (motif2 / 3WT) or mutant KFERQ1 or KFERQ2 / 3 motifs (Motif1mutantand Motif2 / 3mutant) fused to a mCherry protein were generated by direct DNA synthesis and cloned into a MSCV vector (Vector Builder). The detailed sequence information of the mutations is shown in FIGs.15A-D and 16A-I. To test the function of WT and mutant forms of ICOS, WT and mutant forms of ICOS were expressed in ICOS-deficient OT-II CD4+T cells by retroviral transduction, respectively. Briefly, OT-II CD4+T cells were purified from ICOS- / -OT-II mice, stimulated with plate bound anti- CD3 and anti-CD28 for 36 hours. Cells were then infected with retrovirus by a spin-based retrovirus infection protocol45. After retrovirus infection, OT-II CD4+T cells were cultured for at least 24-48 hours before being analysed for cell surface ICOS expression or purified by FACS for in vivo experiments. To investigate whether BCL-6 protein expression was regulated by the CMA pathway, splenic cells from NP-CGG immunized WT mice were cultured under starvation in the presence or absence of 50 µM of CMA inhibitor leupeptin for 24 hours. Cells were then harvested and CBL- B expression in Tfh cells were analysed by FACS. In vitro culture to generate human and mouse Tfh cells: G12810-00883 29 Human peripheral blood mononuclear cells (PBMCs) were isolated from healthy donors by Ficoll™ (Lymphoprep, Stem Cell) gradient centrifugation. Naïve CD4+T cells were purified from PBMCs using a human naïve CD4+T cell isolation kit (Stem Cell Technologies). To polarize Th0 or Tfh cells, naïve CD4+T cells were first stimulated with plate bound anti-CD3 and anti- CD28 for 24 hours. Cells were rested for 24 hours without any stimulation before being subjected to the Th0 (5 mg / mL of anti-CD3, 2.5 mg / mL of anti-CD28) or Tfh polarization condition (5 mg / mL of anti-CD3, 2.5 mg / mL of anti-CD28, 5 ng / mL of hTGF-b, and 5 ng / mL of rhIL-12p70) for 3 days. Cells polarized to the Tfh fate were analyzed by flow cytometry. For in vitro induction of mouse Tfh cells, OT-II CD4+T cells, and B cells were purified from total splenocytes, respectively, using magnetic columns (Stem Cell Technologies). T and B cells were co-cultured in 1:1 ratio in a 48-well plate in the presence of 2 μg / mL of OVA323-339 peptide, 50 ng / mL of IL-21, and 100 ng / mL of IL-6 in RPMI media containing 15% FBS. After 72 hours of culture, CD4+T cells were purified by a magnetic column and analyzed by FACS. In vitro Tfh and B cell co-culture: To access Tfh cell function to promote B cell development, Tfh cells were sorted from NP-OVA immunized Ctrl and Cbl- / -Cbl-b- / -OT-II TCR tg mice. Naïve B cells were purified from AID-GFP mice using a B cell enrichment kit (Stem Cell). In vivo generated Tfh cells and naïve B cells were co-cultured at 1:1 ratio in u-bottom 96-well plate under 2 mg / mL LPS and 5 mg / mL OVA323-339stimulation condition. After 72 hours of culture, cells were harvested, stained with anti- CD19 and IgG1, then analyzed by FACS. Generation of human CBL- / -CBL-B- / -CD4+T cells: An RNP-based CRISPR-Cas9 method was employed to delete CBL and CBL-B genes in human CD4+T cells. The gRNA mixture containing the crRNA specific for CBL and CBL-B genes and tracrRNA oligos at an equal molar concentration at a final duplex concentration of 100 mM was heated at 95°C for 5 min. The mixture was then mixed with equal molar of Cas9 protein to obtain the RNP complex. Pre-activated CD4+T cells were electroporated with the RNP complex using a Neon electroporation system according to manufacture’s instruction (ThermoFisher). Electroporated CD4+T cells were rested for 24 hours, expanded in vitro, and then tested for the deletion efficiency of CBL and CBL-B proteins by Western-blot analysis. Immunization and T cell chimeric mice: For NP-hapten immunization, 6 to 12-week-old and sex-matched mice were immunized intraperitoneally with 50 mg of NP-OVA or NP-CGG precipitated in 200 mL of Alum adjuvant to induce T cell-dependent immune responses. Immunized mice were bled or sacrificed and analyzed at the indicated time points. To generate T cell chimeric mice, CD4+T cells were purified from WT or Cbl- / -Cbl-b- / -OT- II TCR tg mice using a magnetic column (Stem Cell Technologies). 1×106purified cells were transferred into TCRβ- / -mice by intravenous (i.v.) injection. To track in vivo CD4+T cell G12810-00883 30 proliferation and Tfh differentiation, 1×106OT-II CD4+T cells were labelled with CTV and then transferred into TCRb- / -mice. To assess the effect of mutants ICOS or BCL-6 on Tfh cell differentiation in vivo, ICOS- / -or WT OT-II CD4+T cells were infected with the corresponding retroviral vector and purified by FACS based on GFP expression. Virus infected cells were then transferred into TCRβ- / -mice by i.v. injection. T cell chimeric mice were immunized with 50 mg NP-OVA in Alum by intraperitoneal (i.p.) injection one day later and Tfh cells were analyzed by flow cytometry. Flow cytometry: Splenic cells were collected and resuspended in FACS buffer (0.5% BSA in PBS with 0.05% sodium azide). For cell surface staining, cells were stained with the corresponding antibodies in the presence of Fc receptor blocker on ice for 30 min and then analyzed on a FACS BD Fortessa. To stain Tfh cells, splenocytes were first stained with anti-CXCR5-biotin at room temperature (RT ca.21-22°C) for 30 mins followed by staining with PE-CY7-streptavidin and other Tfh related markers on ice for 30 mins. To analyze the expression of BCL-6 in T cells, splenic cells were stained with the corresponding surface markers on ice for 30 min. Cells were then fixed, permeabilized with BD Transcription factor kit on ice for 30 min, and stained with anti-BCL- 6 antibody. For Phosphoflow analysis, T cells were stimulated with either anti-ICOS alone or anti- ICOS and anti-CD3 at RT for 15 min. Cells were then fixed, permeabilized, and stained with anti- pS6 and anti-pAKT antibodies using a BD Transcription factor / Phosphflow kit. Microscopy: To detect kidney antibody deposits, kidneys from 6-8 months old mice were harvested, embedded in TissueTek, and flash-frozen in liquid nitrogen. Tissue sections were cut at 10 mM on a Cryotome and fixed with acetone at -20°C. To visualize antibody deposits, kidney sections were blocked with 4% BSA in PBS for one hour at RT, and then stained with anti-mouse IgG- FITC for one hour at RT. Images were acquired on a Zeiss LSM700 confocal microscope. To generated BCL-6-mCherry and KFERQ-dendra2 co-expressing CD4+T or NIH 3T3 cells, retroviral stocks were prepared by transfection of Phoenix cells with MSCV-BCL-6-mCherry, MSCV-BCL-6 Motif1WT-mCherry, MSCV-BCL-6 Motif1Mutant-mCherry, MSCV-BCL-6 Motif2 / 3WT- mCherry, MSCV-BCL-6 Motif2 / 3Mutant-mCherry, or MSCV-KFERQ-Dendra2 retroviral vector, respectively, together with the packaging vector pCL-Eco by the PEI transfection method. Viral supernatants were collected 48 and 72 hours after transfection. After two-rounds of retroviral spin- infection, mCherry and dendra2 double positive cells were sorted by FACS. To analyze the co- localization of the transgenic proteins, cells with or without CMA induction were fixed with 4% PFA and cell nucleus was counter stained with DAPI. Images were acquired on a Zeiss LSM 700 / 710 confocal microscope. For intracellular staining of the endogenous LAMP-2A and BCL-6, in vitro-induced Tfh cells were fixed with 4% PFA, permeabilized with 0.1% Triton™ X-100, blocked with 5% BSA in G12810-00883 31 PBS, and then stained with anti-LAMP-2A (Thermo Fisher) for one hour at RT, followed by anti- Rabbit Alexa™ 568 secondary antibody and Alexa647 anti-BCL-6 (BD) for one hour at RT, respectively. Cell nuclei were counter stained with DAPI. Images were acquired on a Zeiss LSM 700 / 710 confocal microscope. Anti-Nuclear Antibody (ANA) detection: Anti-nuclear antibodies in mouse serum were detected using a Kallestad Hep-2 kit according to manufacturer’s instructions (Bio-Rad). In brief, Hep-2 slides were stained with serum samples (1:200 dilution) at RT for one hour. After washing, the samples were stained with Alexa fluor-488 conjugated goat-anti-mouse IgG secondary antibody (ThermoFisher). Images were acquired on a Zeiss LSM710 confocal microscope. ICOS downregulation assay: Pre-activated CD4+T or Tfh cells were incubated with 5 mg / mL anti-ICOS-Biotin for 30 min on ice. Unbound antibodies were removed by washing with ice cold PBS. Cells were incubated at 37°C for various periods of time to allow ICOS internalization to occur. The reaction was stopped by fixing cells with 2% PFA. Surface remaining ICOS was stained with streptavidin- PE-CY7 and analyzed by FACS. ICOS internalization rate was calculated as the following equation: ICOS internalization rate= (MFI of ICOS at time 0’-MFI of ICOS at indicated time point) / MFI of ICOS at time 0’. Immunoprecipitation and Western blotting: 293T cells were transfected with different combination of pcDNA-based expression plasmids using PEI solution. Two days later, cells were harvested and stimulated with anti-ICOS antibody for 5 min. After the stimulation, cells were lysed with TNE buffer (50 mM Tris pH 8.0; 140 mM NaCl; 5 mM EDTA; 0.5% SDS) supplemented with protease and phosphatase inhibitors. Cell lysates were first incubated with protein G agarose beads to deplete stimulation used IgG antibody. ICOS-Flag protein was immunoprecipitated by incubation with 1 mg / mL of anti-Flag antibody at 4°C overnight, followed by incubation with Protein G agarose at 4°C for one hour. Immunoprecipitates were washed with TNE buffer and immunoblotted to a PVDF membrane. Membrane was first hybridized with anti-HA to detect ubiquitin or anti-ICOS antibody and then with goat HRP-anti-rabbit. Protein on the membrane was then visualized with enhanced chemiluminescence detection system (GE Healthcare). To detect CBLs in T cells, sorted naïve CD4+T cells and Tfh cells were lysed with 1x TNE buffer and cell lysates were immunoblotted to PVDF membrane. CBL, CBL-B, and β-actin on the membrane were quantified using anti-CBL, anti-CBL-B, and anti-β-actin antibodies, respectively. To analyze protein phosphorylation, Tfh cells were lysed in TNE buffer. Total cell lysates were fractionated by PAGE gel and transferred to a PVDF membrane. Phosphorylated AKT, S6 kinase, and GFAP were visualized with specific antibodies against phospho-AKT(S473), phosphor-S6(S253 / 256), and phosphor-GFAP(S8), respectively. To analyze the association of G12810-00883 32 BCL-6 with SHC70 and GFAP with LAMP-2A, the corresponding proteins in the lysates were first immunoprecipitated with 4 mg / mL of specific antibodies using protein A / G agarose (Invitrogen), washed with TNE buffer, blotted to a PVDF membrane, and hybridized with the antibody against the candidate associated proteins. Immunoprecipitated proteins were quantified by hybridization with the corresponding specific antibodies. The antibodies used were the followings: anti-CBL6 (Santa Cruz); anti-HSC70 (Santa Cruz); anti-LAMP-2A; anti-GFAP (Cell Signaling); anti-p- GFAP(S8) (Bioss); anti-p-AKT(S473) (Cell Signaling); anti-panAKT (Abcam). Horseradish- peroxidase conjugated goat anti-mouse antibody (Cell Signaling). Membranes were developed with an enhanced chemiluminescence detection system (GE Healthcare). RNA-seq and scRNA-seq analyses: To study the transcriptome profiles, WT and Cbl- / -Cbl-b- / -OT-II tg CD4+T cells were transferred into TCRb- / -mice to generate T cell chimeric mice. Mice were immunized with NP- OVA immunization and Tfh cells were purified by FACS sorting. Total mRNA from Tfh cells was isolated using an mRNAEasy Micro Kit (Qiagen) and reversely transcribed into cDNA using a Reverse-Transcription Kit according to manufacturer’s instructions (ThermoFisher). RNA sequencing was performed using an Illumina TruSeq Stranded mRNA Kit on an Illumina™ Hiseq 2000 sequencer. Read quality was confirmed using FastQC v0.10.1 and read alignment was performed using TopHat v2.0.10 on the mouse GRCm38 / mm10 genome. Differential expression analysis was performed with R package Deseq2 using the raw alignment count. Differentially expressed genes was defined as absolute logFC>1. For single cell RNA-seq analysis, the data extracted from GSE174188 was reanalysed with the Scanpy package. Cells from SLE and healthy control groups were filtered based on the label in meta data, and the CD4+T cell population was selected based on the expression of Cd3e and Cd4. The dot plot illustrated genes expression in total CD4+T cells from SLE and healthy groups. Enzyme-Linked Immunosorbent Assay (ELISA): For semiquantitative detections of anti-dsDNA antibody, serum samples were collected from 5- or 10-week-old mice.96-well plates were precoated with 5 mg / mL of salmon sperm DNA (ThermoFisher) at 4°C overnight. Serially diluted serum samples were added to the plates. After washing, the plates were incubated with anti-mouse IgG-HRP conjugated secondary antibody and developed by ECL substrates. Results were presented as relative units using the titer of serum anti-dsDNA antibodies from sicken TC lupus mouse as the control. In vivo blockade of ICOSL and OX40L signaling: CTV labelled CD4+T cells from WT and Cbl- / -Cbl-b- / -OT-II mice were transferred into TCRb- / -mice by i.v. injection, respectively, one day before immunization. At day 1 and 3 post NP- OVA immunization, mice were injected i.p. with either 100 mg / mice of anti-ICOSL or anti-OX40L to block ICOSL or OX40L signaling. Isotype matched antibodies were used as controls. Mice were G12810-00883 33 euthanized for analysis at day 7 post immunization. For the blockade of SLE development, mice were injected with anti-ICOS every three days for 5-7 weeks. Statistical Analysis: Statistical analyses were performed with two-tailed, unpaired Student’s t test or one-way ANOVA test as indicated in figure legends, with GraphPad Prism V7 software. A P value<0.05 was considered statistically significant. Example 2: SLE patients exhibit an impaired expression of CBLs and enhanced Tfh cell responses The expression of CBLs in naïve CD4+T cells and CD4+CXCR5hiPD-1hiblood circulating Tfh (cTfh) cells was examined in a cohort of patients with active SLE and healthy donors aged between 19 and 45 (Table 1). It was found that these SLE patients possessed significantly more cTfh cells relative to healthy individuals (FIG.1A). Additionally, cTfh cells from the SLE patients expressed much higher levels of ICOS and the transcription factor BCL-6 and exhibited enhanced functionality as they upregulated more CD40L upon TCR stimulation relative to healthy controls (FIGs.1B-1D), despite that levels of ICOS, BCL-6, and CD40L mRNA transcripts in lupus and healthy donor cells were comparable (FIG.1E). Interestingly, among the fifteen SLE patients that were examined, thirteen either lacked or significantly downregulated the expression of both CBL and CBL-B in CD4+T cells relative to healthy donors (FIG.1F). The degree of CBL and CBL-B downregulation was strongly correlated with the severity of SLE as determined by SLEDAI-2X (FIG.1G). It was also noted that the defective expression of CBLs was restricted to CD4+T cells, because B cells isolated from the SLE patients expressed normal levels of CBLs (FIG.7A). To further determine whether BCL-6, ICOS, and CD40L gene transcription was altered in SLE patients, the transcription profiles of genes related to Tfh cell development and function in CD4+T cells was also compared using publicly available datasets containing a total of 1.2 million peripheral blood mononuclear cells (PBMCs) collected from 162 SLE patients and 99 healthy individuals34. The SLE patients and healthy donors had comparable levels of ICOS, BCL-6, CBL, and CBL-B transcripts (FIG.7B), consistent with the qRT-PCR analysis of our cohorts of SLE and healthy donors (FIG. 1E). Additionally, no cTfh cell expansion or reduced CBLs was observed / detected in CD4+T cells from rheumatoid arthritis (RA) patients relative to healthy donors (FIGs.7C-7D). These results together reveal that the impaired expression of CBL and CBL-B proteins in CD4+T cells is a common molecular trait specifically shared by the SLE patients. Example 3: Ablation of CBLs in mouse T cells leads to enhanced Tfh cell responses and the manifestation of SLE G12810-00883 34 To investigate whether the impaired expression of CBLs in CD4+T cells is causative of the hyper Tfh cell response and SLE, Cblf / fCbl-b- / -Cd4-cre mice to conditionally delete both Cbl and Cbl-b genes in T lineage cells (termed the Cbl- / -Cbl-b- / -mutation) were generated (FIG.8A). Cbl- / -Cbl-b- / -mice had normal numbers of thymic and peripheral CD4+and CD8+T subsets at about six weeks of age (FIGs.8B-8D). However, the mutant mice possessed significantly more spontaneous Tfh and GC B cells relative to control mice (FIGs.2A-2B). Mutant Tfh cells also expressed higher levels of ICOS and OX40 but not CD5 relative to controls (FIG.2C). In contrast, the numbers of spontaneous Th1, Th2 and Th17 T cells in the mutant mice were comparable to controls (FIGs.8E-8G). In addition, the mutant mice had significantly more age-associate B cells (ABCs)-like B cells in the GC and spleen relative to control mice (FIGs.8H-8I). Strikingly, Cbl- / -Cbl-b- / -mice started to develop SLE-like autoimmune diseases at around ten weeks of age, characterized by high levels of serum antibodies against double-strained DNA (dsDNA) and nuclear antigens (ANA) (FIGs. 2D-2E), IgG antibody deposits and massive infiltration of inflammatory cells in the kidney (FIGs. 2F and 8J), and premature mortality with a 100% penetrance (FIG.8K). Of note, mice deficient in either CBL or CBL-B alone exhibited relatively normal Tfh cell development and GC reaction following immunization (FIGs. 8L and 8M), indicating a functional redundancy of CBL and CBL-B in Tfh cell development. These results thus indicate that the impaired expression of CBLs in T cells is sufficient to cause spontaneous Tfh cell responses and SLE. Hyper Tfh cell and GC responses could be a result of CD4+T cell intrinsic alteration orreduced T follicular regulatory (Tfr) cell function. To understand whether CBLs intrinsically regulated Tfh cell function, GC responses in Cbl- / -Cbl-b- / -mice were analyzed. Since Cbl- / -Cbl-b- / -mice generated more spontaneous Tfh cells and GC B cells which could interfere with the subsequent immunization, it was decided to use T cell chimeric mice for the experiments. In this case, Cbl- / -Cbl-b- / -OT-II TCR transgenic (tg) mice with or without IL-4GFPIL-21KATreporters were generated and purified naïve control and Cbl- / -Cbl-b- / -OT-II TCR tg CD4+T cells, respectively, were transferred into TCR-β- / -mice which lacked pre-existing T and GC B cells. The chimeric mice were then immunized with hapten-carrier antigen 4-hydroxy-3-nitrophenyl acetyl (NP)-OVA and Tfh and GC B cells were analyzed by flow cytometry. It was found that chimeric mice received Cbl- / -Cbl-b- / -OT-II TCR tg CD4+T cells generated markedly and GC B cells relative to controls (FIGs. 2G and 2H). Mutant OT-II TCR tg IL-4GFPIL-21KATT cells also generated significantly more mature IL-4+IL-21+Tfh cells relatively controls (FIG.2I). Additionally, Cbl- / -Cbl- b- / -OT-II TCR tg Tfh cells expressed much high levels of ICOS and OX40 and upregulated more CD40L after TCR stimulation compared to controls (FIGs.2J and 2K), similar to that found in human SLE cTfh cells. Moreover, the mutant OT-II TCR tg Tfh cells boosted the proportions of total NP (NP38) and high affinity NP (NIP5)-binding GC B cells compared to control counterparts (FIGs.9A and 9B), and purified Cbl- / -Cbl-b- / -OT-II TCR tg Tfh cells from the immunized mice were G12810-00883 35 more potent in driving B cell activation and class switch recombination in vitro (FIG.9C). To test the function of CBL and CBL-B in Tfr cells, CBL and CBL-B were deleted using the FoxP3-cre tg mice (termed Cbl- / -Cbl-b- / -Tregmice) and Tfh, GC B, and Tfr cells were examined in NP-CGG immunized mutant mice. Control and Cbl- / -Cbl-b- / -Tregmice generated comparable numbers of Tfh, GC B, and Tfr cells (FIGs.9D-9F). Thus, these results together indicate that T cell intrinsic CBLs do not impose significant influence on the development of Tfr cells, but rather control the development and functionality of Tfh cells. To determine whether the hyper Tfh cell response in Cbl- / -Cbl-b- / -mice caused the SLE, Tfh cell development in Cbl- / -Cbl-b- / -mice was blocked by intravenous injection of anti-ICOSL and then the development of SLE over time was monitored. It was found that mutant mice injected with isotype control antibodies still developed vigorous spontaneous Tfh cell and GC responses (FIGs.2L and 2M) and SLE syndrome (FIGs.2N-2P); in contrast, mutant mice injected with anti- ICOSL exhibited a markedly attenuated Tfh cell and GC responses and prevented lupus syndrome (FIGs. 2L-2P). These results, together with that the Cbl- / -Cbl-b- / -mutation does not enhance Th1, Th2 and Th17 responses, indicate that it is the hyper responses of Tfh, rather than other T effector cells, in Cbl- / -Cbl-b- / -mice that are responsible for the manifestation of the SLE. Example 4: CBLs control the fate commitment and survival of Tfh cells by attenuating ICOS signaling Hyper Tfh cell responses could be caused by the altered Tfh cell fate commitment, proliferation, and / or survival. To distinguish these possibilities, the kinetics of Tfh cell development along T cell division history was analyzed. In this case, naïve control and Cbl- / -Cbl-b- / -OT-II TCR tg CD4+T cells were labeled with the fluorescent dye CTV and transferred into TCRβ- / -mice, respectively. The resulting T cell chimeric mice were then immunized with NP-OVA and the generation of Tfh cells at each cell division was analyzed by flow cytometry. It was found that the ablation of CBLs did not significantly alter T cell proliferation based on the rate of cell division and Ki67 expression (FIGs. 10A and 10B). However, Cbl- / -Cbl-b- / -Tfh cells contained significantly fewer annexin V+cells relative to control counterparts (FIG.10C), suggesting that they survive better relative to controls. Relative to control donor cells, the Cbl- / -Cbl-b- / -mutant cells exhibited markedly enhanced Tfh cell fate commitment, because while a high proportion and number of Cbl- / -Cbl-b- / -T cells differentiated into CXCR5hiPD-1hiTfh cells in less than six cell divisions, control T cells needed minimal eight cell divisions to develop into Tfh cells (FIGs.3A and 3B). The mutant Tfh cells also expressed a higher level of BCL-6 compared to control counterparts (FIG.10D), indicating that they are bona fide Tfh cells. In contrast to Tfh cells, total numbers of Th1, Th2, and Th17 cells derived from control and Cbl- / -Cbl-b- / -OT-II TCR tg T cells were comparable (FIGs.10E-10G), thus indicating that the generation of these T effector cells are not affected by the Cbl- / -Cbl-b- / -mutation under our immunization scheme. G12810-00883 36 Cell fate choice and survival of Tfh cells are regulated by ICOS and OX40 signaling35,36. To determine whether the increased ICOS and OX40 on the mutant cells were responsible for the increased number of Cbl- / -Cbl-b- / -Tfh cells, the above CTV labeled OT-II TCR tg T cell chimeric mice were immunized with NP-OVA and respectively treated with either anti-OX40L or anti-ICOSL to block OX40 and ICOS signaling, and then the development of Tfh cells was examined. It was found that while anti-OX40L treatment had only a marginal effect on the development of Cbl- / -Cbl- b- / -Tfh cells (FIG.10H), anti-ICOSL administration significantly reduced the number of Tfh cells (FIG.3C), even though the mutant donor cells still underwent extensive proliferation similar to that observed in anti-OX40L or control Ig treated mice (FIGs.10I-10J). Based on these results, it was concluded that CBLs control the magnitude of Tfh cell responses by regulating the fate commitment and survival of Tfh cells. This regulation mainly depends on ICOS, however, to much lesser extent OX40 signaling. Example 5: CBLs Restrain Tfh cell development by mediating ICOS ubiquitination It was observed that the Cbl- / -Cbl-b- / -mutation attenuated ICOS downregulation upon anti-ICOS stimulation (FIG.11A), suggesting that CBLs may negatively regulate ICOS signaling by facilitating ICOS ubiquitination and degradation. To assess this possibility, the role of the ubiquitin ligase activity of CBLs in Tfh cell development was first examined. Cblf / fCbl-b- / C373Amice were crossed to Cd4-cre tg mice (termed Cbl- / -Cbl-b- / C373Amutant mice) in which OT-II T cells deleted the CBL and expressed only a mutant form of CBL-BC373Alacking the ubiquitin ligase activity37. After NP-CGG immunization, it was found that Cbl- / -Cbl-b- / C373Amice recapitulated the phenotypes of hyper Tfh and GC B cell responses observed in Cbl- / -Cbl-b- / -mice (FIGs.3D and 3E). In addition, Cbl- / -Cbl-b- / C373ATfh cells expressed a significantly higher amount of ICOS compared to controls (FIG.11B). These results thus support the notion that the ubiquitin ligase activity of CBLs is necessary for controlling the magnitude of Tfh cell responses, possibly by downregulating ICOS expression. Inspection of the cytoplasmic tail of ICOS revealed five (K167, K168, K169, K191, and K192) lysine residues that could serve as the putative sites of ubiquitination by CBLs. Retroviral vectors expressing different mutants ICOS in which all five (5K2R-ICOS), three membrane proximal (3K2R-ICOS), or two distal (2K2R-ICOS) lysine residues were replaced by arginines, respectively, were generated (FIG. 11C). To test whether CBLs are capable of ubiquitinating ICOS, WT and 5K2R-ICOS were first co-expressed with CBL or CBL-B in 293T cells, respectively, and ubiquitination of ICOS after ICOS stimulation was examined. Co-expression of the WT ICOS with either CBL or CBL-B resulted in the increased ubiquitination of ICOS. In contrast, the 5K2R mutation blocked ICOS ubiquitination by either CBL or CBL-B (FIG.3F), indicating that ICOS is indeed ubiquitinated by CBLs. To determine whether ICOS ubiquitination affected Tfh cell development and the GC reaction, WT or different mutant ICOS, respectively, were expressed in G12810-00883 37 Icos- / -OT-II TCR tg CD4+T cells by retroviral transduction, viral transduced T cells were transplanted into TCR-β- / -mice, and then Tfh and GC B cell development in the resulting T cell chimeras was examined. It was found that 5K2R-ICOS and 2K2R-ICOS mutant significantly augmented the development of Tfh and GC B cells, and 5K2R-ICOS upregulated BCL-6 in Tfh cells compared to WT ICOS (FIGs.3G, 3H, and 11D). In contrast, 3K2R mutant ICOS had no impact on Tfh cell and GC development, as compared to WT ICOS. Relative to T cells expressing WT ICOS, Tfh cells reconstituted with 5K2R-ICOS or 2K2R-ICOS expressed much higher levels of mutant ICOS that was also resisted to downregulation upon ICOS stimulation; In contrast, the expression and downregulation of 3K2R-ICOS were comparable to that of WT ICOS (FIGs.3I and 11E). Consistent with the increased cell surface expression, 5K2R-ICOS and 2K2R-ICOS mutants elicited stronger ICOS signaling, including AKT phosphorylation and Ca2+mobilization relative to that induced by the WT or 3K2R mutant (FIGs.11F and 11G). These results together demonstrate that the ubiquitination of lysines K191 and / or K192 at the distal cytoplasmic tail of ICOS by CBLs is necessary for downregulating ICOS expression and ICOS signaling, which in turn prevents hyper Tfh cell responses. Example 6: The ICOS-CBLs signaling axis controls CMA-dependent BCL-6 degradation While it is known that Tfh cell development depends on ICOS, the mechanism by which ICOS regulates Tfh cell development is not fully understood. Given that Cbl- / -Cbl-b- / -Tfh cells had increased BCL-6 protein, however, an equivalent amount of Bcl-6 gene transcripts relative to controls (FIGs.4A and 12A), it was envisioned that the ICOS-CBLs axis may control Tfh cell development by post-transcriptionally regulating BCL-6 expression. Since it was found that CBLs did not ubiquitinate BCL-6 in a co-expression experiment (FIG.12B), it was decided to examine whether they regulated BCL-6 degradation via chaperone-mediated autophagy (CMA) which selectively targets a subset of intracellular proteins containing the KFERQ motif. The CMA process starts with the recognition of the substrate KFERQ motif by heat shock cognate chaperone 70 (HSC70), which then tethers the substrate-HSC70 complex to the lysosomal membrane, where binding of the substrate-HSC70 complex to LAMP-2A enables the translocation of the substrate protein into the lysosomal lumen for degradation upon CMA activation22,23. The bioinformatics analysis revealed that BCL-6 contained three putative KFERQ- like motifs (FIG.12C)38. It was thus hypothesized that the ICOS-CBLs signaling axis controlled the Tfh cell development by regulating BCL-6 proteostasis via CMA. To test this hypothesis, CMA activity in ex vivo generated Tfh cells was first blocked with leupeptin which mainly blocks the activities of several lysosomal proteinases during CMA, and it was found that this treatment indeed increased the level of BCL-6 protein (FIG.4B). To visualize the recruitment of BCL-6 to LAMP-2A+lysosomes in CMA activated cells, a construct expressing WT BCL-6 and mCherry fusion protein (termed BCL-6-mCherry) and a LAMP-2A reporter containing a LAMP-2A KFERQ G12810-00883 38 motif peptide and Dendra2 fusion protein (termed LAMP-2A-Dendra2) was generated, which allowed the detection of polymerized LAMP-2A puncta on lysosomes when CMA is activated (FIG. 12D)39. This reporter system was validated in NIH3T3 cells, and it was found that LAMP-2A- Dendra2 and BCL-6-mCherry did form multiple overlapping puncta after CMA was activated by starvation (FIG.12E). To determine whether BCL-6 was a target of CMA in Tfh cells and the role of CBLs in this regulation, these two reporter proteins were first co-expressed in ex vivo generated control and Cbl- / -Cbl-b- / -Tfh cells and their co-localization was examined. It was found that the LAMP-2A reporter formed significant less puncta and much less BCL-6-mCherry co-localized to the puncta in Cbl- / -Cbl-b- / -Tfh cells relative to controls (FIG.4C). To ascertain that the endogenous BCL-6 was targeted to LAMP-2A+lysosomes in Tfh cells generated in vivo, the LAMP-2A reporter was introduced into control and Cbl- / -Cbl-b- / -OT-II TCR tg CD4+T cells by retroviral transduction, and these cells were transferred into TCR-β- / -mice, respectively. After immunization with NP- OVA, endogenous BCL-6 and LAMP-2A reporter co-localization in isolated Tfh cells was examined by microscopy. It was found that while significant amounts of endogenous BCL-6 were co-localized with LAMP-2A puncta in control Tfh cells, LAMP-2A puncta were reduced and largely devoid of BCL-6 in Cbl- / -Cbl-b- / -Tfh cells (FIG.4D). These results together indicate that BCL-6 is indeed a CMA target in Tfh cells and ablation of CBLs attenuates the CMA activity and translocation of BCL-6 to CMA. To further determine the role of ICOS signaling in BCL-6 translocation to LAMP-2A+lysosomes, control and Cbl- / -Cbl-b- / -Tfh cells were co-stimulated with anti-ICOS and anti-TCR antibodies, and the translocation of the endogenous BCL-6 to LAMP-2A+puncta was examined. In the absence of the stimulation, BCL-6 co-localized with LAMP-2A+lysosomes in control and to a lesser extent in Cbl- / -Cbl-b- / -Tfh cells; however, ICOS and TCR co-stimulation significantly reduced the formation of BCL-6+LAMP-2A+puncta in control cells and even more so in Cbl- / -Cbl- b- / -T cells (FIG.4E). This finding indicates that ICOS signaling attenuates the formation of BCL- 6 and LAMP-2A puncta. In addition, absence of CBLs further impedes the recruitment of BCL-6 to LAMP-2A+lysosomes. To investigate how the ICOS-CBLs signaling axis regulated BCL-6 proteostasis, it was first assessed whether BCL-6 association with HSC70 was affected by the loss of CBLs. It was found that BCL-6 was constitutively associated with HSC70 in both control and Cbl- / -Cbl-b- / -Tfh cells irrespective of TCR and ICOS stimulation and that the association was not affected by the defect in CBLs (FIG.4F). It was next assessed whether CMA activity was affected by CBLs. It has been reported that GFAP associates with LAMP-2A and facilitates LAMP-2A polymerization essential for the substrate translocation to the lysosome lumen. GFAP mediated LAMP-2A polymerization can be negatively regulated by PI3 kinase-AKT signaling, because GFAP phosphorylated by AKT dissociates from LAMP-2A, thus preventing LAMP-2A assembly39,40. It was found that TCR and ICOS co-stimulation elicited significantly higher AKT activity in Cbl- / -Cbl- G12810-00883 39 b- / -Tfh cells relative to controls (FIG. 4G). Consequently, phosphorylation of GFAP was significantly enhanced in Cbl- / -Cbl-b- / -Tfh cells compared to controls (FIG.4H). As a result, the association of GFAP with LAMP-2A was reduced in Cbl- / -Cbl-b- / -Tfh cells relative to control counterparts (FIG. 4I). These findings thus support a model as to how the ICOS-CBLs axis regulates the proteostasis of BCL-6 in Tfh cells: ICOS-activated AKT phosphorylates GFAP and leads to GFAP dissociation from LAMP-2A. Dissociation of GFAP from LAMP-2A prevents LAMP- 2A polymerization, consequently impeding the transport of HSC70-associated BCL-6 to the lysosomal lumen for degradation. Conversely, CBLs limit BCL-6 accumulation by promoting ICOS ubiquitination and degradation, thus counteracting the role of ICOS in regulating the CMA activity and BCL-6 degradation. Example 7: Blockade of BCL-6 degradation via CMA enhances Tfh cell development Enhanced BCL-6 expression in Cbl- / -Cbl-b- / -Tfh cells suggested that the attenuation of CMA-dependent BCL-6 degradation in T cells could be sufficient to amplify Tfh cell responses and the GC reaction. To test this possibility, it was first dissected which KFERQ-like motif in BCL- 6 was responsible for targeting BCL-6 to CMA. A series of retroviral constructs encoding truncated BCL-6-mCherry fusion proteins that contained either a WT or a mutant BCL-6 KFERQ-like motif1 or motif2 / 3 (FIG.5A) were generated. These mutants BCL-6 were then co-expressed with LAMP- 2A reporter in NIH3T3 or Tfh cells, respectively, and their capability to be targeted to CMA was examined. Mutations in either KFERQ-like motif1 or motif2 / 3 impaired the translocation of the mutant BCL-6-mCherry to LAMP-2A+puncta not only in NIH3T3 cells but also in Tfh cells (FIGs. 13A and 5B), indicating that these motifs serve as the HSC70 recognition signal for BCL-6 translocation to CMA. Consequently, these BCL-6 KFERQ-like motif containing mutants were resistant to CMA-mediated downregulation (FIG.13B). To assess whether CMA-mediated BCL- 6 degradation was relevant to Tfh cell development, WT OT-II TCR tg CD4+T cells were next transfected with a retroviral vector expressing either WT or mutant BCL-6 carrying compound motif1 and motif2 / 3 mutations, and the transgene-expressing T cells were transferred into TCR- β- / -mice to generate T cell chimeric mice, respectively. Mice receiving the mutant BCL-6- expressing T cells generated significantly more Tfh and GC B cells as compared to that expressing WT BCL-6 after NP-OVA immunization (FIGs.5C and 5D). Tfh cells expressing the mutant BCL-6 also had a significantly higher level of BCL-6 protein compared to WT controls (FIG.5E). Together, these results indicate that all three KFERQ-like motifs in BCL-6 are involved in the maintenance of BCL-6 proteostasis in Tfh cells and blockade of BCL-6 targeting to CMA in T cells causes the hyper Tfh cell response and GC reaction. Example 8: Ablation of CBLs enhances the development of human Tfh cells G12810-00883 40 To assess whether the impaired expression of CBLs accounted for hyper Tfh cell responses in human SLE, both CBL and CBL-B genes were inactivated in human primary CD4+T cells by CRISPR-based gene targeting. Ablation of CBLs was confirmed by Western blot analysis (FIG. 14A). It was found that human CBL- / -CBL-B- / -CD4+T cells generated from all healthy donors produced significantly more Tfh cells relative to WT controls under the in vitro Tfh polarization condition, and the enhanced development of mutant Tfh cells was observed even under the Th0 polarization condition (FIGs.6A and 6B). Comparing to WT controls, the mutant T cells also markedly elevated the expression of ICOS (FIG.6C). Thus, these findings not only support that CBLs restrain Tfh development in humans, but also suggest that the impaired expression of CBLs could be the direct reason causing the hyper Tfh cell response in SLE patients. Example 9: The ICOS-CBLs signaling axis regulates CMA dependent BCL-6 proteostasis in human T cells Inspection of protein sequences revealed that humans and mice shared the conservated lysine residuals and KFERQ-like motifs in their ICOS and BCL-6, respectively (FIG.14B). It was next determined whether the ICOS-CBL signaling axis also regulated CMA dependent BCL-6 degradation in human T cells. Similar to the mouse counterparts, it was observed that human CBL- / -CBL-B- / -CD4+T cells exhibited much stronger AKT activity relative to WT controls upon TCR and ICOS co-stimulation (FIG.6D). This finding, together with the observation that ICOS expression was also elevated in human SLE cTfh and CBL- / -CBL-B- / -Tfh cells (FIGs.1B and 6C), support the hypothesis that human ICOS is also ubiquitinated by CBLs. To determine whether the CBL- / -CBL-B- / -mutation in human T cells affected BCL-6 translocation to CMA, in vitro generated human WT and CBL- / -CBL-B- / -Tfh cells were co-transfected with the LAMP-2A reporter and BCL-6-mCherry. Confocal microscopy analysis showed that WT Tfh cells exhibited a much higher CMA activity and more BCL-6-mCherry association with LAMP-2A-Dendra2 puncta compared to CBL- / -CBL-B- / -Tfh cells (FIG.6E). These findings thus indicate that the ICOS-CBLs axis also regulates BCL-6 proteostasis via CMA and Tfh cell development in humans. Although the present invention has been described hereinabove by way of specific embodiments thereof, it can be modified, without departing from the spirit and nature of the subject invention as defined in the appended claims. In the claims, the word "comprising" is used as an open-ended term, substantially equivalent to the phrase "including, but not limited to". The singular forms "a", "an" and "the" include corresponding plural references unless the context clearly dictates otherwise.

Claims

G12810-00883 41 WHAT IS CLAIMED IS:

1. A method for determining whether a human subject suffers from systemic lupus erythematosus (SLE) comprising: (a) measuring the protein level of Casitas B-lineage lymphoma (CBL) and / or CBL-B in T lymphocytes from the subject; (b) comparing the protein level of CBL and / or CBL-B in the T lymphocytes from the subject with a reference protein level of CBL and / or CBL-B or predetermined reference value, and (c) determining whether the subject suffers from systemic lupus erythematosus (SLE) based on said comparing.

2. The method of claim 1, wherein (i) the reference protein level or predetermined reference value is a level in a control population not having SLE, and wherein a lower protein level of CBL and / or CBL-B are indicative that the subject suffers from SLE; or (ii) the reference protein level or predetermined reference value is a level in a control population having SLE, and wherein a lower or similar protein level of CBL and / or CBL-B is indicative that the subject suffers from SLE.

3. The method of claim 1 or 2, wherein the method comprises measuring the protein level of CBL protein.

4. The method of any one of claims 1 to 3, wherein the method comprises measuring the protein level of CBL-B.

5. The method of any one of claims 1 to 4, wherein the method comprises measuring the protein level of CBL and CBL-B.

6. The method of any one of claims 1 to 5, wherein the method further comprises (d) measuring the protein level of ICOS and / or BCL-6 in T lymphocytes from the subject; and (e) comparing the protein level of ICOS and / or BCL-6 in the T lymphocytes from the subject with a reference protein level of ICOS and / or BCL-6 or predetermined reference value.

7. The method of claim 6, wherein (i) the reference protein level or predetermined reference value is a level in a control population not having SLE, and wherein a higher protein level of ICOS and / or BCL-6 are indicative that the subject suffers from SLE; or (ii) the reference protein level or predetermined reference value is a level in a control population having SLE, and wherein a higher or similar protein level of ICOS and / or BCL-6 is indicative that the subject suffers from SLE.

8. The method of any one of claims 1 to 7, wherein the biological sample is a blood sample, a peripheral blood mononuclear cell (PBMC) sample, or a tissue sample.

9. The method of any one of claims 1 to 8, wherein the T lymphocytes are naïve T lymphocytes.

10. The method of any one of claims 1 to 9, wherein the T lymphocytes are CD4+T lymphocytes.G12810-00883 42 11. The method of any one of claims 1 to 10, wherein the measuring the protein level of CBL and / or CBL-B is performed using one or more ligands that specifically bind to CBL and / or CBL- B.

12. The method of claim 11, wherein the one or more ligands are one or more antibodies.

13. The method of any one of claims 1 to 12, wherein the measuring is performed by an immunoassay.

14. The method of claim 13, wherein the immunoassay is flow cytometry, enzyme-linked immunosorbent assay (ELISA), radioimmunoassay (RIA), Western blotting, or immunofluorescence.

15. The method of claim 14, wherein the immunoassay is flow cytometry.

16. The method of any one of claims 1 to 15, further comprising administering a treatment for SLE to the subject identified as suffering from SLE using the method defined in any one of claims 1 to 15.

17. The method of claim 16, wherein the treatment comprises an anti-inflammatory agent, corticosteroid, an antimalarial drug, an immunosuppressant, a soluble human B lymphocyte stimulator protein (BLyS) inhibitor, a CD20 binding agent, or any combination thereof.

18. The method of claim 17, wherein the anti-inflammatory agent comprises a corticosteroid (e.g., prednisone), the antimalarial drug comprises hydroxychloroquine, the immunosuppressant comprises azathioprine, mycophenolate, methotrexate, cyclosporine, or leflunomide, the BLyS inhibitor comprises belimumab, and / or the CD20 binding agent comprises rituximab.

19. The method of any one of claims 16 to 18, further comprising monitoring the subject's response to the treatment by: a) periodically measuring the level of CBL protein, CBL-B protein, or both, in subsequent biological samples from the subject; and b) comparing the levels from the subsequent biological samples to the levels measured prior to treatment or to subsequent predetermined reference values, wherein an increase in the level of CBL protein, CBL-B protein, or both, relative to the level measured prior to treatment, is indicative of a positive response to the treatment.

20. A method for treating a patient suffering from systemic lupus erythematosus (SLE) comprising: identifying the patient suffering from SLE using the method of any one of claims 1 to 15; and administering a treatment for SLE to the patient.

21. The method of claim 20, wherein the treatment comprises an anti-inflammatory agent, corticosteroid, an antimalarial drug, an immunosuppressant, a soluble human B lymphocyte stimulator protein (BLyS) inhibitor, a CD20 binding agent, or any combination thereof.G12810-00883 43 22. The method of claim 21, wherein the anti-inflammatory agent comprises a corticosteroid (e.g., prednisone), the antimalarial drug comprises hydroxychloroquine, the immunosuppressant comprises azathioprine, mycophenolate, methotrexate, cyclosporine, or leflunomide, the BLyS inhibitor comprises belimumab, and / or the CD20 binding agent comprises rituximab.

23. A method for assessing the evolution of systemic lupus erythematosus (SLE) in a human patient comprising: (a) measuring the protein level of Casitas B-lineage lymphoma (CBL) and / or CBL-B in T lymphocytes from the subject at a first time point; (b) measuring the protein level of CBL and / or CBL-B in T lymphocytes from the subject at a second, later time point; (c) comparing the protein level of CBL and / or CBL-B at the first and second time points, wherein: (i) a lower protein level of CBL and / or CBL-B at the second time point relative to the first time point is indicative that the patient’s disease has worsened; (ii) a similar protein level of CBL and / or CBL- B at the first and second time points is indicative that the patient’s disease is stable; or (iii) a higher protein level of CBL and / or CBL-B at the second time point relative to the first time point is indicative that the patient’s disease has improved.

24. The method of claim 23, wherein the method comprises measuring the protein level of CBL.

25. The method of claim 23 or 24, wherein the method comprises measuring the protein level of CBL-B.

26. The method of any one of claims 23 to 25, wherein the method comprises measuring the protein level of CBL and CBL-B.

27. The method of any one of claims 23 to 26, wherein the method further comprises (d) measuring the protein level of ICOS and / or BCL-6 in T lymphocytes from the subject at said first and second time points; and (e) comparing the protein level of ICOS and / or BCL-6 at the first and second time points, wherein: (i) a higher protein level of ICOS and / or BCL-6 at the second time point relative to the first time point is indicative that the patient’s disease has worsened; (ii) a similar protein level of ICOS and / or BCL-6 at the first and second time points is indicative that the patient’s disease is stable; or (iii) a lower protein level of ICOS and / or BCL-6 at the second time point relative to the first time point is indicative that the patient’s disease has improved.

28. The method of any one of claims 23 to 27, wherein the biological sample is a blood sample, a peripheral blood mononuclear cell (PBMC) sample, or a tissue sample.

29. The method of any one of claims 23 to 28, wherein the T lymphocytes are naïve T lymphocytes.

30. The method of any one of claims 23 to 29, wherein the T lymphocytes are CD4+T lymphocytes.G12810-00883 44 31. The method of any one of claims 23 to 30, wherein the measuring the protein level of CBL and / or CBL-B is performed using one or more ligands that specifically bind to CBL and / or CBL- B.

32. The method of claim 31, wherein the one or more ligands are one or more antibodies.

33. The method of any one of claims 23 to 32, wherein the measuring is performed by an immunoassay.

34. The method of claim 33, wherein the immunoassay is flow cytometry, enzyme-linked immunosorbent assay (ELISA), radioimmunoassay (RIA), Western blotting, or immunofluorescence.

35. The method of claim 34, wherein the immunoassay is flow cytometry.

36. The method of any one of claims 23 to 35, wherein the patient is undergoing treatment for SLE between the first and second time points, and wherein the method permits to assess the patient’s response to the treatment.

37. A kit for diagnosing or assessing the evolution of systemic lupus erythematosus (SLE) in a human subject, the kit comprising: a) one or more reagents for detecting CBL protein, CBL-B protein, or both, in a biological sample; and b) instructions for comparing the level of CBL protein, CBL-B protein, or both, in the biological sample with a predetermined reference value to diagnose or assess the evolution of SLE.

38. The kit of claim 37, wherein the one or more reagents comprise antibodies specific to CBL protein, CBL-B protein, or both.

39. The kit of claim 37 or 38, wherein the kit further comprises one or more reagents for detecting ICOS, BCL-6 and / or CD4 in a biological sample.

40. The kit of any one of claims 37 to 39, further comprising one or more standards comprising known quantities of CBL protein, CBL-B protein, or both, for generating a standard curve.

41. The kit of any one of claims 37 to 40, wherein the kit is configured for use in an immunoassay.

42. The kit of claim 41, wherein the immunoassay is flow cytometry, enzyme-linked immunosorbent assay (ELISA), radioimmunoassay (RIA), Western blotting, or immunofluorescence.

43. The kit of claim 42, wherein the immunoassay is flow cytometry.

44. Use of one or more reagents for the detection of CBL protein, CBL-B protein, or both, in the manufacture of a diagnostic kit for systemic lupus erythematosus (SLE) in a human subject.G12810-00883 45 45. The use of claim 44, further comprising one or more reagents for the detection of ICOS and / or BCL-6.

46. The use of claim 44 or 45, wherein the one or more reagents are one or more antibodies.

47. A method for treating a subject suffering from systemic lupus erythematosus (SLE) or preventing the development of SLE in an at-risk subject, the method comprising administering to the patient an agent that increases the expression or activity of Casitas B-lineage lymphoma (CBL) and / or CBL-B in T lymphocytes from the subject.

48. The method of claim 47, wherein the agent that increases the activity of CBL and / or CBL- B is a compound that stabilizes CBL and / or CBL-B.

49. The method of claim 47, wherein the agent that increases the expression or activity of CBL is a CBL polypeptide having at least 70% sequence identity with the amino acid sequence of human CBL (SEQ ID NO:16), or a nucleic acid encoding the CBL polypeptide.

50. The method of claim 47, wherein the agent that increases the expression or activity of CBL is a CBL polypeptide having at least 90% sequence identity with the amino acid sequence of human CBL (SEQ ID NO:16), or a nucleic acid encoding the CBL polypeptide.

51. The method of claim 50, wherein the agent that increases the expression or activity of CBL is a CBL polypeptide comprising the amino acid sequence of human CBL (SEQ ID NO:16), or a nucleic acid encoding the CBL polypeptide.

52. The method of any one of claims 47-51, wherein the agent that increases the expression or activity of CBL-B is a CBL-B polypeptide having at least 70% sequence identity with the amino acid sequence of human CBL-B (SEQ ID NO:17), or a nucleic acid encoding the CBL-B polypeptide.

53. The method of claim 52, wherein the agent that increases the expression or activity of CBL-B is a CBL-B polypeptide having at least 90% sequence identity with the amino acid sequence of human CBL-B (SEQ ID NO:17), or a nucleic acid encoding the CBL-B polypeptide.

54. The method of claim 53, wherein the agent that increases the expression or activity of CBL-B is a CBL-B polypeptide comprising the amino acid sequence of human CBL-B (SEQ ID NO:17), or a nucleic acid encoding the CBL-B polypeptide.

55. Use of an agent that increases the expression or activity of Casitas B-lineage lymphoma (CBL) and / or CBL-B in T lymphocytes for treating a human patient suffering from systemic lupus erythematosus (SLE).G12810-00883 46 56. Use of an agent that increases the expression or activity of Casitas B-lineage lymphoma (CBL) and / or CBL-B in T lymphocytes for the manufacture of a medicament for treating a human patient suffering from systemic lupus erythematosus (SLE).

57. The use of claim 55 or 56, wherein the agent that increases the activity of CBL and / or CBL-B is a compound that stabilizes CBL and / or CBL-B.

58. The use of claim 55 or 56, wherein the agent that increases the expression or activity of CBL is a CBL polypeptide having at least 70% sequence identity with the amino acid sequence of human CBL (SEQ ID NO:16), or a nucleic acid encoding the CBL polypeptide.

59. The use of claim 55 or 56, wherein the agent that increases the expression or activity of CBL is a CBL polypeptide having at least 90% sequence identity with the amino acid sequence of human CBL (SEQ ID NO:16), or a nucleic acid encoding the CBL polypeptide.

60. The use of claim 55 or 56, wherein the agent that increases the expression or activity of CBL is a CBL polypeptide comprising the amino acid sequence of human CBL (SEQ ID NO:16), or a nucleic acid encoding the CBL polypeptide.

61. The use of any one of claims 55-60, wherein the agent that increases the expression or activity of CBL-B is a CBL-b polypeptide having at least 70% sequence identity with the amino acid sequence of human CBL-b (SEQ ID NO:17), or a nucleic acid encoding the CBL-B polypeptide.

62. The use of claim 61, wherein the agent that increases the expression or activity of CBL-B is a CBL-B polypeptide having at least 90% sequence identity with the amino acid sequence of human CBL-B (SEQ ID NO:17), or a nucleic acid encoding the CBL-B polypeptide.

63. The use of claim 62, wherein the agent that increases the expression or activity of CBL-B is a CBL-B polypeptide comprising the amino acid sequence of human CBL-B (SEQ ID NO:17), or a nucleic acid encoding the CBL-B polypeptide.

64. The method of claim 47 or the use of claim 55 or 56, wherein the agent is a dual binding molecule that increases the interaction between (i) ICOS and (ii) CBL and / or CBL-B.

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