MITA hinge region mutant polypeptide and application thereof in autoimmune diseases

Abstract

The invention discloses an MITA hinge region mutant polypeptide and application thereof in autoimmune diseases, and relates to the technical field of protein polypeptide drugs. The invention provides an MITA hinge region mutant polypeptide, the amino acid sequence of which is as shown in SEQ ID NO.1, SEQ ID NO.2, SEQ ID NO.3 or SEQ ID NO.4, or a polypeptide formed by extending two ends of the four polypeptides by a proper length. The most common MITAN153S / + mouse model in SAVI is taken as a research object, and it is found that SIP can almost completely eliminate the autoimmune phenotype of the mouse, the lifetime of the treated model mouse is remarkably prolonged, the weight loss speed is slowed down, and the expression level of inflammatory factors in the liver and brain of the model mouse is remarkably reduced. Therefore, the SIP has potential application value for treating the SAVI, and can be widely applied to preparation of drugs for treating SAVI autoimmune diseases caused by MITA function acquired mutation.

Description

Technical Field

[0001] The present invention relates to the technical field of protein polypeptide drugs, and in particular to a MITA hinge region mutant polypeptide and application thereof in autoimmune diseases. Background Art

[0002] Under normal physiological conditions, DNA in cells is packaged in the nucleus and mitochondria. In cases of infection, damage or gene mutation, DNA is released into the cytoplasm and recognized by the receptor cGAS, which then induces the production of the cyclic dinucleoside 2' 3'-cGAMP. 2' 3'-cGAMP binds to the key adaptor protein MITA (also known as STING, MPYS or ERIS) on the endoplasmic reticulum, causing MITA to change its conformation and transfer from the endoplasmic reticulum to the Golgi apparatus for further oligomerization. In this process, MITA recruits and activates TBK1 kinase and transcription factors IRF3 and NF-kB, ultimately inducing the expression of a series of downstream genes, including interferons, interferon-stimulated genes (ISGs) and inflammatory factors, resulting in an inflammatory response.

[0003] However, the gain of function (GOF) mutation of MITA can be transported from the endoplasmic reticulum to the Golgi apparatus in a manner independent of the binding of cGAMP, continuously activating the expression of interferon and inflammatory cytokines, producing a strong inflammatory response, and leading to a type of human autoimmune disease called SAVI (STING-associated vasculopathy with onset infancy, SAVI). SAVI patients generally develop the disease in infancy and have vascular lesions on the skin, manifested as erythema, purpura, etc.; they may also be accompanied by interstitial lung disease, which affects respiratory function; and arthritis, which causes joint pain and swelling. Most children die before they reach adulthood. Taking human MITA protein as an example, so far, the mutation types that have been found to cause SAVI include N154S (asparagine at the 154th position of human MITA protein is replaced by serine), V155M (valine at the 155th position of human MITA protein is replaced by methionine), V147L (valine at the 147th position of human MITA protein is replaced by leucine), G166E (glycine at the 166th position of human MITA protein is replaced by glutamic acid), etc.; among them, N154S is the most common. Corresponding to the above-mentioned human MITA protein mutation types, the mouse MITA protein mutation types are N153S, V154M, V146L and G165E. MITA N153S Mouse (corresponding to human MITA N154S) showed symptoms similar to human SAVI, namely, systemic multi-organ inflammation, significantly increased expression of inflammatory cytokines in serum, and death began after 4-6 weeks.

[0004] Currently, JAK inhibitors are mostly used clinically to treat SAVI. However, there are problems with JAK inhibitors that cannot be ignored, such as the inability to alleviate pulmonary fibrosis in patients and poor treatment effects on elderly patients. More importantly, the "one-size-fits-all" blocking method of JAK inhibitors makes it impossible for patients taking the preparations to function with normal antiviral or bacterial immune functions, making them more susceptible to infections such as herpes zoster virus, rotavirus, and Aspergillus, which seriously threatens their lives and health. Therefore, specifically targeting MITA gain-of-function mutations has become a potential solution for the treatment of SAVI. Summary of the invention

[0005] In order to solve the shortcomings of traditional SAVI treatment, the present invention provides a MITA hinge region mutant polypeptide and its application in autoimmune diseases. Through a large number of experimental studies, it is found that the hinge region domain of MITA is crucial to its abnormal activation of SAVI mutation, and its transport process depends on the interaction between the hinge region amino acid sequence and the transport protein iRhom2. This means that the amino acid sequence of the MITA hinge region gain-of-function mutation specifically binds to the MITA transport protein iRhom2. Therefore, the present invention can simulate the function of the binding domain by designing and synthesizing the amino acid sequence containing the gain-of-function mutation site in the MITA hinge region, competitively bind to the transport protein iRhom2, and destroy the interaction interface between MITA and iRhom2, thereby preventing the spontaneous transport activation of the MITA hinge region SAVI mutation. By designing and synthesizing the sequence polypeptide drugs, it may become a potential solution for treating SAVI diseases.

[0006] In a first aspect, the present invention provides a MITA hinge region mutant polypeptide for treating an autoimmune disease, wherein the autoimmune disease refers to a human autoimmune disease or a murine autoimmune disease caused by a gain-of-function mutation in the amino acid sequence of the human / mouse MITA hinge region; For the human autoimmune disease, the amino acid sequence of the MITA hinge region mutant polypeptide is shown in SEQ ID NO.1, SEQ ID NO.2, SEQ ID NO.3 or SEQ ID NO.4; Alternatively, it is extended from the N-terminus of the sequence shown in SEQ ID NO.1 by 1-2 amino acids and / or from the C-terminus by 1-10 amino acids; Alternatively, it is extended by 1 amino acid from the N-terminus and / or 1-10 amino acids from the C-terminus of the sequence shown in SEQ ID NO.2; Alternatively, it is extended from the N-terminus of the sequence shown in SEQ ID NO.3 by 1-2 amino acids and / or from the C-terminus by 1-10 amino acids; Alternatively, it is extended from the N-terminus of the sequence shown in SEQ ID NO.4 by 1-2 amino acids and / or by 1 amino acid from the C-terminus; For murine autoimmune diseases, the amino acid sequence of the MITA hinge region mutant polypeptide is shown in SEQ ID NO.5, SEQ ID NO.6, SEQ ID NO.7 or SEQ ID NO.8; Alternatively, it is extended from the N-terminus of the sequence shown in SEQ ID NO.5 by 1-2 amino acids and / or from the C-terminus by 1-10 amino acids; Alternatively, it is an extension of 1 amino acid from the N-terminus and / or 1-10 amino acids from the C-terminus of the sequence shown in SEQ ID NO.6; Alternatively, it is extended from the N-terminus of the sequence shown in SEQ ID NO.7 by 1-2 amino acids and / or from the C-terminus by 1-10 amino acids; Alternatively, the sequence is extended from the N-terminus of SEQ ID NO. 8 by 1-2 amino acids and / or from the C-terminus by 1 amino acid.

[0007] Furthermore, the N segment of the MITA hinge region mutant polypeptide is acetylated, and the C terminus is amidated; and / or all amino acids constituting the MITA hinge region mutant polypeptide are in D-type conformation. The above modifications are beneficial to the stability of the MITA hinge region mutant polypeptide.

[0008] Furthermore, the MITA hinge region mutant polypeptide is a derivative in the form of acetate.

[0009] In practical applications, MITA hinge region mutant peptides are mostly in the form of TFA salt (trifluoroacetate). According to the process differences of each company, the content of TFA salt in the synthesized MITA hinge region mutant peptides varies. However, pure TFA salt has certain cytotoxicity. Therefore, it is possible to consider converting these TFA salt forms into acetate forms to reduce the toxicity of MITA hinge region mutant peptides to cells. Of course, some synthetic products have a low content of TFA salt, and it is also possible to convert them to acetate forms without removing TFA salts.

[0010] Through a large number of studies, the present invention found that the amino acid sequence polypeptide containing the N153S mutation near the hinge region (aa150-156, i.e., the amino acid sequence of the 150-156 position of the MITA protein) of the mouse can significantly alleviate the MITA of the SAVI disease model mouse. N153S →WT chimeric mice (i.e., due to MITA N153SThe autoimmune phenotype of SAVI disease caused by mutations is mainly manifested by significantly prolonged survival of mice, higher body weight, significantly reduced spleen volume, and significantly reduced expression levels of inflammatory factors in liver and brain tissues. In addition to N154S, the mutation types of the hinge region of the human MITA protein, V147L, V155M, and G166E gain-of-function mutations can also spontaneously migrate from the endoplasmic reticulum to the Golgi apparatus for activation, leading to abnormal activation of MITA and causing autoimmune diseases.

[0011] Therefore, based on the above findings, the present invention provides the use of MITA hinge region mutant polypeptides in treating the autoimmune disease SAVI caused by gain-of-function mutations in the MITA hinge region.

[0012] For human MITA protein, polypeptides containing four functional gain-of-function site mutations, N154S, V147L, V155M, and G166E, in the hinge region of MITA have the same or similar physiological functions, that is, they can competitively bind to transporters, block the interaction between transporters and MITA proteins, and thus inhibit the progression of SAVI disease. Therefore, amino acid sequences containing V147L, N154S, V155M, or G166E mutations near the hinge region (aa150-156) of human MITA all have the function of inhibiting the spontaneous activation caused by MITA activation mutations in the hinge region, and can be used to prepare drugs for the treatment of human autoimmune diseases.

[0013] Correspondingly, for mouse MITA protein, polypeptides containing four functional gain-of-site mutations, N153S, V146L, V154M, and G165E, in the MITA hinge region all have the function of inhibiting the spontaneous activation caused by MITA activation mutations in the hinge region, and can be used to prepare drugs for the treatment of mouse autoimmune diseases.

[0014] According to statistics, there are 94 mouse and human mutant peptides with MITA hinge region mutations that meet the above physiological functions, totaling 188. V147L MITA N154S MITA V155M MITA G166E .

[0015] The second aspect of the present invention provides a drug for treating autoimmune diseases, comprising the above-mentioned MITA hinge region mutant polypeptide.

[0016] Furthermore, the drug for treating autoimmune diseases also includes pharmaceutically acceptable excipients.

[0017] The third aspect of the present invention provides an application of the above-mentioned MITA hinge region mutant polypeptide in the preparation of a drug for treating an autoimmune disease, characterized in that the autoimmune disease refers to a human autoimmune disease or a mouse autoimmune disease caused by a gain-of-function mutation in the amino acid sequence of the human / mouse MITA hinge region.

[0018] Compared with the prior art, the present invention is beneficial in that: after extensive research and reasonable inference, the present invention provides 188 MITA hinge region mutant polypeptides that have significant therapeutic effects on human or mouse autoimmune diseases SAVI; it has very high potential application value and can be used to prepare drugs for treating SAVI autoimmune diseases.

[0019] Description of the drawings.

[0020] Figure 1-4 SIP (SAVI inhibitory peptide) has a significant inhibitory effect on human or mouse SAVI mutations at the cellular level.

[0021] Figure 1 The sequences of TAT, mouse TAT-SIP1 or TAT-SIP2 (above) were transfected into HEK293 cells with internal control and mouse MITA. N153S After 4 h, the medium was changed and TAT, mouse TAT-SIP1 or TAT-SIP2 was added at a concentration of 2 μM. After another 20 h, a dual luciferase reporter gene experiment was performed to detect IFNβ promoter activation (Figure below).

[0022] Figure 2 For: TAT, human TAT-hSIP2 sequence (above); in HEK293 transfected with internal reference and human MITA V147L MITA N154S MITA V155M or MITA G166E After 4 h, the medium was changed and TAT and human TAT-hSIP2 were added at a concentration of 2 μM. After another 20 h, a dual luciferase reporter gene experiment was performed to detect IFNβ promoter activation (Figure below).

[0023] Figure 3 For: At MITA N153S / + Mouse lung fibroblasts (MLFs) were treated with TAT, mouse TAT-SIP1 or TAT-SIP2 (2 μM or 5 μM) for 24 h, and downstream inflammatory cytokines were detected by RT-qPCR. Ifnb、Isg56 and Il12p40 mRNA expression levels.

[0024] Figure 4 For: MitaKnockout of MLFs restores expression of MITA V146L MITA V154M and MITA G165E Then, the cells were treated with TAT or TAT-SIP2 (5 μM) for 24 h, and downstream inflammatory cytokines were detected by RT-qPCR. Ifb , Isg56 and Cxcl10 mRNA expression levels.

[0025] Figure 5-8 For SIP to MITA N153S →Therapeutic effects in WT chimeric mice.

[0026] Figure 5 and Figure 6 Four weeks after bone marrow transplantation, mice were treated with intraperitoneal injections of TAT (n=18) or TAT-SIP2 (n=20) (20 mg / kg body weight) every other day for a total of 7 times for 2 weeks. Survival analysis of mice was performed (Kaplan-Meier curve), and weight changes of mice treated with TAT (n=9) and TAT-SIP2 (n=10) were statistically analyzed.

[0027] Figure 7 RT-qPCR analysis of mouse liver and brain tissues after two weeks of treatment with TAT (n=6) and TAT-SIP2 (n=6) (7 times in total) Tnf, Ccl2, Ccl3 and Ccl4 Expression level.

[0028] Figure 8 ELISA was performed on the serum samples of TAT (n=6) and TAT-SIP2 (n=10) cells after two weeks of treatment (7 times in total) to analyze the expression levels of CXCL1, CCL5 and TNFα.

[0029] Specific implementation method.

[0030] The technical solution of the present invention will be described clearly and completely below. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of them. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention. Example 1: Construction, preparation and purification of MITA hinge region mutant peptide SIP (SAVI inhibitory peptide).

[0031] The present invention has found through a large number of experimental studies that the hinge region domain of MITA is crucial to the abnormal activation of its SAVI mutation, and its transport process depends on the interaction between the hinge region amino acid sequence and the transport protein iRhom2. This means that the amino acid sequence of the MITA hinge region gain-of-function mutation specifically binds to the MITA transport protein iRhom2. Therefore, the present invention can simulate the function of the binding domain by designing and synthesizing an amino acid sequence containing a gain-of-function mutation site in the MITA hinge region, competitively bind to the transport protein iRhom2, and destroy the interaction interface between MITA and iRhom2, thereby preventing the spontaneous transport activation of the MITA hinge region SAVI mutation. By designing and synthesizing this sequence, polypeptide drugs may become a potential solution for treating SAVI diseases.

[0032] After the above analysis and research, it was finally theoretically believed that the polypeptide containing N154S, V147L, V155M, and G166E mutations near the hinge region of the human MITA protein can significantly alleviate and treat human SAVI disease; the polypeptide containing N153S, V146L, V154M, and G165E mutations near the hinge region of the mouse MITA protein can significantly alleviate and treat mouse SAVI disease.

[0033] The amino acid sequence of the polypeptide for alleviating and treating human SAVI disease: (1) The specific sequence for the N154S mutation type is CEKGNFSVAH (as shown in SEQ ID NO.1); or, it is 1-2 amino acids extended from the N-terminus and / or 1-10 amino acids extended from the C-terminus of the sequence shown in SEQ ID NO.1; as shown in Table 1.

[0034] (2) The sequence for the V147L mutation type is specifically LCEKGNFNVAH (as shown in SEQ ID NO.2), or, it is an extension of 1 amino acid from the N-terminus and / or 1-10 amino acids from the C-terminus of the sequence shown in SEQ ID NO.2; as shown in Table 2.

[0035] (3) The sequence for the V155M mutation type is specifically CEKGNFNMAH (as shown in SEQ ID NO.3), or, it is 1-2 amino acids extended from the N-terminus and / or 1-10 amino acids extended from the C-terminus of the sequence shown in SEQ ID NO.3; as shown in Table 3.

[0036] (4) The specific sequence for the G166E mutation type is CEKGNFNVAHGLAWSYYIE (as shown in SEQ ID NO.4), or, it is 1-2 amino acids extended from the N-terminus and / or 1 amino acid extended from the C-terminus of the sequence shown in SEQ ID NO.4; as shown in Table 4.

[0037] Table 1 Peptides with N154S mutation near the hinge region of human MITA protein.

[0038]

[0039]

[0040] Table 2 Peptides with V147L mutation near the hinge region of human MITA protein.

[0041]

[0042]

[0043] Table 3 Peptides with V155M mutation near the hinge region of human MITA protein.

[0044]

[0045]

[0046] Table 4 Peptides with the G166E mutation near the hinge region of human MITA protein.

[0047]

[0048] The amino acid sequence of the polypeptide for alleviating and treating SAVI disease in mice: (1) The specific sequence for the N153S mutation type is CEEKKLSVAH (as shown in SEQ ID NO.5); or, it is 1-2 amino acids extended from the N-terminus and / or 1-10 amino acids extended from the C-terminus of the sequence shown in SEQ ID NO.5; as shown in Table 5.

[0049] (2) The specific sequence for the V146L mutation type is LCEEKKLNVAH (as shown in SEQ ID NO.6), or, it is an extension of 1 amino acid from the N-terminus and / or 1-10 amino acids from the C-terminus of the sequence shown in SEQ ID NO.6; as shown in Table 6.

[0050] (3) The sequence for the V154M mutation type is specifically CEEKKLNMAH (as shown in SEQ ID NO.7), or, it is 1-2 amino acids extended from the N-terminus and / or 1-10 amino acids extended from the C-terminus of the sequence shown in SEQ ID NO.7; as shown in Table 7.

[0051] (4) The specific sequence for the G165E mutation type is CEEKKLNVAHGLAWSYYIE (as shown in SEQ ID NO.8), or, it is 1-2 amino acids extended from the N-terminus and / or 1 amino acid extended from the C-terminus of the sequence shown in SEQ ID NO.8; as shown in Table 8.

[0052] Table 5 Peptides with N153S mutation near the hinge region of mouse MITA protein.

[0053]

[0054]

[0055] Table 6 Peptides with V146L mutation near the hinge region of mouse MITA protein.

[0056]

[0057]

[0058] Table 7 Peptides with V154M mutation near the hinge region of mouse MITA protein.

[0059]

[0060]

[0061] Table 8 Polypeptides with the G165E mutation near the hinge region of the mouse MITA protein.

[0062]

[0063] Example 2: Using SIP to treat human or mouse SAVI mutations at the cellular level.

[0064] In this example, two polypeptides were selected as representatives for testing, namely SIP1 and SIP2. The amino acid sequence of SIP1 is AVCEEKKLSVAHGLAWSYYIGY (i.e., the N-terminus of the sequence of SEQ ID NO.5 is extended by 2 amino acids AV, and the C-terminus is extended by 10 amino acids GLAWSYYIGY); the amino acid sequence of SIP2 is CEEKKLSVAH (as shown in SEQ ID NO.5). In order to improve the stability of SIP1 and SIP2, SIP1 and SIP2 used in this example are also acetylated at the N-terminus and amidated at the C-terminus, and the amino acids constituting SIP1 and SIP2 are all in the common L-type conformation.

[0065] In this example, in order to enable the MITA hinge region mutant polypeptide SIP constructed in Example 1 to enter the cell and exert its function, the cell-penetrating peptide TAT (amino acid sequence YGRKKRRQRRR, as shown in SEQ ID NO.9) and the linker sequence GSG were sequentially connected to the N-termini of the MITA hinge region mutant polypeptides SIP1 and SIP2, and they were named TAT-SIP1 and TAT-SIP2, respectively. Both TAT-SIP1 and TAT-SIP2 were synthesized by commissioning GenScript.

[0066] Transfection of internal control and mouse MITA in HEK293 cells N153S After 4 h, the medium was changed and TAT, mouse TAT-SIP1 or TAT-SIP2 was added at a concentration of 2 μM. After another 20 h, a dual-luciferase reporter gene assay was performed to detect IFNβ promoter activation.

[0067] The results showed that the use of mouse TAT-SIP1 or TAT-SIP2 significantly inhibited mouse MITA N153S The inhibitory effect of TAT-SIP2 was more obvious at the same concentration. Figure 1 shown.

[0068] Similarly, human hSIP2 can significantly inhibit human MITA V147L MITA N154S MITA V155M or MITA G166E IFNβ promoter activation caused by Figure 2 shown.

[0069] At MITA N153S Mouse TAT-SIP1 or TAT-SIP2 was added to the MLFs culture medium at a concentration of 2 μM or 5 μM for 24 h, and downstream inflammatory cytokines were detected by RT-qPCR. Ifnb、Isg56 and Il12p40 The results showed that the use of mouse TAT-SIP1 or TAT-SIP2 could significantly and dose-dependently inhibit the expression of endogenous MITA N153S downstream inflammatory cytokines such as Ifb , Isg56 and Il12p40 High expression, such as Figure 3 shown.

[0070] Mouse TAT-SIP2 can significantly inhibit endogenous MITA V146L MITA V154M MITA G165E downstream inflammatory cytokines such as Ifb , Isg56 and Cxcl10 High expression, such as Figure 4 shown.

[0071] Example 3: Using SIP to MITA N153S / + Treatment of SAVI disease induced by bone marrow transplantation in mice.

[0072] All mice used in this example were housed in a specific pathogen-free animal facility at Wuhan University, and all animal experiments were performed in accordance with protocols approved by the Institutional Animal Care and Use Committee of Wuhan University (approval number 24020A). The mouse genotype was determined by tail DNA PCR analysis. In order to improve the stability of SIP1 and SIP2, the SIP1 and SIP2 used in this example were also acetylated at the N-terminus and amidated at the C-terminus; and the amino acids constituting SIP1 and SIP2 were reversed from the normal L-type conformation to the D-type conformation.

[0073] This example uses the same MITA hinge region mutant polypeptide as in Example 2 and connects the cell-penetrating peptide TAT and linker sequence (ie, TAT-SIP1 and TAT-SIP2) for the experiment. Both TAT-SIP1 and TAT-SIP2 were commissioned to be synthesized by Qiangyao Biotechnology Co., Ltd.

[0074] C57BL / 6 mice (WT mice) were irradiated with non-lethal doses (7 Gy, 3.5 Gy twice) using a small animal X-ray irradiator (provided by the Instrument Sharing Center of the School of Medicine, Wuhan University) and then bone marrow transplanted. N153S / N153S Homozygous and mutant mice are embryonic lethal, so MITA is used N153S / + The relevant experiments were carried out on mice with a single chromosome carrying a mutation. N153S / + Mice (purchased from Jicui Pharmaceuticals) were killed and bone marrow was obtained from leg bones. Bone marrow cells were injected into irradiated wild-type (WT) mice via tail vein injection to obtain MITA. N153S →WT chimeric mice.

[0075] MITA N153S →WT chimeric mice were divided into two groups: control group (n=9) and treatment group (n=10). They were treated with TAT or TAT-SIP intraperitoneal injection every other day at a dose of 20 mg per kg body weight for 2 weeks, with a total of 7 injections. Survival rate statistics and body weight changes were monitored during the treatment period and after drug withdrawal.

[0076] Six mice from each group were selected for the above treatment and were analyzed after completing the two-week injection treatment: RT-qPCR was used to detect liver and brain Tnf, Ccl2, Ccl3, or Ccl4The expression levels of mRNA were measured; and the expression of CXCL1, CCL5 or TNFα in the serum of the control group (n=6) and treatment group (n=10) mice that underwent the above treatment was detected by ELISA.

[0077] The results showed that compared with the TAT control group, TAT-SIP injection significantly inhibited the expression of MITA N153S →The weight loss of WT chimeric mice, such as Figure 5 As shown; significantly extended MITA N153S →The survival of WT chimeric mice, such as Figure 6 As shown; significantly inhibited MITA N153S →WT chimeric mouse brain Tnf , Ccl2 , Ccl3 or Ccl4 mRNA expression, as well as the expression of CXCL1, CCL5, and TNFα in serum, such as Figure 7 and Figure 8 Together, these data suggest that TAT-SIP2 alleviates the autoimmune phenotype of NS→WT chimeric mice.

[0078] The above specific embodiments describe the implementation of the present invention in detail, but the present invention is not limited to the specific details in the above embodiments. Within the scope of the claims and technical concept of the present invention, the technical solution of the present invention can be modified and changed in many simple ways, and these simple modifications all belong to the protection scope of the present invention.

Claims

1. A MITA hinge region mutant polypeptide for treating autoimmune diseases, characterized in that: The autoimmune disease refers to MITA caused by the amino acid sequence of the hinge region of human / mouse MITA V147L MITA N154S MITA V155M or MITA G166E Human autoimmune diseases or murine autoimmune diseases resulting from mutations; For the human autoimmune disease, the amino acid sequence of the MITA hinge region mutant polypeptide is shown in SEQ ID NO.1, SEQ ID NO.2, SEQ ID NO.3 or SEQ ID NO.4; Alternatively, it is extended from the N-terminus of the sequence shown in SEQ ID NO.1 by 1-2 amino acids and / or from the C-terminus by 1-10 amino acids; Alternatively, it is extended by 1 amino acid from the N-terminus and / or 1-10 amino acids from the C-terminus of the sequence shown in SEQ ID NO.2; Alternatively, it is extended from the N-terminus of the sequence shown in SEQ ID NO.3 by 1-2 amino acids and / or from the C-terminus by 1-10 amino acids; Alternatively, it is extended from the N-terminus of the sequence shown in SEQ ID NO.4 by 1-2 amino acids and / or by 1 amino acid from the C-terminus; For murine autoimmune diseases, the amino acid sequence of the MITA hinge region mutant polypeptide is shown in SEQ ID NO.5, SEQ ID NO.6, SEQ ID NO.7 or SEQ ID NO.8; Alternatively, it is extended from the N-terminus of the sequence shown in SEQ ID NO.5 by 1-2 amino acids and / or from the C-terminus by 1-10 amino acids; Alternatively, it is an extension of 1 amino acid from the N-terminus and / or 1-10 amino acids from the C-terminus of the sequence shown in SEQ ID NO.6; Alternatively, it is extended from the N-terminus of the sequence shown in SEQ ID NO.7 by 1-2 amino acids and / or from the C-terminus by 1-10 amino acids; Alternatively, the sequence is extended from the N-terminus of SEQ ID NO. 8 by 1-2 amino acids and / or from the C-terminus by 1 amino acid.

2. The MITA hinge region mutant polypeptide for treating autoimmune diseases according to claim 1, characterized in that: The N segment of the MITA hinge region mutant polypeptide is acetylated, and the C terminus is amidated; and / or all the amino acids constituting the MITA hinge region mutant polypeptide are in a D-type conformation.

3. The MITA hinge region mutant polypeptide for treating autoimmune diseases according to claim 1, characterized in that: The MITA hinge region mutant polypeptide is a derivative in the acetate form.

4. A drug for treating autoimmune diseases, characterized in that: A polypeptide comprising the MITA hinge region mutant according to claim 1 or 2.

5. The drug for treating autoimmune diseases according to claim 3, characterized in that: Pharmaceutically acceptable excipients are also included.

6. Use of the MITA hinge region mutant polypeptide according to claim 1 or 2 in the preparation of a drug for treating autoimmune diseases, characterized in that: The autoimmune disease refers to a human autoimmune disease or a mouse autoimmune disease caused by a gain-of-function mutation in the amino acid sequence of the hinge region of human / mouse MITA.

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