Secretogranin V Peptides for Native β-Cell Epitope Detection
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Solution Overview
Problem
Current technologies lack a comprehensive understanding of the peptides naturally processed and presented by β cells, which are critical for autoimmune β-cell destruction in type 1 diabetes, limiting effective tolerogenic vaccination strategies and immune staging tools.
Innovation Solution
Identification of antigenic peptides derived from secretogranin V, specifically HLA-restricted epitopes, which are processed and presented by β cells, providing a basis for developing T-cell biomarkers and tolerogenic vaccination strategies.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Measurement precision
If current technologies are used to identify islet antigens, then auto-antibody targeting can be measured, but comprehensive understanding of peptides naturally processed and presented by β cells is lacking
Solution Approach 1:
The patent uses HLA class I molecules as intermediaries to capture and present peptides naturally processed by β cells. By incubating β cells with HLA class I molecules and subsequently analyzing the bound peptides through mass spectrometry, the method indirectly identifies the native β-cell peptidome without requiring direct observation of peptide processing pathways.
Solution Approach 2:
The patent creates a copy of the β-cell peptide presentation system by isolating HLA class I-peptide complexes from β cells and analyzing them in vitro. This allows characterization of the peptides that would naturally be presented to CD8+ T cells without needing to observe the actual immune interaction in real-time.
2Productivity
If available islet antigen catalogue is used, then identification based on auto-antibodies and mouse studies is achieved, but bias due to lack of information about naturally processed peptides occurs
Solution Approach 1:
The patent allows β cells to self-present their naturally processed peptides by incubating them with HLA class I molecules under physiological conditions. This self-service approach enables the cells to automatically display their authentic peptidome without external manipulation or artificial processing, ensuring high reliability in antigen identification.
Solution Approach 2:
The patent replaces traditional mechanical approaches to antigen identification (such as antibody screening and mouse models) with a direct biochemical analysis of HLA class I-peptide complexes using mass spectrometry. This substitution provides more accurate and comprehensive information about naturally processed peptides.
3Adaptability or versatility
If indirect Ag processing pathways are used, then β-cell-reactive CD4+ T cells can be stimulated, but pathways specific to β cells are not reflected
Solution Approach 1:
The patent segments the immune response analysis into two distinct parts: CD4+ T cell responses to processed β-cell material (indirect pathway) and CD8+ T cell responses to native β-cell peptides (direct pathway). By using HLA class I molecules to capture peptides directly from β cells, the method specifically addresses the CD8+ T cell pathway that is currently missing from the antigen catalogue.
Data Source
AI summary
Despite the notion that human CD8+ T cells are the final mediators of autoimmune β-cell destruction in type 1 diabetes (TID), none of their target epitopes has been demonstrated to be naturally processed and presented by β cells. The inventors therefore performed an epitope discovery study combining HLA Class I peptidomics and transcriptomics strategies. Inflammatory cytokines increased β-cell peptide presentation in vitro, paralleling upregulation of HLA Class I expression. Peptide sources included known β-cell antigens and several insulin granule proteins. Secretogranin V (SCG5/7B2) was identified as a novel β-cell antigen, which was processed into HLA-A2- and HLA-A3-restricted epitopes recognized by circulating naïve CD8+ T cells in type 1 diabetic and healthy donors. HLA-A2-bound neo-epitopes were also represented and originated from an alternative SCG5-009 mRNA splice isoform. Accordingly, the present invention relates to antigenic peptides derived from secretogranin V and uses thereof for the diagnosis and treatment of T1D.