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Identification of an immunogenic epitope from RASGRP2 with specificity for HLA-DR15 in multiple sclerosis
Vivien Li1, Kirti Pandey2, Michele D Binder3
1Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville 3010, Australia; Department of Neurology(,) The Royal Melbourne Hospital, Melbourne, Australia.
Journal of Neuroimmunology
|May 19, 2026
Summary
Researchers identified a specific peptide from RAS guanyl releasing protein 2 (RASGRP2) that triggers immune responses in individuals with multiple sclerosis (MS) and the HLA-DR15 genetic type. This finding could lead to new, targeted therapies for MS.
Area of Science:
- Neuroimmunology
- Immunogenetics
- Autoimmunity
Background:
- Identifying specific autoantigens is crucial for developing targeted therapies for multiple sclerosis (MS).
- RAS guanyl releasing protein 2 (RASGRP2) is a potential autoantigen in HLA-DRB1*15:01 (DR15)-positive individuals with MS.
- Developing autoantigen-specific tolerogenic therapies requires precise identification of antigenic epitopes.
Purpose of the Study:
- To identify immunogenic RASGRP2 epitopes for developing novel tolerogenic therapies in MS.
- To investigate the presentation of RASGRP2 peptides by antigen-presenting cells (APCs) in relation to HLA-DR15.
- To characterize the immune response to specific RASGRP2 peptides in DR15-positive individuals.
Main Methods:
- Exposure of peripheral blood mononuclear cells (PBMCs) to RASGRP2-derived peptides with varying DR15 binding affinities.
- Immunoeptidomic analysis to assess peptide presentation by HLA-DR on PBMCs.
- Measurement of CD80 expression and pro-inflammatory cytokine secretion (IFN-γ, IL-17, IL-22).
- Generation of HLA-DR15 tetramers and analysis of CD4+ T-cell frequency, phenotype, and proliferation.
Main Results:
- Moderate affinity RASGRP2 peptides were effectively presented by HLA-DR on PBMCs from both DR15-homozygous and DR15-negative individuals.
- These peptides significantly increased CD80 expression and pro-inflammatory cytokine secretion, particularly in DR15-positive patients.
- A specific immunogenic RASGRP2 peptide was identified, showing a four-fold higher frequency of specific CD4+ T-cells in DR15-positive MS patients compared to controls.
- These T-cells exhibited a pro-inflammatory phenotype and increased proliferation upon peptide stimulation.
Conclusions:
- A novel immunogenic RASGRP2 peptide, selective for HLA-DR15-positive individuals with MS, has been identified.
- This peptide has the potential to serve as a basis for developing autoantigen-specific tolerogenic therapies for MS.
- The findings advance the understanding of MS pathogenesis and offer a new avenue for therapeutic intervention.
