Discover Potential New Epitopes through Post-Translational Modification in Sjögren's Disease

Area of Science:

• Immunology
• Autoimmune Diseases
• Computational Biology

Background:

• Sjögren's syndrome (SjD) is a chronic autoimmune disorder affecting moisture-producing glands.
• The human leukocyte antigen (HLA) class II molecule HLA-DR3 is strongly associated with SjD.
• Post-translational modifications (PTMs) may influence the presentation of SjD autoantigens.

Purpose of the Study:

• To investigate how PTMs affect the binding of SjD-associated autoantigens to HLA-DR3.
• To analyze the impact of PTM-mimic peptides on autoantigen presentation and T cell responses.

Main Methods:

• Computational framework to analyze PTM-mimic peptide binding to HLA-DR3.
• Analysis of full-length SjD autoantigen sequences (Ro60, Ro52, La) for PTM-eligible sites.
• Experimental validation of PTM-mimic peptides and T cell responses.
• Structural modeling of peptide-DR3 complexes.

Main Results:

• PTM substitutions at anchor positions generally reduced predicted binding affinity.
• Specific regions in Ro60, Ro52, and La autoantigens showed high densities of PTM-eligible sites.
• Experimental validation revealed enhanced T cell responses with PTM-mimic peptides, linked to increased HLA-DR3 binding.
• Structural modeling indicated altered peptide-DR3 interactions due to PTM mimics.

Conclusions:

• PTMs can influence autoantigen presentation to T cells in an HLA-DR3-dependent manner.
• PTM-mimic peptides may alter the immunogenicity of SjD autoantigens.
• Findings offer insights into SjD pathogenesis and potential therapeutic strategies targeting T cell responses.