T cell-mediated autoimmune disease due to low-affinity crossreactivity to common microbial peptides

Area of Science:

• Neuroimmunology
• Microbial Immunology
• Autoimmunity

Background:

• Environmental factors contribute significantly to multiple sclerosis (MS) risk, with infections frequently suspected but inconsistently identified as triggers.
• The mechanism by which diverse microbial agents might initiate MS remains unclear, posing a challenge for etiological research.

Purpose of the Study:

• To investigate the role of microbial peptides in inducing MS-like disease through molecular mimicry.
• To elucidate the structural and biophysical basis of T cell receptor (TCR) cross-reactivity between microbial and self-antigens in the context of MS.

Main Methods:

• Induction of MS-like disease in humanized mice using a common bacterial microbial peptide.
• Structural analysis to identify shared binding motifs between microbial and myelin basic protein (MBP) peptides.
• Biophysical studies to quantify the binding affinity of autoreactive T cell receptors (TCRs) to mimicry and autoantigenic peptides.

Main Results:

• A microbial peptide, prevalent across bacterial classes, induced MS-like pathology in humanized mice.
• Structural mimicry, not degenerate recognition, was identified as the mechanism for T cell receptor (TCR) cross-reactivity.
• The autoreactive TCR exhibited significantly lower binding affinity for the microbial peptide compared to the myelin basic protein peptide.

Conclusions:

• Molecular mimicry by a common microbial peptide offers a potential explanation for the diverse and elusive infectious triggers implicated in multiple sclerosis (MS).
• This finding provides a framework for understanding how seemingly unrelated infections could contribute to MS pathogenesis via shared structural epitopes.