Risk HLA Variants Affect the T-Cell Repertoire in Multiple Sclerosis

Area of Science:

• Immunogenetics
• Neuroimmunology
• Genomics

Background:

• The Major Histocompatibility Complex (MHC) is strongly associated with genetic predisposition to Multiple Sclerosis (MS).
• Numerous MHC associations (32 identified) play a role in MS susceptibility.
• The precise impact of these MHC risk alleles on the T-cell repertoire in MS remains to be fully elucidated.

Purpose of the Study:

• To investigate the effect of MHC-associated Multiple Sclerosis (MS) risk alleles on the T-cell receptor (TCR) repertoire in MS patients.
• To determine how specific human leukocyte antigen (HLA) alleles influence TCR diversity, public clones, and repertoire architecture.

Main Methods:

• Whole-genome genotyping and next-generation sequencing were used to analyze 161 untreated relapsing-remitting MS patients.
• Human Leukocyte Antigen (HLA) Class I and II alleles were inferred from genotyping data.
• T-cell receptor (TCR) CDR3 sequences were analyzed to evaluate repertoire features like diversity and architecture.

Main Results:

• Five MS-risk loci, including HLA-DRB1*15:01, were significantly associated with altered TCR diversity.
• Specific MHC risk alleles demonstrated associations with TCR CDR3 amino acid sequence architecture, impacting antigen recognition breadth.
• Shared clonotypes targeting viral antigens, such as Epstein-Barr virus, were identified in individuals carrying MS-risk alleles.

Conclusions:

• The study confirms a significant association between MHC risk alleles and the T-cell repertoire's macrofeatures in Multiple Sclerosis (MS).
• Findings suggest that MHC alleles shape the T-cell response in MS, potentially through influencing antigen recognition.
• Further research is warranted to unravel the specific molecular mechanisms underlying these associations.