Dissection of the multiple sclerosis associated DR2 haplotype

Area of Science:

• Immunogenetics
• Neuroimmunology
• Autoimmune Diseases

Background:

• Human leukocyte antigen (HLA) class II alleles are associated with autoimmune diseases.
• The DR2 haplotype (DRB1*1501, DRB5*0101, DQB1*0602) is the strongest genetic risk factor for multiple sclerosis (MS) in Caucasians.
• The precise roles and mechanisms of individual DR2 alleles in MS pathogenesis are not fully understood due to strong linkage disequilibrium.

Purpose of the Study:

• To investigate the functional roles and interactions of individual alleles within the DR2 haplotype in multiple sclerosis (MS) pathogenesis.
• To elucidate the mechanisms by which DR2 alleles contribute to T cell activation and central nervous system (CNS) myelin autoimmunity.

Main Methods:

• Studies in humanized mouse models to assess functional epistatic interactions between HLA alleles.
• Structural biology analyses to understand allele-specific T cell receptor binding and molecular mimicry.
• Analysis of activation-induced cell death (AICD) in encephalitogenic T cells.

Main Results:

• Functional epistatic interactions between DRB5*0101 and DRB1*1501 modulate MS disease severity in mice.
• DRB5*0101 influences disease severity via AICD of T cells restricted by DRB1*1501.
• Structural studies suggest mechanisms for thymic escape and peripheral T cell activation involving suboptimal binding and molecular mimicry.

Conclusions:

• Individual alleles of the DR2 haplotype play distinct roles in MS pathogenesis.
• Interactions between DR2 alleles, such as DRB5*0101 and DRB1*1501, are critical for modulating autoimmune responses in MS.
• Understanding these mechanisms provides insights into the genetic susceptibility to MS and potential therapeutic targets.