Multiple sclerosis (MS) is a neurodegenerative autoimmune disease in which HLA major histocompatibility complex (MHC) class II molecules are known risk factors. However which of the HLA alleles DRB1*1501, DRB5*0101 and DQB1*0602 contributes most to the disease remains elusive. In September 3 Nature Immunology Heather Langl and colleagues from John Radcliffe Hospital, Oxford, UK, show that both DRB1 and DRB5 loci may influence susceptibility to MS because of their structural mimicry.

Langl et al. observed that a DR2-restricted cross-reactive TCR derived from an MS patient recognized the immunodominant myelin basic protein (MBP) epitope in the context of DRB1*1501 and an Epstein-Barr virus (EBV) DNA polymerase peptide in the context of DRB5*0101. To explain the structural basis of this cross-reactivity, they crystallized the DRB5*0101–EBV peptide complex and compared it to the structure of the DRB1*1501–MBP complex. They observed that the TCR contact surfaces of the DRB5*0101-EBV and DRB1*1501-MBP complexes are very...

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