HLA-DR15-derived self-peptides are involved in increased autologous T cell proliferation in multiple sclerosis

Brain. 2013 Jun;136(Pt 6):1783-98. doi: 10.1093/brain/awt108.


The HLA-DR15 haplotype confers the largest part of the genetic risk to develop multiple sclerosis, a prototypic CD4+ T cell-mediated autoimmune disease. The mechanisms how certain HLA-class II molecules functionally contribute to autoimmune diseases are still poorly understood, but probably involve shaping an autoimmune-prone T cell repertoire during central tolerance in the thymus and subsequently maintaining or even expanding it in the peripheral immune system. Self-peptides that are presented by disease-associated HLA-class II molecules most likely play important roles during both processes. Here, we examined the functional involvement of the HLA-DR15 haplotype in autologous proliferation in multiple sclerosis and the contribution of HLA-DR15 haplotype-derived self-peptides in an in vitro system. We observe increased autologous T cell proliferation in patients with multiple sclerosis in relation to the multiple sclerosis risk-associated HLA-DR15 haplotype. Assuming that the spectrum of self-peptides that is presented by the two HLA-DR15 allelic products is important for sustaining autologous proliferation we performed peptide elution and identification experiments from the multiple sclerosis-associated DR15 molecules and a systematic analysis of a DR15 haplotype-derived self-peptide library. We identify HLA-derived self-peptides as potential mediators of altered autologous proliferation. Our data provide novel insights about perturbed T cell repertoire dynamics and the functional involvement of the major genetic risk factor, the HLA-DR15 haplotype, in multiple sclerosis.

Keywords: HLA-DR15; autologous T cell proliferation; homeostatic proliferation; multiple sclerosis; self-peptides.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Amino Acid Sequence
  • Autoantigens / physiology*
  • Cell Proliferation*
  • Cells, Cultured
  • Female
  • HLA-DR Serological Subtypes / physiology*
  • Haplotypes
  • Humans
  • Male
  • Middle Aged
  • Molecular Sequence Data
  • Multiple Sclerosis / genetics
  • Multiple Sclerosis / pathology*
  • Peptide Fragments / physiology*
  • T-Lymphocytes / metabolism
  • T-Lymphocytes / pathology*
  • Up-Regulation / physiology


  • Autoantigens
  • HLA-DR Serological Subtypes
  • HLA-DR15 antigen
  • Peptide Fragments