Abstract
Risk of the development of multiple sclerosis (MS) is known to be increased in individuals bearing distinct class II human leukocyte antigen (HLA) variants, whereas some of them may have a protective effect. Here we analyzed distribution of a highly polymorphous HLA-DRB1 locus in more than one thousand relapsing-remitting MS patients and healthy individuals of Russian ethnicity. Carriage of HLA-DRB1*15 and HLA-DRB1*03 alleles was associated with MS risk, whereas carriage of HLA-DRB1*01 and HLA-DRB1*11 was found to be protective. Analysis of genotypes revealed the compensatory effect of risk and resistance alleles in trans. We have identified previously unknown MBP153−161 peptide located at the C-terminus of MBP protein and MBP90−98 peptide that bound to recombinant HLA-DRB1*01:01 protein with affinity comparable to that of classical antigenic peptide 306-318 from the hemagglutinin (HA) of the influenza virus demonstrating the ability of HLA-DRB1*01:01 to present newly identified MBP153−161 and MBP90−98 peptides. Measurements of kinetic parameters of MBP and HA peptides binding to HLA-DRB1*01:01 catalyzed by HLA-DM revealed a significantly lower rate of CLIP exchange for MBP153−161 and MBP90−98 peptides as opposed to HA peptide. Analysis of the binding of chimeric MBP-HA peptides demonstrated that the observed difference between MBP153−161, MBP90−98, and HA peptide epitopes is caused by the lack of anchor residues in the C-terminal part of the MBP peptides resulting in a moderate occupation of P6/7 and P9 pockets of HLA-DRB1*01:01 by MBP153−161 and MBP90−98 peptides in contrast to HA308−316 peptide. This leads to the P1 and P4 docking failure and rapid peptide dissociation and release of empty HLA-DM–HLA-DR complex. We would like to propose that protective properties of the HLA-DRB1*01 allele could be directly linked to the ability of HLA-DRB1*01:01 to kinetically discriminate between antigenic exogenous peptides and endogenous MBP derived peptides.
Highlights
Human leukocyte antigen (HLA) genes encode proteins that are capable to bind and present antigenic peptides and, play a critical role in the immune responses against pathogens as well as those resulting in autoimmunity [1,2,3,4]
Dose allele effect was observed when homozygotes ∗01/∗01, ∗03/∗03, and ∗15/∗15 were compared with heterozygotes containing HLA-DRB1∗01, ∗03, or ∗15 alleles in combination with alleles not associated with Multiple sclerosis (MS)
We have shown the strong association of HLA-DRB1∗15 and ∗03 alleles with MS risk and the significant protective effect of HLA-DRB1∗01 and ∗11 alleles in ethnic Russian people
Summary
Human leukocyte antigen (HLA) genes encode proteins that are capable to bind and present antigenic peptides and, play a critical role in the immune responses against pathogens as well as those resulting in autoimmunity [1,2,3,4]. Binding of antigenic peptides to HLA class II molecules produces binary peptide-HLA ligands displayed on the cell surface for recognition by T-cell receptors [5]. The invariant chain is partially degraded leaving HLA class II-associated Ii peptide (CLIP) in the binding groove [7, 8]. The peptide-HLA II complex is translocated to the surface of the antigen presenting cell (APC) for survey by T cells. Identification of self-peptide-HLA class II ligands that are linked to autoimmune reactions promises to provide a clue for understanding of the pathogenesis of autoimmune disorders [13,14,15]
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