Role of a Novel Human Leukocyte Antigen-DQA1*01:02;DRB1*15:01 Mixed Isotype Heterodimer in the Pathogenesis of “Humanized” Multiple Sclerosis-like Disease

Nathali Kaushansky,Miriam Eisenstein,Sigalit Boura-Halfon,Bjarke Endel Hansen,Claus Henrik Nielsen,Ron Milo,Gabriel Zeilig,Hans Lassmann,Daniel M Altmann,Avraham Ben-Nun

doi:10.1074/jbc.m115.641209

Abstract

Gene-wide association and candidate gene studies indicate that the greatest effect on multiple sclerosis (MS) risk is driven by the HLA-DRB1*15:01 allele within the HLA-DR15 haplotype (HLA-DRB1*15:01-DQA1*01:02-DQB1*0602-DRB5*01:01). Nevertheless, linkage disequilibrium makes it difficult to define, without functional studies, whether the functionally relevant effect derives from DRB1*15:01 only, from its neighboring DQA1*01:02-DQB1*06:02 or DRB5*01:01 genes of HLA-DR15 haplotype, or from their combinations or epistatic interactions. Here, we analyzed the impact of the different HLA-DR15 haplotype alleles on disease susceptibility in a new "humanized" model of MS induced in HLA-transgenic (Tg) mice by human oligodendrocyte-specific protein (OSP)/claudin-11 (hOSP), one of the bona fide potential primary target antigens in MS. We show that the hOSP-associated MS-like disease is dominated by the DRB1*15:01 allele not only as the DRA1*01:01;DRB1*15:01 isotypic heterodimer but also, unexpectedly, as a functional DQA1*01:02;DRB1*15:01 mixed isotype heterodimer. The contribution of HLA-DQA1/DRB1 mixed isotype heterodimer to OSP pathogenesis was revealed in (DRB1*1501xDQB1*0602)F1 double-Tg mice immunized with hOSP(142-161) peptide, where the encephalitogenic potential of prevalent DRB1*1501/hOSP(142-161)-reactive Th1/Th17 cells is hindered due to a single amino acid difference in the OSP(142-161) region between humans and mice; this impedes binding of DRB1*1501 to the mouse OSP(142-161) epitope in the mouse CNS while exposing functional binding of mouse OSP(142-161) to DQA1*01:02;DRB1*15:01 mixed isotype heterodimer. This study, which shows for the first time a functional HLA-DQA1/DRB1 mixed isotype heterodimer and its potential association with disease susceptibility, provides a rationale for a potential effect on MS risk from DQA1*01:02 through functional DQA1*01:02;DRB1*15:01 antigen presentation. Furthermore, it highlights a potential contribution to MS risk also from interisotypic combination between products of neighboring HLA-DR15 haplotype alleles, in this case the DQA1/DRB1 combination.

Highlights

HLA-DR15 haplotype (DRB1*15:01-DQA1*01:02-DQB1*0602-DRB5*01:01) association with multiple sclerosis (MS) is conventionally attributed to effects from HLA-DRB1*15:01, with impact on MS risk from the neighboring HLA-DQ locus unclear
We analyzed the impact of the different HLA-DR15 haplotype alleles on disease susceptibility in a new “humanized” model of MS induced in HLA-transgenic (Tg) mice by human oligodendrocyte-specific protein (OSP)/claudin-11, one of the bona fide potential primary target antigens in MS
These results suggest that h⌬OSP harbors a single DRB1*1501-associated immunodominant epitope encompassed within OSP[142– 161] and two DQB1*0602-associated co-dominant epitopes located within the OSP[55– 80] and OSP[142–161] regions, which might be of relevance to autoimmunity against OSP in HLA-DR15ϩ individuals

Summary

Background

HLA-DR15 haplotype (DRB1*15:01-DQA1*01:02-DQB1*0602-DRB5*01:01) association with multiple sclerosis (MS) is conventionally attributed to effects from HLA-DRB1*15:01, with impact on MS risk from the neighboring HLA-DQ locus unclear. OSP/claudin-11, the third most abundant CNS myelin protein, comprising ϳ7% of total CNS myelin proteins [11, 12], is a primary CNS myelin target antigen in MS [2], but, unlike MBP, PLP, MOG, and MOBP, neither the potentially pathogenic OSP epitopes relevant to HLA-DR15ϩ MS nor the HLADR15 haplotype gene product(s) that may determine OSP-related disease susceptibility has been investigated. The demonstration of functional interaction between DQA1*01:02 and DRB1*15:01 further highlights the complex effects of HLA class II genes on susceptibility to MS and provides a rationale for a potential contribution of the DQA1*01:02 allele to MS risk through antigen presentation via functional DQA1*01:02;DRB1*15:01 mixed isotype heterodimers and through epistasis with DRB1*15:01 [13]

Experimental Procedures

Results

Discussion