HLA-DQ6 (DQB1*0601)-Restricted T Cells Protect against Experimental Autoimmune Encephalomyelitis in HLA-DR3.DQ6 Double-Transgenic Mice by Generating Anti-Inflammatory IFN-γ

Abstract

The human MHC class II genes are associated with genetic susceptibility to multiple sclerosis (MS), a chronic inflammatory demyelinating disease of the CNS of presumed autoimmune origin. These genes encode for proteins responsible for shaping immune response. The exact role of HLA-DQ and -DR genes in disease pathogenesis is not well-understood due to the high polymorphism, linkage disequilibrium, and heterogeneity of human populations. The advent of HLA class II-transgenic (Tg) mice has helped in answering some of these questions. Previously, using single-Tg mice (expressing the HLA-DR or -DQ gene), we showed that proteolipid protein (PLP)91–110 peptide induced classical experimental autoimmune encephalomyelitis only in DR3.Aβ° mice, suggesting that DR3 (DRB1*0301) is a disease susceptible gene in the context of PLP. Human population studies have suggested that HLA-DQ6 (DQB1*0601) may be a protective gene in MS. To test this disease protection in an experimental model, we generated double-Tg mice expressing both HLA-DR3 and -DQ6. Introduction of DQ6 onto DR3-Tg mice led to a decrease in disease incidence on immunization with PLP91–110 peptide indicating a dominant protective role of DQ6. This protective effect is due to high levels of IFN-γ produced by DQ6-restricted T cells, which suppressed proliferation of encephalitogenic DR3-restricted T cells by inducing apoptosis. Our study indicates that DQ6 modifies the PLP91–110-specific T cell response in DR3 through anti-inflammatory effects of IFN-γ, which is protective for experimental autoimmune encephalomyelitis. Thus, our double-Tg mouse provides a novel model in which to study epistatic interactions between HLA class II molecules in MS.

HLA-DQB1*0602 Determines Disease Susceptibility in a New “Humanized” Multiple Sclerosis Model in HLA-DR15 (DRB1*1501;DQB1*0602) Transgenic Mice

“…The closely related allele DQB1*0601, most typically found in Asian populations, has been reported in two human studies to be associated with protection from MS (50,51). In accordance with those findings, studies by one of the authors of this manuscript (22,52) argued that the presence of HLA-DQB1*0601 could exert an epistatic protective effect on HLA-DR-dependent, antimyelin autoimmunity. Thus, while HLA-DRB1*1502 Tg mice were susceptible to MOG-induced EAE, the HLA(DRB1*1502 ϫ DQB1*0601) double-Tg mice were resistant (22).…”

Preferential HLA-DRB1*11–dependent presentation of CUB2-derived peptides by ADAMTS13-pulsed dendritic cells

“…The protective effect of HLA-DQB1*601 in experimental autoimmune encephalomyelitis is mediated via the antiinflammatory effects of high levels of interferon-g, which is produced by HLA-DQB1*601-restricted CD41 T cell responses. 39 In view of this finding, it is possible that HLA-DRB1*04-restricted CD41 T cell responses contribute to the observed protective effect of HLA-DRB1*04 in acquired TTP.…”

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

“…However, linkage disequilibrium in the HLA-class II region makes it difficult without functional studies to distinguish whether the functionally relevant effect on MS derives only from the DRB1*15:01 or also from the neighboring genes in the HLA-DR15 region, from their combination, or from their epistatic interaction. Many genetic or immune functional studies implicate DRB1*15:01 as the primary risk factor in MS (5,41,43) while suggesting only a disease-modifying role for the DRB5*01:01 or DQB1*06:02 alleles (44,45). In this respect, the studies presented here showing the dominant role of DRB1* 15:01 in OSP autoimmunity in HLA-Tg mice, together with previously reported susceptibility of DRB1*1501-Tg mice to MBP-or MOG-induced EAE (7,8), are consistent with a primary contribution of the DRB1*15:01 allele to MS risk in HLA-DR15 ϩ individuals.…”