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1
* Department of Immunology and
Department of Neurology, College of Medicine, Mayo Clinic, Rochester, MN 55905
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-
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-, 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.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by National Institute of Health Grants NS 0521732, NS24180, and NS32149 and National Multiple Sclerosis Society Grants CA1011-03 and RG3172.
2 Address correspondence and reprint requests to Dr. Chella David, Department of Immunology, College of Medicine, Mayo Clinic 200, 1st Street SW, Rochester, MN 55905. E-mail address: david.chella{at}mayo.edu
3 Abbreviations used in this paper: MS, multiple sclerosis; PLP, proteolipid protein; MOG, myelin oligodendrocytic glycoprotein; Tg, transgenic; EAE, experimental autoimmune encephalomyelitis; LNC, lymph node cell; DC, dendritic cell; Ptx, pertussis toxin; Ct, cycle threshold; BM-DC, bone marrow-derived DC; Treg, T regulatory cell; Mtb, M. tuberculosis; MNC, mononuclear cell; GITR, glucocorticoid-induced tumor necrosis factor receptor.
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