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* Department of Immunology, The Weizmann Institute of Science, Rehovot, Israel;
Human Disease Immunogenetics Group, Department of Infectious Diseases and Immunity, Imperial College, Hammersmith Hospital, London, United Kingdom;
Department of Immunology, Mayo Clinic, Rochester, MN 55905; and
Center for Brain Research, Department of Neuroimmunology, Medical University of Vienna, Vienna, Austria
The susceptibility to multiple sclerosis (MS), a chronic neurological autoimmune disease that primarily targets CNS myelin, has long been associated with HLA class-II genes. Although several other HLA and non-HLA disease predisposing alleles have been identified, alleles of the HLA-DR15 haplotype (DRB1*1501, DRB5*0101, and DQB1*0602) remain the strongest susceptibility factor. Many studies have suggested that the HLA-DRB1*1501 allele determines MS-associated susceptibility. However, due to strong linkage disequilibrium within the HLA class II region, it has been difficult to unequivocally determine the relative roles of the DRB1*1501 and DQB1*0602 products. In this study we use HLA class-II transgenic mice to illuminate the relative contributions of the DRB1*1501 and DQB1*0602 alleles or their combination to susceptibility toward a new "humanized" MS-like disease induced by myelin-associated oligodendrocytic basic protein (MOBP). Although many immunological studies have focused overwhelmingly on the role of the HLA-DRB1*1501 product in MS, we show that HLA-DRB1*1501 transgenics are refractory to MOBP disease induction, whereas the HLA-DQB1*0602 transgenics are susceptible via T cells reactive against MOBP15–36 and MOBP55–77 encephalitogenic epitopes. Although both transgenics react against these epitopes, the MOBP15–36- and MOBP55–77-reactive T cells are of Th2-type in HLA-DRB1*1501 transgenics and are pathogenic Th1/Th17 cells in the HLA-DQB1*0602 transgenic mice. This new humanized model of MS further implicates autoimmunity against MOBP in MS pathogenesis, provides the first evidence of pathogenic HLA-DQ-associated anti-myelin autoimmunity, and is the first to offer a rationale for HLA-DQB1*0602 association with MS. These findings have important bearing on the candidacy of the DQB1*0602 allele as a genetic risk factor for 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 in part by the Israel Science Foundation, National Multiple Sclerosis Society of New York Grant RG 3195B8/2, the Israel Ministry of Health, the Estate of the Late Florence Blau, and the William Sahm Foundation. Work in the laboratory of D.M.A. was supported Multiple Sclerosis Society of Great Britain and Northern Ireland Grants 0528/99 and 830/05. A. B.-N. is the incumbent of the Eugene and Marcia Applebaum Professorial Chair.
2 Address correspondence and reprint requests to Dr. Avraham Ben-Nun, Department of Immunology, Weizmann Institute of Science, P.O. Box 26, Rehovot 76000, Israel. E-mail address: avraham.ben-nun{at}weizmann.ac.il
3 Abbreviations used in this paper: MS, multiple sclerosis; EAE, experimental autoimmune encephalomyelitis; iNOS, inducible NO synthase; LNC, lymph node cell; MBP, myelin basic protein; MHCII, MHC class II; MOBP, myelin-associated oligodendrocytic basic protein; hMOBP, human MOBP; pMOBP, MOBP peptide; phMOBP, human MOBP peptide; rhMOBP, recombinant human MOBP; MOG, myelin oligodendrocyte glycoprotein; Mt, Mycobacterium tuberculosis; OSP, oligodendrocyte-specific protein; PLP, proteolipid protein; Tg, transgenic.
4 The online version of this article contains supplemental material.
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