HLA-DQB1*0602 determines disease susceptibility in a new "humanized" multiple sclerosis model in HLA-DR15 (DRB1*1501; DQB1*0602) transgenic mice

Nathali Kaushansky, Daniel M. Altmann, Stephanie Ascough, Chella S. David, Hans Lassmann, Avraham Ben-Nun

Research output: Contribution to journalArticle

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Abstract

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 HLADQB1* 0602 association with MS. These findings have important bearing on the candidacy of the DQB1*0602 allele as a genetic risk factor for MS.

Original languageEnglish (US)
Pages (from-to)3531-3541
Number of pages11
JournalJournal of Immunology
Volume183
Issue number5
DOIs
StatePublished - Sep 1 2009

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HLA-DRB1 Chains
Disease Susceptibility
Transgenic Mice
Multiple Sclerosis
Myelin Sheath
Alleles
Autoimmunity
Epitopes
HLA-DQ Antigens
T-Lymphocytes
Th17 Cells
MHC Class II Genes
Th1 Cells
Proteins
HLA-DR15 antigen
HLA-DQB1 antigen
Linkage Disequilibrium
Haplotypes
Autoimmune Diseases

ASJC Scopus subject areas

  • Immunology
  • Medicine(all)

Cite this

HLA-DQB1*0602 determines disease susceptibility in a new "humanized" multiple sclerosis model in HLA-DR15 (DRB1*1501; DQB1*0602) transgenic mice. / Kaushansky, Nathali; Altmann, Daniel M.; Ascough, Stephanie; David, Chella S.; Lassmann, Hans; Ben-Nun, Avraham.

In: Journal of Immunology, Vol. 183, No. 5, 01.09.2009, p. 3531-3541.

Research output: Contribution to journalArticle

Kaushansky, Nathali ; Altmann, Daniel M. ; Ascough, Stephanie ; David, Chella S. ; Lassmann, Hans ; Ben-Nun, Avraham. / HLA-DQB1*0602 determines disease susceptibility in a new "humanized" multiple sclerosis model in HLA-DR15 (DRB1*1501; DQB1*0602) transgenic mice. In: Journal of Immunology. 2009 ; Vol. 183, No. 5. pp. 3531-3541.
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