DQB1*0602 rather than DRB1*1501 confers susceptibility to multiple sclerosis-like disease induced by proteolipid protein (PLP)

Journal of Neuroinflammation

Avraham Ben-Nun¹  Hans Lassmann⁴  Chella S David⁵  Daniel M Altmann³  Nathali Kaushansky² 

[1] Department of Immunology, The Weizmann Institute of Science, P.O. Box 26 Rehovot 76000, Israel;Department of Immunology, The Weizmann Institute of Science, Rehovot 76100, Israel;Human Disease Immunogenetics Group, Section of Infectious Diseases and Immunity, Department of Medicine, Imperial College, Hammersmith Hospital, London, UK;Center for Brain Research, Department of Neuroimmunology, Medical University of Vienna, Vienna, Austria;Department of Immunology, Mayo Clinic, Rochester, MN, USA

关键词: HLA-Tg mice;    MHC;    T Cells;    Neuroimmunology;    Antigens/Peptides/Epitopes;    EAE/MS;   

Others  :  1212810
DOI  :  10.1186/1742-2094-9-29

 received in 2011-11-28, accepted in 2012-02-08,  发布年份 2012

【 摘 要 】

Background

Multiple sclerosis (MS) is associated with pathogenic autoimmunity primarily focused on major CNS-myelin target antigens including myelin basic protein (MBP), proteolipidprotein (PLP), myelin oligodendrocyte protein (MOG). MS is a complex trait whereby the HLA genes, particularly class-II genes of HLA-DR15 haplotype, dominate the genetic contribution to disease-risk. Due to strong linkage disequilibrium in HLA-II region, it has been hard to establish precisely whether the functionally relevant effect derives from the DRB1*1501, DQA1*0102-DQB1*0602, or DRB5*0101 loci of HLA-DR15 haplotype, their combinations, or their epistatic interactions. Nevertheless, most genetic studies have indicated DRB1*1501 as a primary risk factor in MS. Here, we used 'HLA-humanized' mice to discern the potential relative contribution of DRB1*1501 and DQB1*0602 alleles to susceptibility to "humanized" MS-like disease induced by PLP, one of the most prominent and encephalitogenic target-antigens implicated in human MS.

Methods

The HLA-DRB1*1501- and HLA-DQB1*0602-Tg mice (MHC-II^-/-), and control non-HLA-DR15-relevant-Tg mice were immunized with a set of overlapping PLP peptides or with recombinant soluble PLP for induction of "humanized" MS-like disease, as well as for ex-vivo analysis of immunogenic/immunodominant HLA-restricted T-cell epitopes and associated cytokine secretion profile.

Results

PLP autoimmunity in both HLA-DR15-Tg mice was focused on 139-151 and 175-194 epitopes. Strikingly, however, the HLA-DRB1*1501-transgenics were refractory to disease induction by any of the overlapping PLP peptides, while HLA-DQB1*0602 transgenics were susceptible to disease induction by PLP139-151 and PLP175-194 peptides. Although both transgenics responded to both peptides, the PLP139-151- and PLP175-194-reactive T-cells were directed to Th1/Th17 phenotype in DQB1*0602-Tg mice and towards Th2 in DRB1*1501-Tg mice.

Conclusions

While genome studies map a strong MS susceptibility effect to the region of DRB1*1501, our findings offer a rationale for potential involvement of pathogenic DQ6-associated autoimmunity in MS. Moreover, that DQB1*0602, but not DRB1*1501, determines disease-susceptibility to PLP in HLA-transgenics, suggests a potential differential, functional role for DQB1*0602 as a predisposing allele in MS. This, together with previously demonstrated disease-susceptibility to MBP and MOG in DRB1*1501-transgenics, also suggests a differential role for DRB1*1501 and DQB1*0602 depending on target antigen and imply a potential complex 'genotype/target antigen/phenotype' relationship in MS heterogeneity.

【 授权许可】

   
2012 Kaushansky et al; licensee BioMed Central Ltd.

【 图 表 】

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