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

Abstract

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.

• Authors: Nathali Kaushansky, Daniel M Altmann, Chella S David, Hans Lassmann, Avraham Ben-Nun
• Journal: Journal of neuroinflammation (J Neuroinflammation) Vol. 9 Pg. 29 (Feb 08 2012) ISSN: 1742-2094 [Electronic] England
• PMID: 22316121 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cytokines
• Epitopes, T-Lymphocyte
• HLA-DQ beta-Chains
• HLA-DQB1 antigen
• HLA-DRB1 Chains
• HLA-DRB1*15:01 antigen
• Myelin Proteolipid Protein
• Peptides

Topics

• Animals
• Cytokines
• Disease Models, Animal
• Disease Susceptibility
• Encephalomyelitis, Autoimmune, Experimental (chemically induced, genetics, immunology)
• Epitopes, T-Lymphocyte (genetics, immunology)
• Gene Expression Regulation (drug effects, genetics)
• HLA-DQ beta-Chains (genetics, metabolism)
• HLA-DRB1 Chains (genetics, metabolism)
• Humans
• Mice
• Mice, Transgenic
• Multiple Sclerosis (chemically induced, genetics, immunology, physiopathology)
• Myelin Proteolipid Protein (immunology, toxicity)
• Peptides (toxicity)
• T-Lymphocytes (drug effects, immunology)