Genetic and functional studies in multiple sclerosis patients from Martinique attest for a specific and direct role of the HLA-DR locus in the syndrome.

Among candidate genes involved in multiple sclerosis (MS) genetic susceptibility, MHC genes and particularly HLA-DRB11501-DQB10602 haplotype play a major role. Based on the strong linkage disequilibrium observed in Caucasians between DRB11501 and DQB10602 alleles, it is still impossible to draw a firm conclusion about the DRB1 or DQB1 locus involvement. In order to address this issue a strategy associating a genetic and a functional approach was conducted in a population of-non-Caucasian MS patients. We observed that in Martinicans (55 MS and 100 controls), the DRB115 and DRB107 alleles were positively associated with the disease. However in Martinicans the most common DRB115 subtype was 1503 and not 1501. Moreover, in Martinicans, the frequency of DQB10602, found in association with other DRB1 alleles than DRB115 (42% of DQB10602 haplotypes), was not increased in DRB115-negative MS patients, suggesting a neutral role of DQB10602 in MS genetics. In a second step, we demonstrated the capability of the DRB11503 allele associated with MS in Martinicans to present the immunodominant autoantigen MBP 85-99 peptide to a DRB11501 restricted MBP specific T cell line. Interestingly, structural features of DRB11501 or DRB11503 molecules are in good fit with the hypothesis that 1501 and 1503 molecules may act similarly in MS development by presenting the same immunodominant MBP peptide. On the whole, our results show a prominent role of the DRB1 locus (DRB11501 and/or DRB11503 alleles) in the immunodominant MBP 85-99 peptide presentation to genetically different MS patients and suggest a neutral role of the DQB1 encoded molecule in MS susceptibility.