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-DRB1*1501-DQB1*0602 haplotype play a major role. Based on the strong linkage disequilibrium observed in Caucasians between DRB1*1501 and DQB1*0602 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 DRB1*15 and DRB1*07 alleles were positively associated with the disease. However in Martinicans the most common DRB1*15 subtype was *1503 and not *1501. Moreover, in Martinicans, the frequency of DQB1*0602, found in association with other DRB1 alleles than DRB1*15 (42% of DQB1*0602 haplotypes), was not increased in DRB1*15-negative MS patients, suggesting a neutral role of DQB1*0602 in MS genetics. In a second step, we demonstrated the capability of the DRB1*1503 allele associated with MS in Martinicans to present the immunodominant autoantigen MBP 85-99 peptide to a DRB1*1501 restricted MBP specific T cell line. Interestingly, structural features of DRB1*1501 or DRB1*1503 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 (DRB1*1501 and/or DRB1*1503 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.
Quelvennec
E
E
Laboratoire Universitaire d'Immunologie (UPRES EA 1257 - IFR 97), Université de, Rennes 1 and Etablissement Français du Sang Bretagne Rennes, France.
Bera
O
O
Cabre
P
P
Alizadeh
M
M
Smadja
D
D
Jugde
F
F
Edan
G
G
Semana
G
G
D000483:Alleles; D016022:Case-Control Studies; D002460:Cell Line; D005787:Gene Frequency; D006683:HLA-DQ Antigens / Q000235:genetics; D059866:HLA-DQ beta-Chains; D006684:HLA-DR Antigens / Q000235:genetics*; D059811:HLA-DRB1 Chains; D006801:Humans; D008395:Martinique; D009103:Multiple Sclerosis / Q000235:genetics* / Q000276:immunology*; D004676:Myelin Basic Protein / Q000276:immunology; D010446:Peptide Fragments / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology
D006683:HLA-DQ Antigens; D059866:HLA-DQ beta-Chains; C069051:HLA-DQB1 antigen; D006684:HLA-DR Antigens; D059811:HLA-DRB1 Chains; D004676:Myelin Basic Protein; D010446:Peptide Fragments; C107908:myelin basic protein 85-99