Objective. To determine whether the HLA-DMA and DMB genes, whose encoded molecules are involved in HLA class II-restricted antigen presentation, contribute to the genetic susceptibility to rheumatoid arthritis (RA).Methods. One hundred ninety-one RA patients, 147 control subjects, and 218 HLA-DRB1 genotypematched control subjects were oligotyped for DMA and DMB genes.Results. DMA*0103 and DMB*0104 were significantly increased in the RA patients compared with the randomly selected and the matched controls, thus indicating a direct influence of the DM genes. After stratification of the patients and matched controls according to DRBl genotypes, only DMA*0103 was increased in the RA patients with DRBl*Ol, as well as in the patients negative for the RA-susceptibility DR alleles.Conclusion. Our results suggest that DMA*0103 could play an additional role in the genetic susceptibility to RA.Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic inflammatory joint involvement. RA is also a complex, multifactorial disease with a significant genetic influence. Genes within the HLA complex have been shown to determine susceptibility to RA, HLA-DR4 being the first to be associated with RA (1). Advances in molecular biology Supported in part by grants from the Association de Recherche sur la Polyarthrite and GREG (no. 88/94 permitted a more accurate definition of the various HLA-DRBl alleles that confer risk: DRB1*0401, *0404, *0405, *0408, *0101, and *0102. Although the role of the HLA component in the susceptibility to RA is firmly established, the underlying molecular mechanisms are still unknown. In particular, the presence of specific amino acid motifs at positions 70-74 of the HLA-DRP1 molecule, which determine the risk of developing RA, cannot always account for the observed HLA-DRB1 gene distribution in patients. This is especially true when considering the disease phenotype and the genotype configurations of the patients (2,3).The HLA-DMA and DMB genes are located within the HLA class I1 region, between the DP and DQ gene regions. The a and P glycoproteins encoded by the DMA and DMB genes, respectively, are HLA class II-like molecules and form a heterodimer. The HLA-DM molecules have been localized in the endocytic compartment of the B lymphocytes, where the peptides bind to HLA class I1 molecules (4). Cellular mutants analyses have clearly demonstrated the direct involvement of the DM molecules in the HLA class II-restricted antigen presentation pathway (for review, see ref. 5).A limited nucleotide polymorphism has been described in the third exon of the DMA and DMB genes (6). This polymorphism does not involve the putative peptide-binding pocket, but could influence either the transport of the DM molecules across the various cellular compartments or the interaction with the DR molecules that leads to the binding of the antigenic peptides to DR heterodimers.To better understand the molecular basis of the association between the HLA class I1 component and RA, we compared the distributions of the ...
