Polymorphism of the HLA‐DMA and DMB genes in Rheumatoid Arthritis

Abstract

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 ...

Genetic analysis of multiplex rheumatoid arthritis families

“…Other MHC region genes linked to RA include HLA-DMA, HLA-DMB and polymorphisms in prolactin microsatellites. 31,32 While the latter was in linkage disequilibrium with DRB1 in the population studied, the DMA effects appeared to be independent of DRB1. Additional studies examining more MHC region polymorphisms will be necessary to allow further elucidation of the role of other non-class II genes.…”

Cellular Mechanisms that Edit the Immunopeptidome

“…DM is an MHCII homolog and several alleles have been identified so far (Pinet et al, 1997;McTernan et al, 2000). Several DM polymorphisms have been associated with predisposition to diseases such as Rheumatoid Arthritis (RA), Juvenile RA, medicamentosa-like Dermatitis, Primary Antiphospholipid Syndrome, Psoriasis and atopic Dermatitis (Toussirot et al, 2000;West and Reed, 1999;Yue et al, 2007;Sanchez et al, 2004;Pyo et al, 2003;Kuwata et al, 1996).…”

HLA-DMA Polymorphisms Differentially Affect MHC Class II Peptide Loading

“…Several investigations were unable to show HLA-DM polymorphisms to be an additional risk factor in RA, MS, and lupus erythematosus in certain populations (6)(7)(8). Other studies, however, have supported a genetic link between DM and several autoimmune diseases, including T1D, RA, and psoriasis (9)(10)(11)(12)(13)(14)(15). Presumably, the haplotypic combination of the MHCII and HLA-DM alleles expressed in a particular individual will influence the peptide exchange kinetics and the presentation of self-peptides, thereby contributing to autoimmune conditioning.…”

“…In humans, the only allele encoding a change of DMA-155 is the HLA-DMA*0103 allele, which additionally carries a DMA-R184H substitution. Although the frequency of HLA-DMA*0103 is not high when compared with HLA-DMA*0101 among populations in different studies (,2% versus .40% respectively), it is one of the alleles that have been connected, albeit controversially, to immune disorders via genetic association studies (8,10,(12)(13)(14)(15).…”