The down-regulation of HLA-DM gene expression in rheumatoid arthritis is not related to their promoter polymorphism

HLA-DM molecule, a class II-like heterodimer, is a critical factor of HLA c lass II-dependent Ag presentation, It acts as a molecular chaperone and als o functions as a peptide editor favoring the presentation of high-stability peptides, Thus, it appears to skew the peptide repertoire presented to T c ells. Variation in HLA-DM expression has considerable effect on Ag presenta tion and regulation of these genes is likely to be a prerequisite to preven t autoimmunity, In this study, rheumatoid arthritis (RA) was chosen as a mo del of human autoimmune disease since its genetic susceptibility is known t o be associated with the HLA-DR and -DM components,We described a limited n ucleotide polymorphism in the HLA-DM promoters,vith functional impact on ba sal transcriptional activity and IFN-gamma induction as assessed in vitro. However, no difference of allele frequencies was found between controls and RA patients, Despite of this lack of association, expression of HLA-DM mol ecules was also investigated. Interestingly, an underexpression of HLA-DM t ranscripts and protein was shown in peripheral blood B cells from RA patien ts compared with controls or inflammatory arthritis patients. This underexp ression does not affect HLA-DR genes and is responsible for a decrease of t he DM:DR ratio in RA patients. This specific HLA-DM down-regulation is like ly to have important consequences on Ag presentation and could participate in the autoimmune process in RA.