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The Down-Regulation of HLA-DM Gene Expression in Rheumatoid Arthritis Is Not Related to Their Promoter Polymorphism^{1 ,2}

Pascale Louis-Plence^*, Sophie Kerlan-Candon^3,*, Jacques Morel^3,, Bernard Combe, Jacques Clot^*, Valérie Pinet^* and Jean-François Eliaou^4,*

^* Laboratoire d’Immunologie de Montpellier, Unité de Recherche Immunopathologie des Maladies Tumorales et Autoimmunes, Institut National de la Santé et de la Recherche Médicale Unité 475, Montpellier, Cedex, France; and Service d’Immunorhumatologie, Hôpital Lapeyronie, Montpellier, Cedex, France

HLA-DM molecule, a class II-like heterodimer, is a critical factor of HLA class II-dependent Ag presentation. It acts as a molecular chaperone and also functions as a peptide editor favoring the presentation of high-stability peptides. Thus, it appears to skew the peptide repertoire presented to T cells. Variation in HLA-DM expression has considerable effect on Ag presentation and regulation of these genes is likely to be a prerequisite to prevent autoimmunity. In this study, rheumatoid arthritis (RA) was chosen as a model of human autoimmune disease since its genetic susceptibility is known to be associated with the HLA-DR and -DM components. We described a limited nucleotide polymorphism in the HLA-DM promoters with functional impact on basal transcriptional activity and IFN- 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 molecules was also investigated. Interestingly, an underexpression of HLA-DM transcripts and protein was shown in peripheral blood B cells from RA patients compared with controls or inflammatory arthritis patients. This underexpression does not affect HLA-DR genes and is responsible for a decrease of the DM:DR ratio in RA patients. This specific HLA-DM down-regulation is likely to have important consequences on Ag presentation and could participate in the autoimmune process in RA.

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