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 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-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 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.
Louis-Plence
P
P
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.
Kerlan-Candon
S
S
Morel
J
J
Combe
B
B
Clot
J
J
Pinet
V
V
Eliaou
J F
JF
D001172:Arthritis, Rheumatoid / Q000235:genetics* / Q000276:immunology*; D001483:Base Sequence; D015153:Blotting, Western; D002461:Cell Line, Transformed; D015536:Down-Regulation / Q000235:genetics* / Q000276:immunology*; D014644:Genetic Variation / Q000276:immunology; D006681:HLA-D Antigens / Q000032:analysis / Q000096:biosynthesis* / Q000235:genetics*; D006684:HLA-DR Antigens / Q000032:analysis / Q000235:genetics; D006367:HeLa Cells; D000949:Histocompatibility Antigens Class II; D006801:Humans; D008969:Molecular Sequence Data; D009154:Mutation / Q000276:immunology; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide / Q000276:immunology*; D011401:Promoter Regions, Genetic / Q000276:immunology*; D012045:Regulatory Sequences, Nucleic Acid / Q000276:immunology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014158:Transcription, Genetic / Q000276:immunology
C416189:H2-M antigens; D006681:HLA-D Antigens; C084245:HLA-DM antigens; D006684:HLA-DR Antigens; D000949:Histocompatibility Antigens Class II; D016328:NF-kappa B