Determination of the molecular mechanisms influencing HLA-DRB gene expression would allow better understanding of the regulation of the immune response in normal as well as in pathological conditions. We started an extensive sequencing analysis of the proximal promoter regions of the DRB genes and observed a nucleotide polymorphism involving the classical regulatory regions of the DRB promoters. These nucleotide substitutions were observed to induce variations of the promoter activities as assessed by chloramphenicol acetyl transferase assays and the quantification of DRB transcripts. Similar analysis performed in patients with rheumatoid arthritis strongly suggests dysregulation of HLA-DRB gene expression.