Louis-Plence P, Kerlan-Candon S, Morel J, Combe B, Clot J, Pinet V, Eliaou J F
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.
J Immunol. 2000 Nov 1;165(9):4861-9. doi: 10.4049/jimmunol.165.9.4861.
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.
HLA-DM分子是一种类II型异二聚体，是HLA II类依赖性抗原呈递的关键因素。它作为分子伴侣发挥作用，还作为肽编辑器，有利于高稳定性肽的呈递。因此，它似乎会使呈递给T细胞的肽库发生偏差。HLA-DM表达的变化对抗原呈递有相当大的影响，这些基因的调控可能是预防自身免疫的先决条件。在本研究中，类风湿性关节炎（RA）被选作人类自身免疫性疾病的模型，因为已知其遗传易感性与HLA-DR和-DM成分相关。我们描述了HLA-DM启动子中有限的核苷酸多态性，体外评估显示其对基础转录活性和IFN-γ诱导具有功能影响。然而，在对照组和RA患者之间未发现等位基因频率的差异。尽管缺乏这种关联，我们也对HLA-DM分子的表达进行了研究。有趣的是，与对照组或炎性关节炎患者相比，RA患者外周血B细胞中HLA-DM转录本和蛋白表达不足。这种表达不足不影响HLA-DR基因，且导致RA患者中DM:DR比值降低。这种特异性的HLA-DM下调可能对抗原呈递产生重要影响，并可能参与RA的自身免疫过程。
