Rheumatoid Arthritis: Pinet V

Kerlan-Candon S, Louis-Plence P, Wiedemann A, Combe B, Clot J, Eliaou JF, Pinet V. · INSERM U475, Hĵpital Saint-Eloi, Centre Hospitalier Universitaire de Montpellier, France. · Arthritis Rheum. · Pubmed #11407687 links to  free full text

Abstract: OBJECTIVE: To compare levels of HLA-DR expression in rheumatoid arthritis (RA) patients and healthy controls for whom an ordered expression according to the DR alleles is demonstrated and to test the functional consequences of this expression on peptide presentation. METHODS: Using monoclonal antibodies that recognize different DRB1 alleles, DR molecules were quantitated at the surface of the peripheral blood B cells of 23 RA patients and 17 healthy subjects. The functional consequences of the level of DR surface expression was tested using a universal model of antigen presentation and mutated peptides with variable affinities for the T cell receptor. RESULTS: In healthy subjects, surface HLA-DR molecules were expressed at different levels according to allele (DR53, DR4, and DR11 less than DR1 less than DR7 less than DR15). In RA patients, this hierarchy was not conserved and, furthermore, the density of RA-associated DR4 and DR1 molecules was enhanced in patients compared with the basal density in healthy individuals. We demonstrated that an increased expression of DR molecules at the surface of antigen-presenting cells allowed a noteworthy presentation of low-affinity peptides that under normal conditions are not efficient in generating a T cell response at physiologic surface density of the DR molecules. CONCLUSION: Our results suggest that the specific overexpression of RA-associated HLA molecules could be responsible for the presentation of low-affinity autopeptides and therefore the activation of peripheral autoreactive T cells.

Kerlan-Candon S, Combe B, Vincent R, Clot J, Pinet V, Eliaou JF. · Laboratoire d'Immunologie, Centre Hospitalo-Universitaire de Montpellier and Fédération de Rhumatologie, Centre Hospitalo-Universitaire de Montpellier, Montpellier, France. · Clin Exp Immunol. · Pubmed #11359453 links to  free full text

Abstract: Susceptibility to rheumatoid arthritis (RA) is associated with defined HLA-DRB1 alleles. However the molecular basis of this association is not known. Peculiarities in the expression of disease-linked DRB1 alleles could be involved since in healthy controls HLA-DRB1 gene expression varies according to the alleles in B cells. Peripheral blood B cells of healthy controls and RA patients were examined for their level of allelic DRB1 transcripts using a competitive PCR approach. Levels of DRB1 transcripts were greatly modified in RA and influenced by HLA-DRB1 genotype: patients with double dose of RA-associated alleles displayed up-regulated amounts of DRB1 gene transcripts whereas patients carrying either a single or no at risk allele had low levels of DRB1 transcripts, compared to control individuals. These differential levels of DRB1 gene expression were not influenced in any way by clinical, biological or therapeutic features of the patients. Various amounts of DRB1 mRNA may be related to variations of the density of DR molecules on B cells and consequently could influence the response of CD4 T cells. This particular regulation of DRB1 gene expression in RA patients could therefore represent one of the molecular mechanisms involved in the association of HLA DRB1 genes to RA.

Louis-Plence P, Kerlan-Candon S, Morel J, Combe B, Clot J, Pinet V, Eliaou JF. · 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. · Pubmed #11046010 links to  free full text

Abstract: 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.