Specific overexpression of rheumatoid arthritis-associated HLA-DR alleles and presentation of low-affinity peptides

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.

Discordant expression of HLA class II-associated co-chaperones and HLA-DRB alleles in cultured fibroblast-like synoviocytes

“…Differential expression of HLA-DRB alleles has been reported in various cell types and diseases [32,33]. Particularly relevant is a report by Kerlan-Candon et al [20] that showed SE-bearing alleles (DRB1*04 and B1*01) were more highly expressed in B cells from RA patients than in those from healthy individuals. Although a similar trend was seen in this study, a larger number of samples would be required to determine differences in SE ϩ allele expression between RA and non-RA cFLS.…”

“…Differences in antigen-presenting capabilities of APC from RA patients have been reported, including reduced HLA-DM expression in B cells [19] and increased expression of RA-associated alleles [20]. Although some studies have examined the ability of HLA class IIpositive fibroblasts to activate T cells [21], little is known regarding the presence or function of various components of the class II pathway in cFLS.…”

Paeoniflorin inhibits function and down-regulates HLA-DR and CD80 expression of human peripheral blood monocytes stimulated by RhIL-1β

“…Indeed, HLA-DR can provide a first signal to the development of an effective immune response by the specific peptide-MHC antigen complex formation. In the context of RA, the elevated levels of HLA-DR4, DR1, and DR10 gene, which promote Th1 predominant advantage within RA immune imbalance, have previously been described for various cell types [41][42][43][44][45]. In addition to a first signal, the T and B lymphocytes require the other nonspecific signal, which is provided by the interaction between co-stimulatory molecules expressed on the membrane of APC and the lymphocytes, to become fully activated.…”

cDNA macroarray analysis of gene expression in synoviocytes stimulated with TNFα

“…The decreased and increased expression of ARPI and TNFAIP3, respectively, might be a feedback system suppressing further inflammation. HLA‐DRB1, a genotype known to be a risk factor of RA [29], was increased in RA [30]. Its expression might relate to autoantigen presentation.…”