HLA-DRB1 gene transcripts in rheumatoid arthritis

Abstract

SUMMARYSusceptibility 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 RAassociated 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.

Skewed T-cell receptor BV14 and BV16 expression and shared CDR3 sequence and common sequence motifs in synovial T cells of rheumatoid arthritis

“…In this regard, it is important to note that this cohort of Chinese RA patients is preferentially associated with DRB1*0405 (43% patients), which is different from two other genotypes of DR4 (DRB1*0404 and DRB1*0401) closely linked with Caucasian RA patients. [3][4][5] Our study further revealed a trend toward correlation between the overexpression of BV16 but not BV14 in synovial T cells and DRB1*0405 in RA patients. However, the sample size was too small to allow meaningful statistical analysis.…”

“…In this cohort of Chinese RA patients, genotype DRB1*0405 represented the most dominant DR4 (16/37, 43%) compared to two other DR4 genotypes (DRB1*0401 (8%) and DRB1*0404 (3%)) that are typically associated with Caucasian RA patients. [3][4][5] In addition, DRB1*09012 (35%) and three DQB1 genotypes (0301, 0303 and 0401) were also frequently expressed in this cohort of RA patients (30-41%).…”

“…1,2 This is supported by marked infiltration and accumulation of Th1 proinflammatory cells in the synovial membrane of RA in close association with MHC Class II genes, including DR4 (genotypes DRB1*0404 and DRB1*0401) and DQ (DQB1*0302 and DQB1*0301), in Caucasian RA patients. [3][4][5] Further supporting evidence includes skewing of cytokine environment in favor of T cell-mediated inflammation and clonal expansion of infiltrating T cells in the affected joints. [6][7][8][9][10][11][12] However, the antigen specificity of the infiltrating T cells in rheumatoid synovium is unknown.…”

Regulation of major histocompatibility complex class II gene expression, genetic variation and disease

“…81 There was, however, consistency seen between the in vitro reporter assays and assayed transcript levels in vivo with higher transcript abundance in resting peripheral B cells with the DR52 haplogroup (HLA-DRB1*03, *11, *13 and *14) as compared with the DR53 haplogroup (HLA-DRB1*04, *01 and *09). 79,80 The evidence from H-2 genes in the mouse supports haplotype-specific differential gene expression with striking evidence of specific promoter variants, for example, in the X2 box, resulting in allele-specific expression. Remarkably, this was specific to particular cell types, in macrophages, for example, altering the subsequent T-cell cytokine response.…”

“…[71][72][73] Polymorphism altered gene expression in resting cells [71][72][73][74] but interestingly after cytokine activation, variation in the Y rather than the X1 box was significant. 75 For HLA-DRB1, low and high expressing alleles were defined based on reporter gene analysis using specific promoter constructs 72,73,[76][77][78] and assays of transcript abundance in immortalized B-cell lines or B cells from peripheral blood, 77,79,80 although analysis of nascent and steady-state messenger RNA using the latter did also indicate a role for post-transcriptional mechanisms in some of the differences observed. 81 There was, however, consistency seen between the in vitro reporter assays and assayed transcript levels in vivo with higher transcript abundance in resting peripheral B cells with the DR52 haplogroup (HLA-DRB1*03, *11, *13 and *14) as compared with the DR53 haplogroup (HLA-DRB1*04, *01 and *09).…”