Differential expression of HLA class II genes associated with disease susceptibility and progression in rheumatoid arthritis

Abstract

Objective. Rheumatoid arthritis (RA)-associated HLA class II genes are assumed to promote susceptibility to and/or progression of the disease. Among the various modes of action proposed so far is the effect of the differential expression of HLA class II genes in different types of antigen-presenting cells on the Th1/ Th2 balance. The aim of this study was to investigate the differential expression of genes encoded within the RA-associated HLA-DR4 superhaplotype and within the neutral DR7 and DR9 superhaplotypes.Methods. The promoters encoded within these 3 haplotypes were first analyzed for sequence polymorphisms. To test for functional consequences, we assumed that the binding of nuclear factors to the promoter elements was correlated with the transcription activity, and we used surface plasmon resonance technology. To that end, oligonucleotides representing the polymorphic regulatory sequences and nuclear extracts from a monocyte cell line and a B cell line were used.Results. While the promoters of the highly polymorphic HLA-DRB1*04, *07, and *09 alleles showed comparable binding of nuclear factors, differential binding was observed for the 2 promoters that drive the relatively nonpolymorphic DRB4 alleles in linkage disequilibrium with DRB1. Interestingly, analysis of RA patients positive for DR4, DR7, and DR9 revealed the segregation of radiographic progression with the stronger of the 2 DRB4 promoters, independent of the DRB1 allele. Moreover, DRB1*04 alleles in RA patients showed a reduced association with the DRB4 splice variant, completely preventing DRB4 expression.Conclusion. Our findings represent the first evidence of a correlation between the differential expression of HLA class II genes and both the susceptibility and the progression of RA.

HLA–DRB4 as a genetic risk factor for Churg‐Strauss syndrome

“…A number of diseases are linked to these specificities, some of which also have clinical and pathogenetic features relevant to CSS. Among autoimmune conditions, RA is associated with HLA-DRB1*04 (35), and HLA-DRB7 has been found to correlate with the occurrence of anticardiolipin antibodies in systemic lupus erythematosus (36). Some vasculitides are also associated with such HLA alleles: giant cell arteritis is significantly associated with HLA-DRB1*04 (14).…”

Polymorphism in the bovine BOLA-DRB3 upstream regulatory regions detected through PCR-SSCP and DNA sequencing

“…Furthermore, this one-nucleotide difference might explain the high affinity interactions between the DRA promoter and the transcription factors RFX and NF-Y. Recently, Heldt et al (2003) demonstrated in human the functional consequences of variation close to the TATA box. Since the DNA -protein binding and functional analyses were not done in the present study, the functional role of detected polymorphisms in the promoter region in the regulation of the expression of BoLA-DRB3 gene is unknown.…”

The Role of HLA Promoters in Autoimmunity

“…The assays used over the recent years comprise reporter constructs and RT-PCR [28], plasmon resonance combined with gel shifts [51], and FACS analysis of peripheral blood cells from donors with a restricted set of haplotypes [52]. The picture emerging is still contradictory.…”