Cutting Edge: Chronic NF-κB Activation in CD4+ T Cells in Rheumatoid Arthritis Is Genetically Determined by HLA Risk Alleles

• Published in: The Journal of immunology (1950) Vol. 195; no. 3; pp. 791 - 795
• Main Authors: Spurlock, Charles F, Tossberg, John T, Olsen, Nancy J, Aune, Thomas M
• Format: Journal Article
• Language: English
• Published: United States 01.08.2015
• Subjects: Arthritis, Rheumatoid - genetics; Arthritis, Rheumatoid - immunology; CD4-Positive T-Lymphocytes - immunology; Enzyme Activation; HLA-DRB1 Chains - genetics; HLA-DRB1 Chains - immunology; Humans; JNK Mitogen-Activated Protein Kinases - antagonists & inhibitors; JNK Mitogen-Activated Protein Kinases - metabolism; NF-kappa B - metabolism; NFATC Transcription Factors - antagonists & inhibitors; NFATC Transcription Factors - metabolism; Polymorphism, Genetic; Receptors, Antigen, T-Cell - immunology; Transcription Factor AP-1 - antagonists & inhibitors; Transcription Factor AP-1 - metabolism
• ISSN: 0022-1767; 1550-6606; 1550-6606
• DOI: 10.4049/jimmunol.1500267

Of identified genetic variants, HLA polymorphisms confer the greatest risk for developing autoimmune diseases, including rheumatoid arthritis (HLA-DRB1*04). There are strong influences of HLA polymorphisms on cell type–specific gene expression in B cells and monocytes. Their influence on gene expression in CD4+ T cells is not known. We determined transcript and proteins levels of target genes in lymphocyte/monocyte subsets in healthy controls and rheumatoid arthritis subjects as a function of HLA-DRB1*04 haplotype. We identified gene expression dependent on HLA-DRB1*04 genotype in CD4+ T cells. NF-κB activity in CD4+ T cells was also dependent on HLA-DRB1*04 genotype, and blocking HLA-DR inhibited NF-κB activity in CD4+ T cells and normalized gene expression, as did pharmacologic inhibition of NF-κB. We conclude that interactions between TCR and MHC class II encoded by HLA-DRB1*04 create a proinflammatory “hum” altering CD4+ T cell phenotype.