title: Cutting Edge: Chronic NF-κB Activation in CD4+ T Cells in Rheumatoid Arthritis Is Genetically Determined by HLA Risk Alleles.
abstract: 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.
authors.affiliation: Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232;
authors.forename: Charles F
authors.initials: CF
authors.lastname: Spurlock
authors.affiliation: Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232;
authors.forename: John T
authors.initials: JT
authors.lastname: Tossberg
authors.affiliation: Department of Medicine, Penn State Hershey Milton S. Hershey Medical Center, Hershey, PA 17033; and.
authors.forename: Nancy J
authors.initials: NJ
authors.lastname: Olsen
authors.affiliation: Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232; Department of Pathology, Microbiology, and Immunology, Vanderbilt University School of Medicine, Nashville, TN 37232 tom.aune@vanderbilt.edu.
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Aune
mesh_terms: D001172:Arthritis, Rheumatoid / Q000235:genetics* / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D004789:Enzyme Activation; D059811:HLA-DRB1 Chains / Q000235:genetics* / Q000276:immunology*; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism*; D050778:NFATC Transcription Factors / Q000037:antagonists & inhibitors / Q000378:metabolism; D011110:Polymorphism, Genetic; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D018808:Transcription Factor AP-1 / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D059811:HLA-DRB1 Chains; C527195:HLA-DRB1*04 antigen; D016328:NF-kappa B; D050778:NFATC Transcription Factors; D011948:Receptors, Antigen, T-Cell; D018808:Transcription Factor AP-1; D048031:JNK Mitogen-Activated Protein Kinases