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

Charles F Spurlock1, John T Tossberg1, Nancy J Olsen2

  • 1Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232;

Journal of Immunology (Baltimore, Md. : 1950)
|June 21, 2015
PubMed

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.

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