Systemic lupus erythematosus (SLE) is characterized by a loss of immunologic tolerance to a multitude of self-antigens. Widespread innate and adaptive immune dysfunction includes interferon pathway dysregulation, high titer autoantibody production, and deficiencies in complement function and immune complex clearance. Inflammatory processes result in systemic end-organ damage. Despite decades of research, the underlying genetic basis of lupus is clearly complex and incompletely understood. Our laboratory identified TNFAIP3, a potent negative regulator of NF-KB signaling, as an SLE risk gene. In addition to SLE, genetic variants in the region of TNFAIP3 are associated with rheumatoid arthritis, psoriasis, Crohn's disease, celiac disease, type 1 diabetes, Sjogren's syndrome, systemic sclerosis and juvenile rheumatoid arthritis. Therefore, clarifying the mechanisms that regulate TNFAIP3 expression and function are likely to have broad impact in autoimmunity. By fine mapping in SLE cohorts of multiple ethnicities and deep sequencing of TNFAIP3 risk haplotypes, we isolated two functional variants (rs148314165, rs200820567) responsible for association with SLE in the region of TNFAIP3. Our preliminary data, confirm that rs148314165 and rs200820567 (referred to as the TT>A variants) reside in an enhancer element that binds NF-KB and SATB1 enabling the interaction of the enhancer with the TNFAIP3 promoter through long-range DNA looping. Impaired binding of NF-KB to the enhancer harboring the TT>A risk allele, inhibits interaction of the enhancer with the TNFAIP3 promoter resulting in reduced A20 expression. These results elucidate a novel functional mechanism by which rs148314165 and rs200820567 attenuate A20 expression and support a causal role for these variants in the predisposition to autoimmune disease. The primary scientific objective of this proposal will be to elucidate mechanisms of TNFAIP3 transcriptional control that influence autoimmune disease risk. Resources available to us through the ACE will support our efforts to define the dynamic chromatin state of the TT>A enhancer following stimulation or SLE flare using ChlP-sequencing, characterize the transcription factors and chromatin modifiers that assemble on the TT>A enhancer in the context of the SLE risk and non-risk alleles and explore the functional effect of a putative novel enhancer 55 kb upstream of the TNFAIP3 promoter. These studies will serve to clarify the functional mechanisms that regulate TNFAIP3 expression and lay the groundwork for developing of rational therapeutics aimed at restoring homeostatic potency of TNFAIP3 in autoimmune disease.
TNFAIP3 functions as a key negative regulator ofthe inflammatory signaling pathways governed by NF-KB. Genetic variants in TNFAIP3 are associated with SLE and many other autoimmune diseases and influence TNFAIP3 expression. The experiments proposed in this project will characterize the functional mechanisms that regulate TNFAIP3 expression in the context of SLE risk variants. These studies will provide key insights that may lead to novel therapies for autoimmune diseases.
|Morris, D L; Fernando, M M A; Taylor, K E et al. (2014) MHC associations with clinical and autoantibody manifestations in European SLE. Genes Immun 15:210-7|
|Rasmussen, Astrid; Ice, John A; Li, He et al. (2014) Comparison of the American-European Consensus Group Sjogren's syndrome classification criteria to newly proposed American College of Rheumatology criteria in a large, carefully characterised sicca cohort. Ann Rheum Dis 73:31-8|
|Ritterhouse, Lauren L; Lu, Rufei; Shah, Hemangi B et al. (2014) Vitamin d deficiency in a multiethnic healthy control cohort and altered immune response in vitamin D deficient European-American healthy controls. PLoS One 9:e94500|
|Young, K A; Terrell, D R; Guthridge, J M et al. (2014) Smoking is not associated with autoantibody production in systemic lupus erythematosus patients, unaffected first-degree relatives, nor healthy controls. Lupus 23:360-9|
|Guthridge, Joel M; Lu, Rufei; Sun, Harry et al. (2014) Two functional lupus-associated BLK promoter variants control cell-type- and developmental-stage-specific transcription. Am J Hum Genet 94:586-98|
|Munroe, Melissa E; Vista, Evan S; Guthridge, Joel M et al. (2014) Proinflammatory adaptive cytokine and shed tumor necrosis factor receptor levels are elevated preceding systemic lupus erythematosus disease flare. Arthritis Rheumatol 66:1888-99|
|James, Judith A (2014) Clinical perspectives on lupus genetics: advances and opportunities. Rheum Dis Clin North Am 40:413-32, vii|
|Kim-Howard, Xana; Sun, Celi; Molineros, Julio E et al. (2014) Allelic heterogeneity in NCF2 associated with systemic lupus erythematosus (SLE) susceptibility across four ethnic populations. Hum Mol Genet 23:1656-68|
|Sakurai, Daisuke; Zhao, Jian; Deng, Yun et al. (2013) Preferential binding to Elk-1 by SLE-associated IL10 risk allele upregulates IL10 expression. PLoS Genet 9:e1003870|
|Manku, Harinder; Langefeld, Carl D; Guerra, Sandra G et al. (2013) Trans-ancestral studies fine map the SLE-susceptibility locus TNFSF4. PLoS Genet 9:e1003554|
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