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.
|Munroe, Melissa E; Vista, Evan S; Merrill, Joan T et al. (2017) Pathways of impending disease flare in African-American systemic lupus erythematosus patients. J Autoimmun 78:70-78|
|Arriens, Cristina; Wren, Jonathan D; Munroe, Melissa E et al. (2017) Systemic lupus erythematosus biomarkers: the challenging quest. Rheumatology (Oxford) 56:i32-i45|
|Aberle, Teresa; Bourn, Rebecka L; Chen, Hua et al. (2017) Use of SLICC criteria in a large, diverse lupus registry enables SLE classification of a subset of ACR-designated subjects with incomplete lupus. Lupus Sci Med 4:e000176|
|Langefeld, Carl D; Ainsworth, Hannah C; Cunninghame Graham, Deborah S et al. (2017) Transancestral mapping and genetic load in systemic lupus erythematosus. Nat Commun 8:16021|
|Munroe, Melissa E; Young, Kendra A; Kamen, Diane L et al. (2017) Discerning Risk of Disease Transition in Relatives of Systemic Lupus Erythematosus Patients Utilizing Soluble Mediators and Clinical Features. Arthritis Rheumatol 69:630-642|
|Glauzy, Salomé; Boccitto, Marco; Bannock, Jason M et al. (2017) Accumulation of Antigen-Driven Lymphoproliferations in Complement Receptor 2/CD21-/low B Cells From Patients With Sjögren's Syndrome. Arthritis Rheumatol :|
|Jog, Neelakshi R; James, Judith A (2017) Biomarkers in connective tissue diseases. J Allergy Clin Immunol 140:1473-1483|
|Merrill, Joan T; Immermann, Fred; Whitley, Maryann et al. (2017) The Biomarkers of Lupus Disease Study: A Bold Approach May Mitigate Interference of Background Immunosuppressants in Clinical Trials. Arthritis Rheumatol 69:1257-1266|
|Young, Kendra A; Munroe, Melissa E; Guthridge, Joel M et al. (2017) Combined role of vitamin D status and CYP24A1 in the transition to systemic lupus erythematosus. Ann Rheum Dis 76:153-158|
|Sandhya, Pulukool; Kurien, Biji Theyilamannil; Danda, Debashish et al. (2017) Update on Pathogenesis of Sjogren's Syndrome. Curr Rheumatol Rev 13:5-22|
Showing the most recent 10 out of 116 publications