Amr H. Sawalha,
Recent work from our lab includes genome-wide DNA methylation studies demonstrating that naïve CD4+ T cells in lupus are epigenetically poised for pathologic levels of type-1 interferon regulated gene expression. This work provided a mechanistic explanation for type-1 interferon hyper-responsiveness in autoimmunity. Our work in Behçet’s disease led to the identification of multiple independent genetic susceptibility loci in the HLA region, including a variant between MICA and HLA-B genes that explains the association previously attributed to HLA-B*51. Outside of the HLA, we discovered the genetic association with UBAC2 in Behçet’s disease, and provided strong evidence that reversible epigenetic modifications of cytoskeletal dynamics in monocytes and CD4+ T cells underlie the pathogenesis and therapeutic response in this disease. Our recent work in Takayasu arteritis identified five genetic susceptibility loci, both inside and outside of the HLA, including genes encoding for immune system molecules that are potential therapeutic targets, such as IL12B and FCGR2A. Future studies will also focus on functional characterization of these susceptibility loci to determine how they contribute to the pathogenesis of these complex immune-mediated diseases.
Jeffries M, Dozmorov M, Tang Y, Merrill JT, Wren JD, Sawalha AH. Genome-wide DNA methylation patterns in CD4+ T cells from patients with systemic lupus erythematosus. Epigenetics. 2011;6(5):593-601. (PMCID#3121972).
Koelsch KA, Webb R, Jeffries M, Dozmorov MG, Frank MB, Guthridge JM, James JA, Wren JD, Sawalha AH. Functional characterization of the MECP2/IRAK1 lupus risk haplotype in human T cells and a human MECP2 transgenic mouse. Journal of Autoimmunity. 2013 Feb 18. doi:pii: S0896-8411(13)00014-0. 10.1016/j.jaut.2012.12.012. [Epub ahead of print]
Hughes T, Coit P, Adler A, Yilmaz V, Aksu K, Düzgün N, Keser G, Cefle A, Yazici A, Ergen A, Alpsoy E, Salvarani C, Casali B, Kötter I, Gutierrez-Achury J, Wijmenga C, Direskeneli H, Saruhan-Direskeneli G, Sawalha AH. Identification of multiple independent susceptibility loci in the HLA region in Behçet's disease. Nature Genetics. 2013 Feb 10. doi: 10.1038/ng.2551. [Epub ahead of print]
Coit P, Jeffries M, Altorok N, Dozmorov MG, Koelsch KA, Wren JD, Merrill JT, McCune WJ, Sawalha AH. Genome-wide DNA methylation study suggests epigenetic accessibility and transcriptional poising of interferon-regulated genes in naïve CD4+ T cells from lupus patients. Journal of Autoimmunity. 2013 Apr 24. doi:pii: S0896-8411(13)00050-4. 10.1016/j.jaut.2013.04.003. [Epub ahead of print]
Sawalha AH. Overexpression of methyl-CpG-binding protein 2 and autoimmunity: Evidence from MECP2 duplication syndrome, lupus, MECP2 transgenic and Mecp2 deficient mice. Lupus. 2013;22(9):870-2.
Altorok N, Coit P, Hughes T, Koelsch KA, Stone DU, Rasmussen A, Radfar L, Scofield RH, Sivils KL, Farris AD, Sawalha AH. Genome-wide DNA methylation patterns in naïve CD4+ T cells from patients with primary Sjögren’s syndrome. Arthritis and Rheumatism. 2013 Nov 18. doi: 10.1002/art.38264. [Epub ahead of print]
Hughes T, Ture-Ozdemir F, Alibaz-Oner F, Coit P, Direskeneli H, Sawalha AH. Epigenome-wide scan identifies a treatment-responsive pattern of altered DNA methylation among cytoskeletal remodeling genes in monocytes and CD4+ T cells in Behçet’s disease. Arthritis and Rheumatology. 2014 Feb 19. doi: 10.1002/art.38409. [Epub ahead of print]