Multiple autoimmune diseases including lupus (SLE), scleroderma (SSc), Sjogren's Syndrome (SS), rheumatoid arthritis (RA), autoimmune hepatitis (AH), and primary biliary cirrhosis (PBC) sometimes occur in the same person. The reason is unknown. All these diseases require multiple genetic susceptibility loci and an environmental contribution. Agents causing oxidative stress also associate with these diseases, but how this contributes to disease pathogenesis is unclear. T cells responding to host MHC molecules in chronic graft-vs-host disease (cGVHD) cause a similar disease spectrum. Why T cells responding to host MHC cause these diseases in cGVHD is unclear, but may be due to the host's genetic makeup. Inhibiting DNA methylation in CD4''T cells makes them responsive to self MHC molecules, similar to the response causing cGVHD, and mice receiving the modified cells develop anti-dsDNA antibodies, with or without autoimmune disease depending on the strain. Oxidative stress also causes DNA demethylation, and T cells treated with oxidizers cause autoimmunity in mice. We have now found that the genes overexpressed by experimentally demethylated CD4+ T cells are all co-expressed on a novel CD4+ CD28+ KIR+CD70 hiCD11a hi CD40L hi subset. The same subset is found in patients with active SLE, SSc, SS, and RA. We hypothesize that this MHCresponsive subset contributes to human autoimmune diseases that resemble cGVHD. Since oxidative stress induces this subset in vitro, we also hypothesize that oxidative stress causes its development in patients with these autoimmune diseases. We will test these hypotheses by: 1. Comparing the size of the demethylated CD4+ D28+ KIR+ subset in patients with active and inactive systemic autoimmune diseases (SLE, SS, SSc, RA and autoimmune liver disease) to age, sex and ethnicity-matched controls and patients with active infections, and 2. Determining the relationship of subset size to disease activity and biomarkers of oxidative stress in these subjects and controls. Future studies would determine the relationship of disease manifestations to genetic predisposition.

Public Health Relevance

Lupus, scleroderma, Sjogren's syndrome, and rheumatoid arthritis require multiple genetic susceptibility loci and an environmental agent like oxidative stress to develop and flare. The genes can overlap in the same person as well as between diseases, perhaps contributing to overlap syndromes. We found a T cell subset, caused by oxidative stress, in patients with active lupus, RA, SSc and SS. This project compares subset size and oxidative damage in patients with these diseases and overlap syndromes, providing insights into common mechanisms.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Program--Cooperative Agreements (U19)
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Special Emphasis Panel (ZAI1)
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University of Michigan Ann Arbor
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Gensterblum, Elizabeth; Renauer, Paul; Coit, Patrick et al. (2018) CD4+CD28+KIR+CD11ahi T cells correlate with disease activity and are characterized by a pro-inflammatory epigenetic and transcriptional profile in lupus patients. J Autoimmun 86:19-28
Ray, Donna; Strickland, Faith M; Richardson, Bruce C (2018) Oxidative stress and dietary micronutrient deficiencies contribute to overexpression of epigenetically regulated genes by lupus T cells. Clin Immunol 196:97-102
Richardson, Bruce (2018) The interaction between environmental triggers and epigenetics in autoimmunity. Clin Immunol 192:1-5
Weeding, Emma; Coit, Patrick; Yalavarthi, Srilakshmi et al. (2018) Genome-wide DNA methylation analysis in primary antiphospholipid syndrome neutrophils. Clin Immunol 196:110-116
Alperin, Jessie M; Ortiz-Fernández, Lourdes; Sawalha, Amr H (2018) Monogenic Lupus: A Developing Paradigm of Disease. Front Immunol 9:2496
Strickland, F M; Mau, T; O'Brien, M et al. (2017) Oxidative T Cell Modifications in Lupus and Sjogren's Syndrome. Lupus (Los Angel) 2:
Dozmorov, Mikhail G; Coit, Patrick; Maksimowicz-McKinnon, Kathleen et al. (2017) Age-associated DNA methylation changes in naive CD4+ T cells suggest an evolving autoimmune epigenotype in aging T cells. Epigenomics 9:429-445
Teruel, Maria; Sawalha, Amr H (2017) Epigenetic Variability in Systemic Lupus Erythematosus: What We Learned from Genome-Wide DNA Methylation Studies. Curr Rheumatol Rep 19:32
Tsou, Pei-Suen; Sawalha, Amr H (2017) Unfolding the pathogenesis of scleroderma through genomics and epigenomics. J Autoimmun 83:73-94
Tsou, Pei-Suen; Wren, Jonathan D; Amin, M Asif et al. (2016) Histone Deacetylase 5 Is Overexpressed in Scleroderma Endothelial Cells and Impairs Angiogenesis via Repression of Proangiogenic Factors. Arthritis Rheumatol 68:2975-2985

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