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
Ann Arbor
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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:
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
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
Tsou, Pei-Suen; Sawalha, Amr H (2017) Unfolding the pathogenesis of scleroderma through genomics and epigenomics. J Autoimmun 83:73-94
Namas, Rajaie; Renauer, Paul; Ognenovski, Mikhail et al. (2016) Histone H2AX phosphorylation as a measure of DNA double-strand breaks and a marker of environmental stress and disease activity in lupus. Lupus Sci Med 3:e000148
Figueroa-Romero, Claudia; Hur, Junguk; Lunn, J Simon et al. (2016) Expression of microRNAs in human post-mortem amyotrophic lateral sclerosis spinal cords provides insight into disease mechanisms. Mol Cell Neurosci 71:34-45
Patel, D; Gorelik, G; Richardson, B (2016) Protein Phosphatase 5 Contributes to the Overexpression of Epigenetically Regulated T-Lymphocyte Genes in Patients with Lupus. Lupus (Los Angel) 1:
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
Strickland, Faith M; Patel, Dipak; Khanna, Dinesh et al. (2016) Characterisation of an epigenetically altered CD4(+) CD28(+) Kir(+) T cell subset in autoimmune rheumatic diseases by multiparameter flow cytometry. Lupus Sci Med 3:e000147
Delaney, Colin; Garg, Sanjay K; Yung, Raymond (2015) Analysis of DNA Methylation by Pyrosequencing. Methods Mol Biol 1343:249-64