Lupus is a poorly understood systemic autoimmune disease causing disability and sometimes death in those afflicted. Familial clustering and susceptibility loci indicate a genetic contribution, but incomplete concordance in identical twins and reports that drugs like procainamide and hydralazine cause a lupus- like disease suggest an environmental component as well. Work from the Richardson lab indicates that environmental agents may contribute to human lupus through effects on DNA methylation, an epigenetic mechanism determining chromatin structure. Procainamide and hydralazine inhibit T cell DNA methylation, resulting in changes in gene expression and cellular function that cause lupus in animal models, and all patients with active lupus have the same changes in their T cell DNA methylation, gene expression and cellular function. Studies performed over the past 5 years reveal that hydralazine treated and lupus T cells have impaired ERK pathway signaling, resulting in failure to upregulate the maintenance DNA methyltransferase Dnmt1 during mitosis. This results in failure to methylate newly synthesized DNA, altering chromatin structure and causing overexpression of genes that promote T cell autoreactivity. The autoreactive cells then kill macrophages and overstimulate B cells, inducing autoimmunity. More recent work suggests that oxidative damage to the signaling molecule PKC4 is responsible for the ERK pathway signaling defect in hydralazine treated and lupus T cells. Based on these observations, we hypothesize that oxidative stress alters chromatin structure and gene expression in T lymphocytes by modifying PKC4, resulting in decreased ERK pathway signaling, decreased Dnmt1 expression, and subsequent demethylation and overexpression of methylation sensitive T cell genes, resulting in lupus-like autoimmunity. This hypothesis will be tested by: 1. Characterizing the effects of oxidative stress on the structure and function of PKC4 and downstream effects on ERK pathway signaling, DNA methyltransferase expression, chromatin structure and gene expression, 2. Determining if decreased PKC4 signaling, due to oxidative damage, is sufficient to induce lupus-like autoimmunity, and 3. Determining if similar biochemical changes in PKC4 occur in T cells from patients with active lupus. These studies will establish the mechanism(s) causing PCK4 inactivation in lupus, and the role of PCK4 inactivation in lupus-like autoimmunity. Evidence that oxidative damage to PKC4 leads to lupus activation and lupus-like autoimmunity will provide a compelling rationale for studies directed at correcting or preventing PKC4 inactivation as a treatment for human lupus.

Public Health Relevance

Lupus is an autoimmune disease causing disability and sometimes death in people. The cause of lupus is unknown but important to understand, because knowledge of the mechanisms will indicate ways to fix the problems. Our group has found that a mechanism regulating gene expression, called DNA methylation, is defective in T lymphocytes. These cells regulate the immune response. Problems with DNA methylation cause overexpression of pathologic genes, changing normal T cells into cells which cause lupus. We have traced this problem to a regulatory molecule controlling DNA methylation, and found that this molecule doesn't work in lupus patients because it is damaged. The studies described in this application will figure out how and why it is damaged, and confirm that the damage causes autoimmunity. Understanding how this happens will suggest ways to fix the problem.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR042525-19
Application #
8513772
Study Section
Arthritis, Connective Tissue and Skin Study Section (ACTS)
Program Officer
Mancini, Marie
Project Start
1993-09-30
Project End
2014-07-31
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
19
Fiscal Year
2013
Total Cost
$309,860
Indirect Cost
$106,713
Name
University of Michigan Ann Arbor
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Li, YePeng; Gorelik, Gabriela; Strickland, Faith M et al. (2014) Oxidative stress, T cell DNA methylation, and lupus. Arthritis Rheumatol 66:1574-82
Richardson, Bruce C; Patel, Dipak R (2014) Epigenetics in 2013. DNA methylation and miRNA: key roles in systemic autoimmunity. Nat Rev Rheumatol 10:72-4
Somers, E C; Richardson, B C (2014) Environmental exposures, epigenetic changes and the risk of lupus. Lupus 23:568-76
Strickland, Faith M; Hewagama, Anura; Wu, Ailing et al. (2013) Diet influences expression of autoimmune-associated genes and disease severity by epigenetic mechanisms in a transgenic mouse model of lupus. Arthritis Rheum 65:1872-81
Hewagama, Anura; Gorelik, Gabriela; Patel, Dipak et al. (2013) Overexpression of X-linked genes in T cells from women with lupus. J Autoimmun 41:60-71
Strickland, Faith M; Hewagama, Anura; Lu, Qianjian et al. (2012) Environmental exposure, estrogen and two X chromosomes are required for disease development in an epigenetic model of lupus. J Autoimmun 38:J135-43
Gorelik, Gabriela J; Yarlagadda, Sushma; Patel, Dipak R et al. (2012) Protein kinase C? oxidation contributes to ERK inactivation in lupus T cells. Arthritis Rheum 64:2964-74
Hughes, Travis; Adler, Adam; Merrill, Joan T et al. (2012) Analysis of autosomal genes reveals gene-sex interactions and higher total genetic risk in men with systemic lupus erythematosus. Ann Rheum Dis 71:694-9
Hughes, Travis; Adler, Adam; Kelly, Jennifer A et al. (2012) Evidence for gene-gene epistatic interactions among susceptibility loci for systemic lupus erythematosus. Arthritis Rheum 64:485-92
Namjou, Bahram; Choi, Chan-Bum; Harley, Isaac T W et al. (2012) Evaluation of TRAF6 in a large multiancestral lupus cohort. Arthritis Rheum 64:1960-9

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