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.
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.
|Strickland, Faith M; Li, YePeng; Johnson, Kent et al. (2015) CD4(+) T cells epigenetically modified by oxidative stress cause lupus-like autoimmunity in mice. J Autoimmun 62:75-80|
|Gorelik, Gabriela; Sawalha, Amr H; Patel, Dipak et al. (2015) T cell PKCÎ´ kinase inactivation induces lupus-like autoimmunity in mice. Clin Immunol 158:193-203|
|Li, YePeng; Gorelik, Gabriela; Strickland, Faith M et al. (2014) Oxidative stress, T cell DNA methylation, and lupus. Arthritis Rheumatol 66:1574-82|
|Somers, E C; Richardson, B C (2014) Environmental exposures, epigenetic changes and the risk of lupus. Lupus 23:568-76|
|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|
|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; 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|
|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|
|Sawalha, Amr H; Wang, Lu; Nadig, Ajay et al. (2012) Sex-specific differences in the relationship between genetic susceptibility, T cell DNA demethylation and lupus flare severity. J Autoimmun 38:J216-22|
|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|
Showing the most recent 10 out of 80 publications