Epigenetically Altered T Cells Contribute to Lupus Flares

Abstract

Lupus flares when genetically predisposed people encounter exogenous agents such as infections and sun exposure and drugs such as procainamide and hydralazine, but the mechanisms by which these agents trigger the flares has been unclear. Current evidence indicates that procainamide and hydralazine, as well as inflammation caused by the environmental agents, can cause overexpression of genes normally silenced by DNA methylation in CD4⁺ T cells, converting them into autoreactive, proinflammatory cytotoxic cells that are sufficient to cause lupus in mice, and similar cells are found in patients with active lupus. More recent studies demonstrate that these cells comprise a distinct CD4⁺ T cell subset, making it a therapeutic target for the treatment of lupus flares. Transcriptional analyses of this subset reveal proteins uniquely expressed by this subset, which may serve as therapeutic to deplete these cells, treating lupus flares.

Keywords: DNA methylation; environment; epigenetics; lupus.

Figure 1

Splenocytes from SJL mice were stimulated with concanavalin A, treated as indicated, then injected into syngeneic recipients every two weeks for a total of seven injections. Anti-dsDNA antibodies were measured by enzyme-linked immunosorbent assays (ELISA) at the indicated weeks. The Y axis shows the optical density (OD) of the ELISA.

Figure 2

CD4⁺ T cells treated with 5-azaC, H₂O₂ or ONOO⁻ cause an immune complex glomerulonephritis. Kidneys from the mice shown in Figure 1 were removed for histologic analysis. Hematoxylin and eosin stained kidney sections from mice receiving untreated (A), 5-azaC treated (C), H₂O₂ treated (E) or ONOO⁻ treated (G) CD4⁺ T cells. Panels B, C, F and H show glomeruli from the same mice stgained for IgG deposition using immunoperoxidase staining.

Figure 3

Anti-dsDNA IgG Antibody Levels Decline in DOX-Treated Transgenic Mice Fed the MS Diet. Standard diet weeks 14–18 vs. MS diet weeks 20–26, p = 0.006 (linear regression); Standard diet vs. MR diet p = 0.368 (linear regression). MS vs. MR diet, week 26, p = 0.01.