Renal involvement in lupus is characterized by unique DNA methylation changes in naïve CD4+ T cells

Abstract

Systemic lupus erythematosus is a multi-system disease characterized by wide-spread DNA methylation changes. To identify epigenetic susceptibility loci for lupus nephritis, genome-wide DNA methylation changes in naïve CD4+ T cells were compared between two sets of lupus patients with and without a history of renal involvement. A total of 56 lupus patients (28 with renal involvement and 28 without renal involvement), and 56 age-, sex-, and ethnicity-matched healthy controls were included in our study. We identified 191 CG sites and 121 genes that were only differentially methylated in lupus patients with but not without a history of renal involvement. The tyrosine kinase gene TNK2 involved in cell trafficking and tissue invasion, and the phosphatase gene DUSP5 which dephosphorylates and inhibits the ERK signaling pathway, were among the most hypomethylated. Independent of disease activity, renal involvement is characterized by more robust demethylation in interferon regulated genes differentially methylated in both sets of lupus patients with and without renal involvement (fold change 1.4, P = 0.0014). The type-I interferon master regulator gene IRF7 is only hypomethylated in lupus patients with renal involvement. IRF-7 is an upstream transcription factor that regulates several loci demethylated only with renal involvement such as CD80, HERC5, IFI44, IRF7, ISG15, ISG20, ITGAX, and PARP12 (P = 1.78 × 10−6). Among the CG sites only hypomethylated with renal involvement, CG10152449 in CHST12 has a sensitivity of 85.7% and a specificity of 64.3% for stratifying lupus patients for a history of renal involvement (P = 0.0029). Our data identified novel epigenetic susceptibility loci that are differentially methylated with renal involvement in lupus. These loci will help better understand lupus nephritis, and provide a proof of principle for the potential applicability of specific methylation changes as predictors for specific organ involvement in lupus.

Chronic Exposure to Water Pollutant Trichloroethylene Increased Epigenetic Drift in CD4 + T cells

“…, and CD40L [21][22][23][24]. The events that initiate these disease-related epigenetic alterations are not clear, but in some cases appear to involve a reduction in DNA methyltransferase activity [24].…”

Epipolymorphisms associated with the clinical outcome of autoimmune arthritis affect CD4+T cell activation pathways

“…Epigenetic mechanisms are believed to integrate environmental influences on gene expression, possibly affecting immune system dysregulation and autoimmune manifestations (3). In this regard, epigenetic variation has been associated with various rheumatic diseases, including adult rheumatoid arthritis (RA) (4,5), lupus (6,7), and JIA (8). In addition, Liu et al (9) identified two differentially methylated regions within the major histocompatibility complex (MHC) locus between RA patients and healthy controls, and suggested that a proportion of the risk conferred by the MHC region in RA is in fact mediated by altered DNA methylation.…”

Epigenetic Alterations in Cellular Immunity: New Insights into Autoimmune Diseases

“…[77, 78] The association between wide-ranged DNA hypomethylation in lupus and disease activity is on the basis of the study that applying DNA methylation inhibitors in CD4+ T cells would lead to a lupus-like syndrome. Recent studies applying sequence analysis technology have gained meaningful results that provide us with more information about lupus heritability [79], ethnicity variance [80] and renal involvement with DNA methylome analysis in CD4+ T cells [81]. Coit et al confirmed a group of interferon-related genes that are aberrantly hypomethylated, including IFN-induced protein 44-like (IFI44L), IFN-induced protein with tetratricopeptide (IFIT1), IFIT3, MX dynamin-like GTPase 1 (MX1), signal transducer and activator of transcription 1 (STAT-1), bone marrow stromal cell antigen 2 (BST2) and tripartite motif containing 22 (TRIM22), in lupus CD4+ T cells [82].…”