Overexpression of X-Linked genes in T cells from women with lupus

Abstract

Women develop lupus more frequently than men and the reason remains incompletely understood. Evidence that men with Klinefelter’s Syndrome (XXY) develop lupus at approximately the same rate as women suggests that a second X chromosome contributes. However, since the second X is normally inactivated, how it predisposes to lupus is unclear. DNA methylation contributes to the silencing of one X chromosome in women, and CD4+ T cell DNA demethylation contributes to the development of lupus-like autoimmunity. This suggests that demethylation of genes on the inactive X may predispose women to lupus, and this hypothesis is supported by a report that CD40LG, an immune gene encoded on the X chromosome, demethylates and is overexpressed in T cells from women but not men with lupus. Overexpression of other immune genes on the inactive X may also predispose women to this disease. We therefore compared mRNA and miRNA expression profiles in experimentally demethylated T cells from women and men as well as in T cells from women and men with lupus. T cells from healthy men and women were treated with the DNA methyltransferase inhibitor 5-azacytidine, then X-linked mRNAs were surveyed with oligonucleotide arrays, and X-linked miRNA’s surveyed with PCR arrays. CD40LG, CXCR3, OGT, miR-98, let-7f-2*, miR 188-3p, miR-421 and miR-503 were among the genes overexpressed in women relative to men. MiRNA target prediction analyses identified CBL, which downregulates T cell receptor signaling and is decreased in lupus T cells, as a gene targeted by miR-188-3p and miR-98. Transfection with miR-98 and miR-188-3p suppressed CBL expression. The same mRNA and miRNA transcripts were also demethylated and overexpressed in CD4+ T cells from women relative to men with active lupus. Together these results further support a role for X chromosome demethylation in the female predisposition to lupus.

Sexual dimorphism in autoimmunity

“…The X chromosome encodes many immune-associated genes, including CD40L, CXCR3, OGT, FOXP3, TLR7, TLR8, IL2RG, BTK, and IL9R (79). Overexpression and/or hypomethylation of CD40L, CXCR3, and OGT have been reported in female but not male patients with SLE (77,78).…”

“…As such, males with the XXY karyotype have a risk of developing SLE that is similar to that of the general female population. In addition, several reports suggest that expression of genes from the partially inactive X chromosome can play a role in autoimmunity (77,78). Thus, Turner and Klinefelter syndromes indicate that aberrations in the content of X chromosomes in the host do affect autoimmune disease, although the one-to-one linkage between numbers of X and Y chromosomes and particular diseases is still unclear.…”

Sexual dimorphism in cancer

“…In one study of an autoimmune disease, Systemic lupus erythematosus (SLE), several X-linked miRNAs were found overexpressed in T cells of female versus male patients 72 . Several of the differentially expressed miRNAs are located within 5000bp of an estrogen response element and, among the predicted targets, was CBL, a negative regulator of T cell receptor activity, which is down-regulated in T cells of the SLE patients 72 .…”

Immunopathogenesis of systemic lupus erythematosus and rheumatoid arthritis: the role of aberrant expression of non-coding RNAs in T cells

“…By comparing the mRNA and miRNA expression profiles in experimentally demethylated T cells from women and men as well as in T cells from women and men with lupus, Hewagama et al identified that miR-98, let-7f-2*, miR-188-3p, miR-421 and miR-503 were overexpressed in women relative to men. They also reported that Casitas B-lineage lymphoma (CBL) protein, an E3 ubiquitin-protein ligase, was targeted by miR-98 and miR-188-3p [33]. Their findings supported that CBL downregulation in T cells could alter T cell receptor signalling pathways and thus potentially contribute to lupus pathogenesis.…”