Lymphocyte function—associated antigen 1 overexpression and t cell autoreactivity

Abstract

Objective. To determine if DNA methylation inhibitors make T cells autoreactive by inducing lymphocyte function-associated antigen type 1 (LFA-1) ( C D l l d CD18) overexpression.Methods. T cell clones were treated with 3 distinct DNA methylation inhibitors or were stably transfected with a CD18 cDNA in a mammalian expression vector, and the effects on LFA-1 expression and activation requirements were examined.Results. LFA-1 overexpression, caused by DNA methylation inhibitors or by transfection, correlates with the development of autoreactivity.Conclusion. LFA-1 overexpression may contribute to T cell autoreactivity.

Clinical images: Epidural lipomatosis in a 14‐year‐old boy with systemic lupus erythematosus

“…This gene was selected because it is overexpressed following treatment with DNA methylation inhibitors (6-9), because LFA-1 overexpression causes T cell autoreactivity in vitro and a lupus-like disease in vivo (4,8), and because a similar LFA-1 overexpression occurs on an autoreactive T cell subset in lupus (9,10). It is likely that DNA hypomethylation affects other T cell genes in addition to ITGAL, and recent studies using oligonucleotide arrays have demonstrated that transcription of Ͼ100 known genes increases following treatment with 5-azaC, including genes of possible relevance to lupus, such as perforin and CD70 (Richardson B: unpublished observations).…”

“…Plasmid DNA was introduced into Jurkat cells by electroporation using a modification of previously described protocols (4,8). Twenty-four hours later, the cells were washed twice, suspended in 400 l reporter lysis buffer (Promega), and lysed by freeze-thaw.…”

“…The 2 drugs most frequently associated with lupus, procainamide and hydralazine, can cause a lupus-like disease through effects on T cell DNA methylation. Treating T cells with procainamide, hydralazine, or 5-azacytidine (5-azaC; the prototypic DNA methylation inhibitor) demethylates DNA, alters gene expression, and induces major histocompatibility complex-specific T cell autoreactivity (1)(2)(3)(4)(5). Adoptive transfer of the autoreactive cells causes a lupus-like disease in animal models (5)(6)(7).…”

“…Adoptive transfer of the autoreactive cells causes a lupus-like disease in animal models (5)(6)(7). The autoimmune effects of the methylation inhibitors are due, in part, to overexpression of lymphocyte functionassociated antigen 1 (LFA-1) (CD11a/CD18), because increasing T cell LFA-1 by transfection causes an identical autoreactivity in vitro, and a similar autoimmune disease in vivo (4,8).…”

Defective T-cell ERK signaling induces interferon-regulated gene expression and overexpression of methylation-sensitive genes similar to lupus patients

“…10 CD4+ T cells treated with DNA methylation inhibitors overexpress LFA-1 (CD11a/CD18) and become autoreactive, responding to self-class II MHC without the addition of exogenous antigen. 11 The autoreactivity is due to demethylation and overexpression of the ITGAL (CD11a) gene, 12,13 and T cells overexpressing LFA-1 by transfection display identical autoreactivity. 14 Hypomethylated, autoreactive CD4+ cells also spontaneously kill autologous macrophages (Mø), causing release of antigenic nucleosomes through mechanisms including demethylation and subsequent overexpression of the PRF1 (perforin) gene.…”