Hydralazine and procainamideinduced autoimmunity

Hydralazine and procainamide have been shown to interfere with central and peripheral mechanisms of tolerance and to lower the threshold of T-cell activation rendering them autoreactive [58, 59].

A metabolite of procainamide, injected into the thymus of (C57BL6 x DBA/2) F1 mice induces the emergence of autoreactive chromatin specific T-cells [58, 59]. In addition, procainamide impairs peripheral T-cell anergy [60].

Therapeutic concentrations of hydralazine and pro-cainamide inhibit methyl transferase activity [61, 62,

63]. Methylation of deoxycytosine residues of gene promoters takes place during cell ontogeny and silences genes through fixation of methylcytosin binding proteins and changes in chromatin structures (developed in [64]); this pattern is maintained through subsequent mitoses by methyltransferases. It was shown that antigen specific T-cell clones, incubated with inhibitors of these enzymes, overexpressed LFA-1 and became able to proliferate in the presence of autologous antigen presenting cells, even in the absence of the nominal antigen. Autoreactivity is probably the consequence of the increase in LFA-1 expression since antigen specific T-cells transfected with LFA-1 also became autoreactive [63]. The injection of T-cells rendered autoreactive by incubation with procainamide [65] or with hydralazine [66] or of T-cells transfected with LFA-1 [63] into a non-irradiated syngeneic normal recipient triggers an autoimmune disease [66]. This disease is marked by anti-DNA antibody production, proliferative glomerulone-phritis, pulmonary alveolitis, liver lesions resembling primary biliary cirrhosis, and histologic changes in the brain resembling central nervous system lupus [64].

Histone deacetylases are also important with respect to the accessibility of chromatin and gene expression; acetylation of histones is required for gene expression while deacetylation correlates with inhibition of transcription. Moreover, methylcytosine binding proteins associate with histone deacetylases directing the deacetylase activity to regions destined for inacti-vation [67]. This suggests a role for inhibitors of de-acetylases in targeting gene expression including IFN-Y and IL-4 [68], which could contribute to the development of autoimmunity.

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