Effects of lupus‐inducing drugs on the B to Z transition of synthetic DNA

Thomas, Thresia; Messner, Ronald P.

doi:10.1002/art.1780290508

Cited by 41 publications

(28 citation statements)

References 34 publications

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“…In contrast to the poor immunogenicity of B-DNA, Z-DNA is immunogenic. PA can facilitate the conversion of B-DNA to Z-DNA (13) and, thus, may disrupt nuclear structure, with the potential for exposure of histones in an immunogenic form. In this study, 34 patients (65.4%) had IgM and/or IgG antibodies to total histones.…”

Section: Discussionmentioning

confidence: 99%

Serologic Evaluation of Patients Receiving Procainamide

Mongey

Donovan-Brand

Thomas

et al. 1992

Arthritis & Rheumatism

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This controlled study examined the characteristics of serologic abnormalities in 52 patients receiving procainamide for cardiac arrhythmias, who had no symptoms of a connective tissue disease. Antinuclear antibodies occurred in 43 patients (83%). Significant elevation of antibody binding to single-stranded DNA (mean f SEM 30 f 2.6%), double-stranded DNA (13 f l.l%), Z-DNA (optical density 0.54 f 0.06), and p l y A (7.2 2 0.6%) was seen (P < 0.001). Thirty-four patients (65.4%) had antibodies to total histones, most frequently, the J42A/2B dmer. IgG antibodies to H2A/2B correlated with the cumulative procainamide dose. One patient subsequently developed drug-related lupus. Procainamide (PA) is the agent most commonly implicated in drug-related lupus (DRL), with DRL occurring in 30% of patients positive for fluorescent antinuclear antibody (FANA) who take PA. Many of the features of DRL are nonspecific, thus making diagnosis difficult. Autoantibodies have been proposed to be of value in the diagnosis of DRL and, possibly, in the identification of people at risk for the development of DRL (1). Antinuclear and antihistone antibodies (AHA) have been reported to be highly sensitive for DRL (1,2). However, there is little information regarding the prevalence, and type of serologic abnormalities in patients without symptoms of a connective tissue disease. We report here the results of our serologic evaluation of 52 such patients receiving long-term therapy with procainamide. PATIENTS AND METHODSPatients. Fifty-two patients receiving PA who were attending the outpatient departments of the Veterans Administration (VA) or University of Cincinnati (UC) hospitals were included. There were 50 males (39 Caucasian and 11 black) and 2 females (1 black and 1 Caucasian). Their mean age was 65.8 years (range 47-82). The average daily dose of PA was 3.0 gm (range 0.75-5 gm), and the mean duration of therapy was 40 months (range 1 month to 8 years). Patients with evidence of systemic lupus erythematosus (SLE) at the time of study entry were excluded. Reevaluation of all patients was attempted to determine if evidence of lupus subsequently developed. DRL was diagnosed if patients developed musculoskeletal or pleuropericardial features which resolved upon discontinuation of PA. All 52 of these patients are part of a prospective study (3).Controls. Three groups of control subjects were assessed. One was a group of elderly subjects who were preselected based on age. These were 33 Caucasian individuals who were taking no medications; 28 were men and 5

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Section: Discussionmentioning

confidence: 99%

Serologic Evaluation of Patients Receiving Procainamide

Mongey

Donovan-Brand

Thomas

et al. 1992

Arthritis & Rheumatism

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“…5-azaC is incorporated into newly synthesized DNA, where it covalently binds the methyltransferase that methylates cytidine in the newly synthesized DNA strand when 5-methyldeoxycytidyldeoxyguanosine is recognized on the parent strand (18). Pca and Hyd bind DNA (19)(20)(21), and may interfere with the action of the methyltransferase, resulting in hypomethylation of the newly synthesized strand.…”

Section: Discussionmentioning

confidence: 99%

N‐acetylprocainamide is a less potent inducer of t cell autoreactivity than procainamide

Richardson

Cornacchia

Golbus

et al. 1988

Arthritis & Rheumatism

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We have reported that an inhibitor of DNA methylation, 5-azacytidine, makes cloned, antigenspecific CD4+ T cells autoreactive, and that procainamide and hydralazine mimic this effect. Those results suggested that procainamide and hydralazine may induce autoimmunity by inhibiting DNA methylation and causing T cell autoreactivity. We report now that Nacetylprocainamide, a procainamide derivative that does not induce lupus, is also a DNA methylation inhibitor, but it is 100 times less potent than procainamide in inducing T cell autoreactivity.DNA methylation inhibitors induce expression of genes normally suppressed by mechanisms associated with cytosine methylation (1) and, in certain systems, can change cellular phenotype and alter differentiation (2,3). We have previously reported that 5-azacytidine (5-azaC), a DNA methylation inhibitor, made 4 cloned antigen-reactive T cells respond to autologous class I1 major histocompatibility complex (MHC) determinants without specific antigen, presumably by inducing expression of suppressed genes (4). This response was termed autoreactivity.In those studies, we demonstrated that the 5- azaC-treated T cells responded to autologous but not allogeneic macrophages, and that monoclonal antibodies to class I1 but not class I MHC determinants would inhibit activation (4). Those results suggested the possibility that similar inhibition of T cell DNA methylation in vivo could lead to an autoimmune disease.To determine if inhibitors of DNA methylation could produce an autoimmune disease, we tested whether 2 drugs known to induce a lupus-like syndrome inhibit DNA methylation and induce T cell autoreactivity. We found that hydralazine (Hyd) and procainamide (Pca) mimicked the effects of 5-azaC on T cells by inducing T cell autoreactivity in these cloned lines and decreasing deoxymethylcytidine (d"C) content in T cell DNA, thus supporting the hypothesis that DNA methylation inhibitors may induce autoimmune disease (5).To further test this hypothesis, we compared Pca and Hyd with structural analogs, using the assays previously developed. N-acetylprocainamide (Napa) is a procainamide derivative that rarely induces lupus ( 6 4 , and hydralazine is a phthalazine (Phth) derivative containing a hydrazine side chain (l-hydrazinophthalazine) (9,lO). Previously, investigators speculated that the hydrazine side chain of hydralazine may be responsible for the lupus-like syndrome (9); therefore, we compared Pca with Napa and Hyd with Phth, for the ability to induce T cell autoreactivity and inhibit DNA methylation. MATERIALS AND METHODST cell cultures. CD4 + , cloned, tetanus toxoid (TTh reactive, interleukin-2 (IL-2tdependent T cell lines were generated and maintained as previously described (4,ll).

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“…Mercuric chloride can induce antifibrillarin antibodies in susceptible mouse strains (79), and mercury ions will bind fibrillarin, potentially altering its antigenicity (80). Hydralazine, procainamide, and to a lesser degree, isoniazid and D-penicillamine change the usual right-handed helical configuration of DNA (B DNA) to a more immunogenic left-handed helical configuration (Z DNA) in vitro (81). This conversion has been proposed as a mechanism contributing to the development of anti-DNA antibodies in druginduced lupus (81).…”

Section: Signaling Modifiersmentioning

confidence: 99%

“…Hydralazine, procainamide, and to a lesser degree, isoniazid and D-penicillamine change the usual right-handed helical configuration of DNA (B DNA) to a more immunogenic left-handed helical configuration (Z DNA) in vitro (81). This conversion has been proposed as a mechanism contributing to the development of anti-DNA antibodies in druginduced lupus (81). Others have shown that bioreactive metabolites of phenytoin can covalently bind and modify MHC molecules (82).…”

Section: Signaling Modifiersmentioning

confidence: 99%

Environmentally induced autoimmune diseases: potential mechanisms.

Rao

Richardson

1999

Environ Health Perspect

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Environmental and other xenobiotic agents can cause autoimmunity. Examples include drug-induced lupus, toxic oil syndrome, and contaminated l-tryptophan ingestion. Numerous mechanisms, based on (italic)in vitro(/italic) evidence and animal models, have been proposed to explain how xenobiotics induce or accelerate autoimmunity. The majority of these can be divided into three general categories. The first is those inhibiting the processes involved in establishing tolerance by deletion. Inhibiting deletion can result in the release of newly generated autoreactive cells into the periphery. The second mechanism is the modification of gene expression in the cells participating in the immune response, permitting lymphocytes to respond to signals normally insufficient to initiate a response or allowing the antigen-presenting cells to abnormally stimulate a response. Abnormal gene expression can thus disrupt tolerance maintained by suppression or anergy, permitting activation of autoreactive cells. The third is the modification of self-molecules such that they are recognized by the immune system as foreign. Examples illustrating these concepts are presented, and related mechanisms that have the potential to similarly affect the immune system are noted. Some mechanisms appear to be common to a variety of agents, and different mechanisms appear to produce similar diseases. However, evidence that any of these mechanisms are actually responsible for xenobiotic-induced human autoimmune disease is still largely lacking, and the potential for numerous and as yet unidentified mechanisms also exists.

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Effects of lupus‐inducing drugs on the B to Z transition of synthetic DNA

Cited by 41 publications

References 34 publications

Serologic Evaluation of Patients Receiving Procainamide

Serologic Evaluation of Patients Receiving Procainamide

N‐acetylprocainamide is a less potent inducer of t cell autoreactivity than procainamide

Environmentally induced autoimmune diseases: potential mechanisms.

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