Drugs and autoimmunity – A contemporary review and mechanistic approach

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Abstract

Drug-induced autoimmunity is an idiosyncratic, non-IgE immune related drug reaction. Interestingly, although many drugs have been reported to induce autoantibodies, only a few have a definitive association with drug-induced autoimmune disease. The prototype disease is drug-induced lupus and the typical drug for drug-induced lupus is minocycline. The production of autoantibodies and the induction of symptoms in drug-induced lupus results from a variety of mechanisms, which can include suppression of central or peripheral tolerance, alteration of gene transcription in T and B cells, abnormal cytokine and/or cytokine receptor balance and function, chromatin structure modification and antigen modification. Multiple mechanisms may apply for different drugs, and understanding the pharmacological actions of these agents helps us decipher the etiology. For example, DNA hypomethylation may occur with hydralazine, which leads to increased transcription, increased LFA-1, the generation of autoreactive T cells and a breakdown in peripheral tolerance. Frequently, more than one pathway may be involved. Interestingly, most patients with newly formed autoantibodies resulting from drugs do not develop clinical disease. Nonetheless, the explosion in the use of biological modifiers has been associated with production of autoantibodies, an observation that illustrates the complex nature of these interactions, in that these agents are frequently used to treat autoimmunity, yet may produce autoimmune diseases themselves.

Introduction

Adverse effects of drugs constitute the primary cause of iatrogenic illness in the world, leading to significant morbidity and mortality. It is estimated that drug reactions may occur in anywhere from 5 to 15 percent of therapeutic courses of medication use and serious drug reactions account for about 100,000 deaths in the United States per year. Drug reactions can be classified into two broad categories, those that are predictable (sometimes referred to as type A, intrinsic, drug-dependent or pharmacologic) and those that are unpredictable (type B, idiosyncratic). Predictable drug reactions result from some pharmacologic action of the drug, which may or may not be for its intended use. These generally cause the same effect in the majority of people, and there is usually a well defined mechanism for the effect and a predictable dose response curve. An example of this is the sedative effect of first generation antihistamines. Idiosyncratic reactions, on the other hand, do not cause side effects in all patients, and even in those patients that experience side effects, they are often quite variable in nature. In these cases, the mechanism of action may be more complex, involving various drug effects or host factors, and frequently a combination of these factors. More specifically, genetic susceptibility, the patient's overall health and the co-existence of other disease states, interaction with other drugs, and other environmental exposures, such as sunlight, may all play a role in the development of idiosyncratic drug reactions. Many cellular and molecular pathways may be involved, and the reason for the unpredictable nature of these reactions is that our own knowledge of the mechanisms of action of each component leading to the drug reaction is incomplete.

Idiosyncratic adverse drug reactions can be further classified into immune related and non-immune related. Immune related adverse drug reactions can be divided into those that are IgE-mediated and those that are not. IgE-mediated reactions are allergic reactions, or hypersensitivity reactions mediated by a known physiologic pathway, and are relatively easy to understand. Drug-induced autoimmunity is a non-IgE immune related event that can involve the production of autoantibodies, and/or the presence of cell mediated reactions against self. The presence of autoantibodies does not always correlate with the existence of clinical symptoms or signs, and conversely, patients may have features of autoimmunity without detectable autoantibodies.

Section snippets

Drug-induced lupus

Over 100 autoimmune diseases affect approximately 5–10% of the world's population [1]. Systemic lupus erythematosus is one of the most common of these diseases. Drug-induced lupus (DIL) accounts for about 10% of all systemic lupus cases in the United States, with the incidence being about 15,000–30,000 cases per year [2]. Indeed, drug-induced lupus is the most common form of an iatrogenic induced autoimmune disease. Nearly 100 drugs have been associated with lupus, but those that have a well

Mechanisms of action

Large macromolecules like insulin can bind antibody and initiate an immune or allergic response on their own. But most drugs are small molecules, the majority being less than 1000 Da, and are by themselves, not immunogenic. On the other hand, these smaller molecules can bind to carrier proteins and become immunogenic, a process called haptenization. In allergic reactions to drugs, the target antigen is the drug or haptenized drug. However, the drug may instead elicit an immune response to self,

Abrogation of central tolerance by metabolites of procainamide

Procainamide induced lupus was first described in 1962. Since then, this has been the prototype drug for drug-induced autoimmunity. Procainamide treatment for cardiac arrhythmias in 52 patients, who had no previous evidence of lupus or connective tissue disease, was associated with the formation of anti-nuclear antibodies in 43/52 of these patients [6]. Autoantibodies to histones were present in 34/52 patients, with the most commonly detected target being the H2A.H2B dimer. There appeared to be

The effects of inhibition of DNA methylation on peripheral tolerance

Early studies pointed to a defect in DNA methylation as a possible mechanism of action for the mitigation of peripheral tolerance, although the cellular effects of DNA methylation were not completely clear at the time. We now know that DNA methylation is a mechanism for regulating gene expression. DNA methylation takes place at the cytosine residues in CpG dinucleotides, and involves the formation of 5-methylcytosines on the fifth carbon of the pyrimidinyl ring. In human DNA, most CpG

Cross-reactivity – possible mechanism of action of minocycline-induced autoimmunity

Minocycline is a semisynthetic tetracycline antibiotic also used in the treatment of acne vulgaris. The first report of minocycline-associated lupus appeared in 1992 [24]. Since then, multiple reports of minocycline-induced lupus have been reported, and minocycline has also been associated with autoimmune hepatitis [25]. A study of 60 minocycline-induced lupus patients and 24 minocycline-induced autoimmune hepatitis patients revealed that 13 of the patients studied had both conditions. In these

The role of macrophages in the development of autoimmunity – d-penicillamine

d-Penicillamine has been associated with lupus and a variety of other autoimmune diseases, including myasthenia gravis, pemphigus, pemphigoid, membranous glomerulonephritis, polymyositis and dermatomyositis. An animal model for d-penicillamine-induced autoimmunity developed in Brown Norway rats suggests that the activation of macrophages occurs via the interaction of penicillamine with an aldehyde groups on the macrophage [29]. The same aldehyde group on the macrophage is involved in reversible

Anti-TNF drugs and apoptosis

The recent development of immunomodulatory drugs used in the treatment of rheumatologic diseases and cancer has led to the observation that autoantibodies can develop in conjunction with the use of these drugs (Table 3) [32]. The most widely used immunomodulatory agents include the TNF inhibitors. Tumor-necrosis factor is a proinflammatory cytokine that is involved in systemic inflammation. Overproduction of TNFα leads to promotion of the inflammatory response that is seen in autoimmune

Mechanism of action of other biologics – effects of cytokine profile changes

Cytokine profiles and cytokine levels can also play a role in drug-induced autoimmunity. These effects can affect signaling pathways. A study on neonatal exposure in a Sjogren's mouse model (NFS/sld mice) to low-dose 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), which has been shown to influence immune responses, demonstrated the appearance of autoimmune lesions in the salivary glands and other organs [52]. An increase in the production of IL-2 and IFN-γ from splenic T cells was also observed.

Mechanism of action of other drugs associated with autoimmunity – isoniazid, chlorpromazine, methyldopa, quinidine – is there a common mechanism?

Quinidine has been implicated in the development of autoimmune polyarthropathies attributed to a drug-induced lupus syndrome [58]. Not all patients with polyarthropathy had autoantibodies. The lack of autoantibodies was associated with a milder form of the disease. Rechallenge with quinidine causes recurrence of the disease. Anti-histone IgG antibodies to H1, H2A.H2B complex, and H3.H4 complex were detected but not to the core histones. Antiphospholipid antibodies have also been detected in a

Statins and autoimmunity

3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, also known as statins, are used for primary and secondary prevention of atherosclerosis associated cardiovascular events. A recent 2007 review revealed 28 cases of statin related autoimmunity [64]. Ten cases were systemic lupus erythematosus, 3 were subacute cutaneous lupus erythematosus, and there were seven cases each of polymyositis and dermatomyositis. The remaining case was one of lichen planus pemphigoides. A proposed

Other agents and autoimmunity

Chlorpromazine induced lupus erythematosus has also been described. It has been found that chlorpromazine induces apoptosis in human lymphoblasts by stimulating proapoptotic signaling pathways [69]. This is in contrast to the mechanism proposed for TNFα induced autoimmunity, in which case a defect in apoptosis leads to the failure to eliminate autoreactive B and T cells, leading to a breakdown of central or peripheral tolerance. Further research on the death receptor, and the regulation of

Diagnosis and treatment of drug-induced autoimmunity

Until we understand better the mechanisms leading to disease, our treatment of drug-induced autoimmune disease is limited. Correct diagnosis is critical, part of which involves establishing a temporal relationship between the onset of drug use and disease. Unfortunately, this may not be possible because features of DIL may take up to several months to develop following exposure to the drug. Moreover, there does not seem to be any correlation between drug dosage and incidence or severity of the

Summary

The mechanism of action of drug-induced immunity is different for various classes of medications (4) (Table 4). In the end, the production of autoantibodies results from a loss of tolerance to self antigens. Signaling pathways in T and B cells, activation of macrophages, direct effects of metabolites of the drugs leading to the production of neoantigens, effects on cytokine profiles and cytokine levels, haptenization and the development of cross-reacting antigens can all play a role in the

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