Drug-induced autoimmunity provides a fascinating glimpse of the environment’s contribution to the development of anti-self reactivity. After a period of treatment, certain drugs induce, in a subset of individuals, clinical signs that are typically found only in autoimmune disorders. The clinical features of drug-induced autoimmunity are a reminder that genetic predisposition to self reactivity usually needs a trigger from the environment in order to initiate a self-sustaining vicious circle. Notably, the cessation of drug therapy typically brings about the resolution of the autoimmune manifestations. Thus, studies of drug-induced autoimmunity provide an opportunity to learn not only about environmental triggers that lead to a loss of tolerance, but also about how a disruption of a specific stimulus may allow the immune system to return to a previous state of nonautoimmune homeostasis. Historically, hydralazine, a hypertension medication, was the first to be reported to induce systemic lupus erythematosus (SLE) in up to 24–50% of the patients taking it (1). This medication can also induce symptoms of vasculitis. Other medications, such as procainamide, chlorpromazine, penicillamine, and sulfasalazine, were observed to induce SLE and vasculitis. The discovery of drugs that induce autoimmunity prompted researchers to examine possible mechanisms. Various hypotheses have been proposed, including that the drug structure mimics the autoantigen, that the drug chemically modifies the autoantigen structure, that it inhibits DNA methylation thereby leading to perturbed T cell regulation, that it alters mechanisms of antigen presentation or lymphocyte activation, or that the drug is converted into chemically more reactive compounds in the body. However, thus far the testing of the proposed mechanisms has been difficult, and few conclusions have been put forth to explain how drugs induce autoreactivity (2). The article by Nakazawa et al in this issue of Arthritis & Rheumatism (3) presents a new twist on drug-mediated induction of autoimmunity. The authors examined the connection between propylthiouracil (PTU), a drug that is commonly prescribed for hyperthyroidism or Graves’ disease, and the subsequent development of a form of vasculitis that is associated with the production of autoantibodies to myeloperoxidase (MPO), an enzyme stored in neutrophil granules. The authors explored the role of neutrophil cell death in PTU-induced autoimmunity. It is of interest to view the findings of Nakazawa et al in the context of previous observations on the role of PTU in the induction of vasculitis and other autoimmune manifestations. PTU is a thionamide drug that, since 1947, has been prescribed to millions of patients with elevated levels of thyroid hormone. Graves’ disease is frequently caused by autoantibodies that bind the thyroidstimulating hormone receptor and lead to the overproduction of thyroid hormone. PTU blocks a key enzyme in the synthesis of T4 from its precursor thyroglobulin. The thyroid gland secretes T4 following its iodination on tyrosine by thyroid peroxidase (TPO). PTU inhibits oxidation of iodide by TPO and therefore effectively limits the production of thyroid hormone. TPO is structurally related to lactoperoxidase and MPO. The similarity between members of this family of proteins is so high that MPO can be used in enzyme studies as a stand-in for TPO (4), and structural similarity between MPO and TPO was exploited to express chimeric molecules and map antibody epitopes on TPO (5). In that light, it is perhaps not surprising that PTU also inhibits the enzymatic reactions of MPO (6). The side effects of PTU in patients with hyperthyroidism include the production of antibodies to MPO, Dr. Radic’s research related to this topic was supported by the Lupus Research Institute of New York. Marko Radic, PhD: University of Tennessee Health Science Center, Memphis; Mariana J. Kaplan, MD: University of Michigan Medical School, Ann Arbor. Address correspondence to Marko Radic, PhD, Department of Microbiology, Immunology and Biochemistry, University of Tennessee Health Science Center, 858 Madison Avenue, Suite 211, Memphis, TN 38163. E-mail: mradic@uthsc.edu. Submitted for publication June 18, 2012; accepted in revised form June 28, 2012.
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Dec 28, 2015
Gabriela P Diniz + 4
Open Access
