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Drug-Induced Lupus

R.L. Rubin, A. Kretz-Rommel

Drug-induced lupus, a syndrome similar to the autoimmune disease systemic lupus erythematosus, can occur as a side effect of therapy with several dozen medications. For most of these medications, drug-induced lupus is a rare clinical phenomenon and can be cured simply by discontinuing use of the causative agent. Nevertheless, the capacity of a small foreign molecule to profoundly alter immune homeostasis to produce a disease remarkably similar to the well-described systemic lupus erythematosus suggests that understanding the mechanism that underlies drug-induced lupus could provide insight into regulation of the immune system. In particular, how the immune system discriminates self-antigens from foreign pathogens is still poorly understood, and drug-induced lupus may provide a window to this process.

We have shown that a common denominator that links lupus-inducing drugs is their capacity to undergo biotransformation by activated neutrophils. Procainamide, the most common lupus-inducing drug, is metabolized to procainamide-hydroxylamine (PAHA). PAHA cannot activate mature T cells or B cells or enhance antigen presentation, findings that suggest that the peripheral immune system is not the site of action for induction of autoimmunity. However, neutrophils are abundant and widely distributed, raising the possibility that labile, reactive drug metabolites could be formed within regions of the central immune system where tolerance to self is initially established.

We have developed a mouse model for PAHA-induced autoantibodies to (H2A-H2B)-DNA, the signature feature of patients with drug-induced lupus. In this model, young adult, normal mice are given intrathymic injections of PAHA. In mice given 2 intrathymic injections of PAHA 2 weeks apart, IgG antibodies to chromatin developed approximately 3 weeks after the second injection. T-cell reactivity to chromatin was also detected in the periphery and after a 2-day ex vivo exposure of thymuses to PAHA, indicating that appearance of autoreactive T cells was a consequence of the effect of PAHA during T-cell maturation in the thymus.

When chromatin-reactive T cells from PAHA-treated mice were adoptively transferred into naive mice, the resultant autoantibody profile of the recipients largely reproduced that of the PAHA-treated mice, but the requirement for large numbers of chromatin-reactive T cells suggests that normal mice have a mechanism for homeostatically controlling autoreactive T cells. However, in Fas-deficient C57BL/6-lpr/lpr mice, which are defective in activation-induced cell death, antibodies to chromatin developed after a single intrathymic injection of PAHA (Fig. 1). This finding suggests that the capacity of chromatin-reactive T cells to mediate autoimmunity is limited by programmed cell death of activated lymphocytes.

These and other data indicate that chromatin-reactive T cells produced by intrathymic PAHA provided helper activity for normally resident B cells, resulting in somatic mutation and class switching of immunoglobulin genes when the B cells are subjected to a heavy load, a second wave, or an unregulated source of autoreactive T cells.

It is generally assumed that potentially autoreactive T cells are normally deleted during T-cell development in the thymus. Therefore, we tested the capacity of PAHA to block deletion (negative selection) of high-affinity self-reactive T cells. PAHA had no effect on negative selection of V_ß8-specific T cells by Staphylococcus enterotoxin B or on negative selection of transgenic T cells specific for an epitope in pigeon cytochrome c.

We sought to determine the effect of PAHA on the intrinsic self-nonresponsiveness of pre-T cells after the cells had undergone positive selection by low-affinity interaction with self-antigen presented by the MHC. The presence of PAHA in reaggregate cultures of thymic stromal cells with CD4⁺CD8⁺ pre-T cells from normal mice or with transgenic T cells bearing the T-cell receptor for pigeon cytochrome c allowed the outgrowth of T cells that reacted with chromatin or with pigeon cytochrome c, respectively. These studies suggest that PAHA initiates autoimmunity by preventing the induction of nonresponsiveness to self during the positive selection of T cells on endogenous self-antigen.

PUBLICATIONS

Jiang, X., Wu, T.-H., Rubin, R.L. Bridging of neutrophils to target cells by opsonized zymosan enhances the cytotoxicity of neutrophil-produced H₂O₂. J. Immunol. 159:2468, 1997.

Kretz-Rommel, A., Rubin, R.L. Persistence of autoreactive T-cell drive is required to elicit antichromatin antibodies in a murine model of drug-induced lupus. J. Immunol., in press.

Rubin, R.L. Antihistone antibodies. In: Systemic Lupus Erythematosus, 3rd ed. Lahita, R.G. (Ed.). Academic Press, New York, in press.

Rubin, R.L. Environmentally induced systemic lupus. In: Rheumatic Diseases and the Environment. Kaufman, L.D., Varga, J. (Eds.). Chapman and Hall, New York, 1998, p. 91.