What hypotheses have been proposed for pathogenetic mechanisms causing Drug induced Lupus Erythematosus

What hypotheses have been proposed for pathogenetic mechanisms causing Drug induced Lupus Erythematosus?

• Genetic: slow acetylator status (see Question #16).

• Epigenetic: procainamide and hydralazine can decrease T-cell DNA methylation leading to overexpression of LFA-1 that induces autoreactivity.

• Adaptive immunity: drug-induced changes in T-cell signaling and function.

– Small molecule drugs can act as haptens or agonists for drug-specific T cells.

• Innate immunity: activated neutrophils

– Procainamide is oxidized by activated neutrophils resulting in production of the toxic metabolite, procainamide hydroxylamine, which can cause direct cytotoxicity. Several other drugs causing DILE can also undergo biotransformation similar to procainamide resulting in the generation of toxic metabolites.

– Activated neutrophils can release MPO and reactive oxygen species, which can cause direct cytotoxicity.

– Some drugs causing DILE can trigger neutrophil extracellular trap formation leading to nuclear autoantigen exposure that can stimulate autoreactive T and B cells.

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