Drug-induced lupus erythematosus pathophysiology
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Overview
- the exact pathophysiology of drug-induced lupus erythematosus is not fully understood.
- some genetic risk factors include HLA-DR4, HLA-DR0301, and complement C4 null allele.
Pathophysiology
- Three mechanisms are implicated in the causation of drug-induced lupus erythematosus:
- Slow acetylation with genetic deficiency of N-acetyltransferase. It is found that slow acetylators with genetic deficiency of N-acetyltransferase are at higher risk of DIL, especially from procainamide and hydralazine.
- Inhibition of DNA methylation of CD4+ T-cells. the demethylation of CD4+ T-cells makes them auto-reactive by over-expression of the LFA-1 adhesion molecule. These auto-reactive T-cells can then overstimulate autoantibody production by interaction with self class II MHC molecules on B-cells and induce apoptosis of macrophages by interacting with self class II MHC molecules on macrophages which release the highly antigenic apoptotic chromatin from the dying macrophages. This autoantibody production and release of antigenic macrophages chromatin is thought to contribute to the development of lupus-like autoimmunity.
- The metabolites of the offending drug are subjected to oxidative metabolism and serve as a substrate for myeloperoxidase; which is activated in polymorphonuclear neutrophils. This interaction results in the formation of reactive metabolites that directly affect lymphocyte function in the thymus making them auto-reactive. Virtually all lupus-inducing drugs undergo oxidative metabolism, whereas analogous non-lupus-inducing drugs do not. Also, both mouse and human studies implicate thymic activity in the pathophysiology of DILE.