Anti-malarial drugs: possible mechanisms of action in autoimmune disease and prospects for drug development

Abstract

A wide variety of mechanisms of anti-rheumatic action have been proposed for antimalarial agents. The molecular actions of chloroquine have been most thoroughly studied in vitro and in vivo, but it is likely that hydroxychloroquine works by a similar mechanism. Both agents are weak diprotic bases that can pass through the lipid cell membrane and preferentially concentrate in acidic cyto-plasmic vesicles. The resulting slight elevation of pH within these vesicles in macrophages or other antigen-presenting cells may influence the immune response to autoantigens. We hypothesize that anti-malarial agents influence the association of autoantigenic peptides with class II MHC molecules in the compartment for peptide loading and/or the subsequent processing and transport of the peptide-MHC complex to the cell membrane. This model of anti-malarial action provides a method to test additional drugs for their ability to modulate the immune response.