Anti-malarial drugs: possible mechanisms of action in autoimmune disease and prospects for drug development.
A wide variety of mechanisms of anti-rheumatic action have been proposed for anti-malarial 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.
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Division of Rheumatology, Scripps Clinic and Research Foundation, La Jolla, CA 92037, USA.
D017951:Antigen Presentation / Q000187:drug effects; D000962:Antimalarials / Q000737:chemistry / Q000494:pharmacology*; D001324:Autoantigens / Q000378:metabolism; D001327:Autoimmune Diseases / Q000188:drug therapy* / Q000276:immunology; D002738:Chloroquine / Q000737:chemistry / Q000494:pharmacology; D015195:Drug Design; D000949:Histocompatibility Antigens Class II / Q000378:metabolism; D006801:Humans; D006863:Hydrogen-Ion Concentration; D006886:Hydroxychloroquine / Q000737:chemistry / Q000494:pharmacology; D010455:Peptides / Q000276:immunology / Q000378:metabolism; D012216:Rheumatic Diseases / Q000188:drug therapy / Q000276:immunology; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology
D000962:Antimalarials; D001324:Autoantigens; D000949:Histocompatibility Antigens Class II; D010455:Peptides; D006886:Hydroxychloroquine; D002738:Chloroquine