Novel molecular targets for systemic lupus erythematosus

A review. For a long time the complement cascade has been believed to be the predominant pathway to inflammation and tissue destruction in autoimmune diseases such as systemic lupus erythematosus. Recently, new evidences show that FcRs may share the primacy with complement cascade, playing an equal or greater role in the disease process. The generation of specific mouse strains deficient in individual components has clarified the different role played by complement and Fe receptors in their interaction with ICs, illustrating that complement is essential for innate immunity against microbial pathogens, requiring natural antibodies to mediate its protective effects, whereas FcgRs have evolved as the principal system for coupling antigen-antibody complexes to effector cells and initiate the inflammatory cascade. Validation of FcRs as new therapeutic targets for autoimmune diseases, in particular for Systemic Lupus Erythematosus (SLE), has been provided by a large no. of studies where the biol. action of sol. forms of FcgRs or of monoclonal antibodies targeting Fc receptors has been assessed. Addnl. support to the role of FcRs in SLE has been provided by data obtained with compds. derived from combinatorial chem., such as TG19320, a tetrameric tripeptide which interferes with IgG/FcgR interaction in vitro and prevents glomerulonephritis in vivo in a SLE susceptible mouse strain. These findings might open the way to new therapeutic approaches for disorders where the role of FcRs has been established, including not only autoimmune diseases like systemic lupus erythematosus, rheumatoid arthritis, multiple myeloma, but also acquired immunodeficiency syndrome (AIDS).