Fc Receptor Structure and the Design of Antiinflammatories New Therapeutics for Autoimmune Disease

Geoffrey A. Pietersz, Maree S. Powell, Paul A. Ramsland and P. Mark Hogarth Austin Research Institute Austin and Repatriation Medical Center, Studley Road, Heidelberg, Victoria 3084,

Australia

Introduction - Inflammation caused by immune complexes in the blood vessels (vasculitis), the kidney (glomerulonephritis) and in the joints (arthritis) is a major cause of morbidity in autoimmune diseases. It is also one of the major mechanisms of tissue destruction in diseases including rheumatoid arthritis especially in the extra articular disease, immune thrombocytopenia (ITP), systemic lupus erythematosus (SLE) and Wegner's granulomatosis. Whilst clear that in autoimmune diseases the likely initiation of the autoimmune process is a corruption of T cell regulation, the tissue damage and the perpetuation of disease are due to immune complexes. In the last decade, the role of Fc receptors as major initiators of inflammation caused by immune complexes has become more precisely defined with the use of recombinant Fc receptor (FcR) and gene knock-out or transgenic mice (1-8).

Fc receptors are cell surface glycoproteins of inflammatory leukocytes and lymphocytes that specifically bind the Fc portion of immunoglobulins (1-8). The receptors have been identified for each of the immunoglobulin classes and the best characterised of these are the IgE receptor, FceRI, the IgA receptor, FcaRI and the IgG receptors, FcyRI, FcyRII, FcyRIII. For the most part, the binding of immunoglobulins to these receptors either as immune complexes or as monomeric Ig and its subsequent cross linking with antigen activates inflammatory cells leading in normal circumstances to the elimination of pathogens. However, this process in autoimmunity leads to powerful pathological inflammatory responses and severe tissue destruction.

VALIDATION OF FcyRlla AS A TARGET FOR ANTI-INFLAMMATORY

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