Key Words Fc receptor Systemic lupus erythematosus Single nucleotide polymorphism Genetics Dr. Robert P. Kimberly University of Alabama at Birmingham Birmingham, AL 35294-0006 E-mail: rpk@uab.edu 177 © 2002 Humana Press Inc. 0257–277X/02/ 26/1–3:177–189/$13.25 Diversity and Duplicity Human Fc γ Receptors in Host Defense and Autoimmunity Immunologic Research 2002;26/1–3:177–189 Robert P. Kimberly Jianming Wu Andrew W. Gibson Kaihong Su Hongwei Qin Xiaoli Li Jeffrey C. Edberg Division of Clinical Immunology and Rheumatology, Departments of Medicine and Microbiology, The University of Alabama at Birmingham Introduction Decreased function of receptors for IgG in patients with sys- temic lupus erythematosus (SLE) was identified more than 20 yr ago (1). The magnitude of dysfunction correlated with immune complex levels (2), varied with disease activity within individual patients and across patient cohorts (2–5), and was also found in patients with various types of immune complex disease (6,7). Insight into the molecular basis for these find- ings was accelerated by the subsequent cloning of the human receptors for IgG (Fcγ receptors). Eight distinct genes, grouped in three highly homologous families, yield at least 10 distinct protein products through alternative splicing (8–14). Together these observations have provided the foundation for under- standing the role of Ig receptors and their genetic variants in autoimmune diseases (Table 1). Despite the high degree of structural homology and func- tional overlap among these receptors, a fundamental question has been, does each receptor have a distinct biology? Support for the perspective of distinct biologies is most obvious in the comparison of FcγRIIa, which has an immunoreceptor tyro- sine-based activation motif (ITAM) in its cytoplasmic domain,