Humoral Pathogenesis

It is widely appreciated that autoimmunity and end-organ damage, which are essential elements of systemic lupus erythematosus (SLE), are regulated by Fcγ receptors (FcγRs). FcγR polymorphisms, together with other genetic and environmental factors, dictate susceptibility to disease by altering the humoral response to lupus autoantigens, as well as by modifying the inflammatory response responsible for end-organ damage. Inhibitory FcγRIIB inhibits B-cell reactivity to autoantigens. On the other hand, a balance of inhibitory and activating FcγRs on leukocyte subsets, such as macrophages, promotes immune complex clearance; on neutrophils, monocytes, and macrophages set the threshold for activation of cellular effector responses that potentially have deleterious effects on host tissue. In this chapter, the structural and functional features of individual FcγR family members are outlined. The role of FcγRs in the initiation of autoantibody production, immune complex clearance, and SLE manifestations (e.g., nephritis) are discussed primarily in the context of murine models of disease as mice with genetically engineered modification of FcγRs expression have served as important tools in this area. Finally, the association of FcγR polymorphisms with susceptibility to SLE in humans, and current drug therapeutics that may target FcγR functions and thus potentially attenuate manifestations of SLE, such as lupus nephritis, are also reviewed.