IgG1, IgG2a, complement and FcR in immune complex disease (90.16)

Abstract

Abstract Immune complexes (IC) contribute to tissue damage in some diseases but prevent it in others. We hypothesize that this contrast occurs because different immunoglobulin (Ig) isotypes involved in the IC interact differently with both stimulatory and inhibitory FcγR and complement (C). To study this we compared IgG1 (which poorly activates C and stimulatory FcγR) to other Ig isotype-mediated IC processing using a model in which wild-type (WT) mice immunized with goat anti-mouse IgD antiserum (GaMD), produce a large, predominantly IgG1 Ab response, produce large amounts of IC, and eliminate them without developing renal disease. In GaMD-immunized IgG1-deficient mice, IgG2a (which activates C and interacts with stimulatory FcγR) predominates and mice develop severe, lethal IC-mediated renal disease that can be prevented by immunization with antigen-specific IgG1. Renal disease also develops in C3-deficient, FcγRIIb-deficient and anti-FcγRII/III mAb treated WT but not in FcRγ-deficient mice immunized with GaMD. Surprisingly, GaMD-immunized IgG1-deficient mice that are also lacking both FcRγ and C3 or lacking FcRγ and treated with a C5aR antagonist still develop renal disease. Together these findings suggest that IgG1 may protect against IC disease through a C- and FcγRIIb-dependent mechanism, while non-IgG1, presumably IgG2a, may mediate IC injury through a FcRγ- and either C3 or C5aR-independent mechanism.