Defective Fc gamma RIIb1 signaling contributes to enhanced calcium response in B cells from patients with systemic lupus erythematosus

B lymphocytes from patients with systemic lupus erythematosus (SLE) display enhanced B cell antigen receptor (BCR)-mediated early signal transduction events, including increased fluxes of intracytoplasmic calcium ([Ca2+](i)). Because crosslinking of Fc gamma RIIb1 (CD32) in normal B cells suppresses the BCR-initiated signal transduction process, we investigated whether the increased BCR-initiated [Ca2+](i) response in SLE B cells is the consequen ce of decreased Fc gamma RIIb1-mediated suppression. To this end, we used f low cytometry to study the [Ca2+](i) responses of indo-1-loaded negatively gated B cells stimulated with F(ab')(2) fragments or whole IgG anti-human m u Ab. We found that the ratio of F(ab')(2) to whole anti-mu Ab [Ca2+](i) re sponse was significantly lower in SLE B cells compared to B cells from pati ents with other systemic rheumatic diseases or normal individuals (P < 0.01 ). Because the surface expressions of Fc gamma RIIb1 and surface IgM were s imilar in B cells from SLE patients and disease and normal controls, these data indicate a decrease in Fc gamma RIIb-mediated suppression in SLE B cel ls. In addition, the whole IgG anti-mu Ab but not its F(ab'), fragment caus ed increased redistribution of SH2 domain-containing inositol 5'phosphatase in SLE compared to normal and disease control B cells. In conclusion, defi cient Fc gamma RIIb1-mediated suppression contributes to the augmented [Ca2 +]i responses of human SLE B cells.