Secreted antibodies inhibit continuing B-cell activation by forming antigen-antibody complexes that simultaneously bind to antigen receptors and inhibitory Fcγ receptors on antigen-specific B cells (Fig. 1). This is the explanation for a phenomenon called antibody feedback, which refers to the downregulation of antibody production by secreted IgG anti bodies. IgG antibodies form complexes with the antigen, and these complexes bind to a B-cell receptor for the Fc portions of the IgG, called the Fcγ receptor II (FcγRIIB, or CD32). The cytoplasmic tail of FcγRIIB contains an immunoreceptor tyrosine-based inhibition motif (ITIM). When this Fcγ receptor is engaged, the ITIM on the cytosolic tail of the receptor is phosphorylated on tyrosine residues, and it forms a docking site for the inositol 5-phosphatase SHIP (SH2 domain–containing inositol phosphatase). The recruited SHIP removes a phosphate on the lipid signaling molecule phosphatidylinositol trisphosphate (PIP3) and thereby inactivates this molecule. By this mechanism, engagement of FcγRIIB terminates the B-cell response to the antigen. The antigen-antibody complexes simultaneously inter act with the antigen receptor (through the antigen) and with FcγRIIB (through the antibody), and this brings the inhibitory phosphatases close to the antigen receptors whose signaling is blocked.
Fig1. Regulation of B-cell activation by FcγRIIB. (A) Antigen-antibody complexes can simultaneously bind to membrane immunoglobulin (through antigen) and the FcγRIIB receptor through the Fc portion of the antibody. (B) As a consequence of this simultaneous ligation of receptors, phosphatases associated with the cytoplasmic tail of the FcγRIIB inhibit signaling by the B-cell antigen receptor (BCR) complex and block B-cell activation. Ig, Immunoglobulin; Th, T helper.
Fc receptor–mediated antibody feedback is a physiologic control mechanism in humoral immune responses because it is triggered by secreted antibody and blocks further antibody production. The importance of FcγRIIB-mediated inhibition is demonstrated by the uncontrolled antibody production seen in mice in which the gene encoding this receptor has been knocked out. A polymorphism in the FcγRIIB gene has been linked to susceptibility to the autoimmune disease systemic lupus erythematosus in humans.
B cells express another inhibitory receptor called CD22, which is a sialic acid–binding lectin; its natural ligand is not known, nor is it known exactly how CD22 is engaged during physiologic B-cell responses. However, knockout mice lacking CD22 show greatly enhanced B-cell activation. The cytoplasmic tail of this molecule contains ITIM tyrosine residues, which, when phosphorylated by the SRC family kinase LYN, bind the SH2 domain of the tyrosine phosphatase SHP1. SHP1 removes phosphates from the tyrosine residues of several enzymes and adaptor proteins involved in BCR signaling and thus abrogates B-cell activation. A mouse strain called moth eaten, which develops severe autoimmunity with uncontrolled B-cell activation and autoantibody production, has a naturally occurring mutation in SHP1. Conditional deletion of SHP1 as well as the engineered loss of Lyn in B cells leads to a breakdown of peripheral B-cell tolerance and the development of autoimmunity.
