Antibody Feedback Regulation Of Humoral Immune Responses By Fc Receptors

Secreted antibodies inhibit continuing B cell activation by forming antigen-antibody complexes that simultaneously bind to antigen receptors and inhibitory Fcy receptors on antigen-specific B cells (Fig. 11-21). This is the explanation for a phenomenon called antibody feedback, which refers to the downregulation of antibody production by secreted IgG antibodies. IgG antibodies inhibit B cell activation by forming complexes with the antigen, and these complexes bind to a B cell receptor for the Fc portions of the IgG, called the Fcy receptor II (FcyRIIB, or CD32). (The biology of Fc receptors is discussed in Chapter 12.) As discussed in Chapter 7, the cytoplasmic tail of FcyRIIB contains a six-amino acid (isoleucine-x-tyrosine-x-x-leucine) motif shared by other receptors in the immune system that mediate negative signals, including inhibitory receptors on NK cells. By analogy to ITAMs, this inhibitory motif is called an immunoreceptor tyrosine-based inhibition motif (ITIM). When the Fcy receptor of B cells is engaged, the ITIM on the cytosolic tail of the receptor is phosphory-lated on tyrosine residues, and it forms a docking site for the inositol 5-phosphatase SHIP (SH2 domain-containing inositol phosphatase). The recruited SHIP hydrolyses a phosphate on the signaling lipid intermediate phosphatidylinositol trisphosphate (PIP3) and inactivates this molecule. By this mechanism, engagement of FcyRII terminates the B cell response to antigen. The antigen-antibody complexes simultaneously interact with the antigen receptor (through the antigen) and with FcyRIIB (through the antibody), and this brings the inhibitory phosphatases close to the antigen receptors whose signaling is blocked. In addition to B cells, FcyRIIB binds and sends inhibitory signals to myeloid cells, including macrophages and dendritic cells, and perhaps also plasma cells.

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. We have stated earlier in the chapter that antibodies can also amplify antibody production by activating complement and generating C3d. It is not clear under which circumstances secreted antibodies provide complement-mediated amplification or Fc receptor-mediated inhibition. A likely scenario is that early in humoral immune responses, IgM antibodies (which activate complement but do not bind to the Fcy receptor) are involved in amplification, whereas increasing production of IgG leads to feedback inhibition.

The importance of FcyRIIB-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 FcyRIIB gene has been linked to susceptibility to the autoimmune disease systemic lupus erythematosus in humans.

B cells express another inhibitory receptor called CD22. CD22 is a sialic acid-binding lectin; its natural ligand is not known, and we do not know exactly how it 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 phosphory-lated by the Src family kinase Lyn, bind the SH2 domain of the tyrosine phosphatase SHP-1. SHP-1 removes phosphates from the tyrosine residues of several enzymes and adaptor proteins involved in BCR signaling and thus

Protein antigen

Secreted antibody forms complex with antigen

Protein antigen

Antibody-

antigen complex

Antigen-antibody complex binds to B cell Ig and Fc receptor

Fc receptor-associated phosphatase, SHIP, converts PIP3 to PIP2 in B cell -receptor complex

Polyvalent i antigen ^^^

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