Mast cells: bad enemies or good friends? A study of the effects of IgG immune complexes on mast cell biology

Abstract: Mast cells are classically defined as bad enemies to human health due to their critical involvement in IgE-dependent allergy by virtue of the expression of the high affinity IgE receptor, FcgammaRI, on these cells. However, mouse mast cells also express FcgammaRIIB and FcgammaRIIIA, two receptors that bind IgG especially in the form of IgG immune complexes. In this project, we aimed to explore the responsiveness of mouse mast cells to stimulation by IgG immune complexes through these two Fcgamma receptors. FcgammaRIIB is an inhibitory Fc receptor which may dampen cellular activation through binding IgG immune complexes and co-crosslinking this receptor with activating receptors. FcgammaRIIB crosslinking to itself by IgG immune complexes mediates apoptosis of B-linage cells. Here, we demonstrated that such FcgammaRIIB-induced apoptosis also exists in mast cells. Bone marrow derived cultured mouse mast cells (BMMC) cultured for 6 weeks from the wild type, but not FcgammaRIIB-/- mice, were responsive to immune complex-mediated apoptosis. Interestingly, 3-week old BMMC resisted the induction of apoptosis by IgG immune complexes. BMMC expressed similar levels of FcgammaRIIB at 3 weeks and 6 weeks of culture, but higher levels of FcgammaRIIIA in the former than the latter. Importantly, 3-week old BMMC-deficient in FcgammaRIIIA responded to IgG immune complexes by executing apoptosis, confirming that FcgammaRIIIA can antagonize FcgammaRIIB-mediated apoptosis. This mechanism may be exploited to design new therapeutic approaches for treating allergic disorders by reducing the number of mast cells. Mast cell activaton through the activating Fc receptor, FcgammaRIIIA, can result in mast cell degranulation and cytokine production. Our research demonstrated that mast cell activation by IgG immune complexes facilitated the activity of mucosal adjuvant. We focused on CTA1-DD, which is a fusion protein composed of CTA1, the ADP-ribosylating part of cholera toxin, and DD, two immunoglobulin-binding domains derived from S. aureus protein A. CTA1-DD complexed with IgG could activate mast cells by degranulation and production of tumor necrosis factor-alpha. Furthermore, intranasal immunization with antigen admixed to CTA1-DD/IgG complexes produced an increased humoral immune response measured as serum antigen-specific antibodies and higher numbers of bone marrow antigen-specific plasma cells. CTA1-DD/IgG complex-mediated immune enhancement is suppressed in mast cell-deficient mice indicating the critical role of mast cells in the responses. In conclusion, our data suggest that the CTA1-DD/IgG complexes have the capacity to activate mast cells and that this augmenting effect through mast cell activation could be further exploited for improving the efficacy of mucosal vaccines.