Regulatory role of C5a anaphylatoxin on the Fcγ Rs effector system in immune complex-induced diseases
© The Author(s) 2004
Published: 13 September 2004
Enhanced effector cell activation to deposited autoantibodies and immune complexes (IC) is a significant factor causing inflammatory responses in immunologic diseases like autoimmune hemolytic anemia, rheumatoid arthritis, lupus nephritis and Goodpasture's syndrome. Recent studies in animal models show that the development of such diseases is caused by the impairment of balance between activating/inhibitory Fc receptors (FcγRs). The ratio of the opposing FcγRs is critical in determining whether an antibody-dependent response will result. In the present study we aimed to investigate the role of C5a anaphylatoxin on the FcγR effector system in IC lung injury. We analysed the reverse passive arthus reaction in the lungs of mice lacking different FcγRs, or C5aR. The expression of FcγR mRNA/protein on alveolar macrophages (AM) effector cells was studied by TaqMan real-time PCR and FACS analysis. The contribution of AM to the IC alveolitis was investigated using the AM-depletion/AM-transfer technique. The autocrine synthesis of C5a by AM and the role of G-protein-dependent signalling was studied using in vitro stimulation of MH-S AM cells with IgG1 IC.
We have shown that C5a anaphylatoxin is produced in the lung of mice already 2 hours after IC deposition. Moreover, C5a:C5aR interaction exacerbates IC inflammation by altering the ratio of activating to inhibitory FcγR expression on AM, enhancing the former and suppressing the latter. Elimination of AM results in diminished IC alveolitis similar to that observed in FcγRIII-/- and C5aR-/- mice, as well as in AM-deficient mice with transplanted FcγRIII-/- or C5aR-/-AM. In vitro blockade of C5aR on MH-S cells using anti-C5aR antibodies, or pertussis toxin, confirms IgG IC-dependent generation of C5a by AM.
These data establish the critical link between complement and FcγRs in the initiation of IC lung injury. Moreover, AM effector cells provide cellular cross-talk of C5a and FcγR effector systems. In vitro studies suggest the central role of G-protein-dependent C5aR signalling in the control of FcγR activation of AM.
Supported by a grant from the DFG (GE892/8-1).