Prof. Dr. Falk Nimmerjahn
Understanding the role of the human inhibitory Fcγ receptor for autoreactive and protective humoral immune responses in vivo
Inbred mouse model systems have demonstrated that the inhibitory FcgRIIb is an important negative regulator of B cell activation. These studies have also demonstrated that the loss of self-tolerance and the development and severity of autoimmune pathology is modulated by the genetic background. To understand the function of human FcgRIIb on B cells in the context of a genetically outbred human immune system we developed a humanized mouse model in which the function of human FcgRIIb in maintaining humoral tolerance can be studied. Using this humanized mouse model system, we could demonstrate in the last funding period that humanized mice carrying an FcgRIIb allele (FcgRIIb-232T), which has an impaired inhibitory signalling function, are more prone to loosing humoral tolerance. Moreover, the targeted reduction of FcgRIIb expression resulted in the generation of more late B cell differentiation stages, suggesting that FcgRIIb controls memory B cell and plasma cell differentiation. Finally, our studies provide evidence for the first time that human FcgRIIb is a critical checkpoint controlling both protective and autoreactive humoral immune responses in the course of an infection with Borrelia burgdorferi. In the next funding period, we will focus on studying the interaction of FcgRIIb with other susceptibility genes leading to delayed removal of apoptotic cells and autoantigens in vivo. Moreover, we will investigate the feedback regulation of immune complexes on human B cell responses via FcgRIIb and FcRL5.
Fig. 1. Summary of the proposed functions of FcgRIIB throughout B cell development in mice. FcgRIIB expression can be found during early and late B cell development. Depending on the B cell stage, different outcomes of FcgRIIB crosslinking were identified. Whereas isolated triggering of FcgRIIB results in apoptosis of mouse pre-B cells, activated B cells, and plasma cells, an inhibition of proliferation is observed in pro-B cells and upon co-crosslinking of FcgRIIB with the B cell receptor on mature B cells.
Ludwig, R.J., Vanhoorelbeke, K., Leypoldt, F., Kaya, Z., Bieber, K., McLachlan, S.M., Komorowski, L., Luo, J., Cabral-Marques, O., Hammers, C.M., et al. (2017). Mechanisms of Autoantibody-Induced Pathology. Front Immunol 8, 603.
Schwab, I., Lux, A., and Nimmerjahn, F. (2015). Pathways Responsible for Human Autoantibody and Therapeutic Intravenous IgG Activity in Humanized Mice. Cell Rep 13, 610-620.
Seeling, M., and Nimmerjahn, F. (2015). Releasing the brakes: targeting FcgRIIB on B cells to enhance antibody-dependent lymphoma immunotherapy. Cancer Cell 27, 427-428.
Bruhl, H., Cihak, J., Talke, Y., Rodriguez Gomez, M., Hermann, F., Goebel, N., Renner, K., Plachy, J., Stangassinger, M., Aschermann, S., et al. (2015). B-cell inhibition by cross-linking CD79b is superior to B-cell depletion with anti-CD20 antibodies in treating murine collagen-induced arthritis. Eur J Immunol 45, 705-715.
Muller, J., Lunz, B., Schwab, I., Acs, A., Nimmerjahn, F., Daniel, C., and Nitschke, L. (2015). Siglec-G Deficiency Leads to Autoimmunity in Aging C57BL/6 Mice. J Immunol 195, 51-60.
Quast, I., Cueni, F., Nimmerjahn, F., Tackenberg, B., and Lunemann, J.D. (2015). Deregulated Fcg receptor expression in patients with CIDP. Neurol Neuroimmunol Neuroinflamm 2, e148.
Kao, D., Lux, A., Schwab, I., and Nimmerjahn, F. (2014). Targeting B cells and autoantibodies in the therapy of autoimmune diseases. Semin Immunopathol 36, 289-299.
Lux, A., and Nimmerjahn, F. (2013). Of mice and men: the need for humanized mouse models to study human IgG activity in vivo. J Clin Immunol 33 Suppl 1, S4-8.
Lux, A., Yu, X., Scanlan, C.N., and Nimmerjahn, F. (2013). Impact of immune complex size and glycosylation on IgG binding to human FcgRs. J Immunol 190, 4315-4323.
Lehmann, B., Schwab, I., Bohm, S., Lux, A., Biburger, M., and Nimmerjahn, F. (2012). FcgRIIB: a modulator of cell activation and humoral tolerance. Expert Rev Clin Immunol 8, 243-254.
Baerenwaldt, A., Lux, A., Danzer, H., Spriewald, B.M., Ullrich, E., Heidkamp, G., Dudziak, D., and Nimmerjahn, F. (2011). Fcg receptor IIB (FcgRIIB) maintains humoral tolerance in the human immune system in vivo. Proc Natl Acad Sci U S A 108, 18772-18777.