Prof. Dr. Falk Nimmerjahn

Lehrstuhl Genetik
Department Biologie
Friedrich-Alexander-Universität Erlangen-Nürnberg
Erwin-Rommelstr. 3
91058 Erlangen   

Tel. +49 (0) 9131 85 25050
falk.nimmerjahn@fau.de

Project summary:

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. 

Summary of the proposed functions of FcγRIIB throughout B cell development in mice.

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.

Publications P 13:

Kara, S., Amon, L., Luhr, J.J., Nimmerjahn, F., Dudziak, D., and Lux, A. (2020). Impact of Plasma Membrane Domains on IgG Fc Receptor Function. Front. Immunol. 11, 1320.

Danzer, H., Glaesner, J., Baerenwaldt, A., Reitinger, C., Lux, A., Heger, L., Dudziak, D., Harrer, T., Gessner, A., and Nimmerjahn, F. (2020). Human Fcgamma-receptor IIb modulates pathogen-specific versus self-reactive antibody responses in lyme arthritis. Elife 9.

Zaytseva, O.O., Seeling, M., Kristic, J., Lauc, G., Pezer, M., and Nimmerjahn, F. (2020). Fc-Linked IgG N-Glycosylation in FcgammaR Knock-Out Mice. Front. Cell Dev. Biol. 8, 67.

Nimmerjahn, F. (2020). Keeping T-he Killers at Bay via FcgammaRIIb. Immunity 52, 9-11.

Schaffert, A., Hanic, M., Novokmet, M., Zaytseva, O., Kristic, J., Lux, A., Nitschke, L., Peipp, M., Pezer, M., Hennig, R., Rapp, E., Lauc, G., and Nimmerjahn, F. (2019). Minimal B Cell Extrinsic IgG Glycan Modifications of Pro- and Anti-Inflammatory IgG Preparations in vivo. Front. Immunol. 10, 3024.

Kovacs, B., Tillmann, J., Freund, L.C., Nimmerjahn, F., Sadik, C.D., Bieber, K., Ludwig, R.J., Karsten, C.M., and Kohl, J. (2019). Fcgamma Receptor IIB Controls Skin Inflammation in an Active Model of Epidermolysis Bullosa Acquisita. Front. Immunol. 10, 3012.

Grotsch, B., Lux, A., Rombouts, Y., Hoffmann, A.C., Andreev, D., Nimmerjahn, F., Xiang, W., Scherer, H.U., Schett, G., and Bozec, A. (2019). Fra1 Controls Rheumatoid Factor Autoantibody Production by Bone Marrow Plasma Cells and the Development of Autoimmune Bone Loss. J. Bone Miner. Res. 34, 1352-1365.

Pfeifle, R., Rothe, T., Ipseiz, N., Scherer, H.U., Culemann, S., Harre, U., Ackermann, J.A., Seefried, M., Kleyer, A., Uderhardt, S., Haugg, B., Hueber, A.J., Daum, P., Heidkamp, G.F., Ge, C., Bohm, S., Lux, A., Schuh, W., Magorivska, I., Nandakumar, K.S., Lonnblom, E., Becker, C., Dudziak, D., Wuhrer, M., Rombouts, Y., Koeleman, C.A., Toes, R., Winkler, T.H., Holmdahl, R., Herrmann, M., Bluml, S., Nimmerjahn, F., Schett, G., and Kronke, G. (2017). Regulation of autoantibody activity by the IL-23-TH17 axis determines the onset of autoimmune disease. Nat. Immunol. 18, 104-113.

Kao, D., Lux, A., Schaffert, A., Lang, R., Altmann, F., and Nimmerjahn, F. (2017). IgG subclass and vaccination stimulus determine changes in antigen specific antibody glycosylation in mice. Eur. J. Immunol. 47, 2070-2079.

Müller, 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.