Prof. Dr. Hermann Eibel

Centrum für Chronische Immundefizienz
Universitätsklinikum Freiburg
Breisacher Straße 115 
79106 Freiburg                      

Tel. +49 (0) 761 270 77752
hermann.eibel@uniklinik-freiburg.de   

Project summary:

BAFF-Receptor function in B cell survival and immune responses

BAFF-receptor (BAFFR), a member of the TNF-receptor family, is an essential B cell survival receptor that binds the TNF-like ligand BAFF (Pieper et al. 2013). The levels of circulating BAFF are regulated by the number of circulating B cells as high levels are found in immunodeficient patients with low B cell numbers (Kreuzaler et al. 2012) High BAFF concentrations promote autoimmunity and the treatment of patients suffering from systemic lupus erythematodes with neutralizing anti-BAFF antibodies improves clinical symptoms. Deletion of the BAFF-R gene in humans and mice arrested B cell maturation at the immature B cell stage. Humans with BAFF-R deficiency have very few B cells, extremely low serum IgM and IgG titers and fail to mount protective immune responses (Warnatz et al. 2009). Within the human population, there exist several SNP-encoded missense mutations in BAFF-R gene. The substitution of the proline residue at position 21 with arginine (P21R) disturbs ligand-independent BAFFR multimerization, reduces BAFF-binding to B cells, impairs downstream signalling and inhibits the differentiation of marginal zone B cells into plasma cells producing antibodies against pneumococcal cell wall antigens (Pieper et al. 2014). Binding of BAFF to BAFFR activates the non-canonical NF-kB pathway and induces a variety of pro-survival functions (Willmann et al. 2014). However, in TACI-expressing marginal zone B cells and switched-memory B cells BAFF binding to BAFFR also induces processing of BAFFR by the metalloproteases ADAM10 and ADAM17. This shedding of BAFFR limits BAFFR-dependent survival of activated B cells and of B cells in the dark zone of germinal centers.

In our project, we try to understand the role of BAFFR function for human B cells. To this end, we investigate the differences in BAFFR signaling between human naive, marginal zone and switched memory B cells. The signals regulating BAFFR processing by ADAM10 and ADAM17 are analyzed in primary human B cells and in various human B cell lines which were genetically engineered by CRISPR/Cas9 mutagenesis. In a proteomic approach, we study the interactions between BAFFR and other proteins before and after ligand binding. We hope that our approach will help to understand how BAFF and BAFFR regulate human B cell survival, humoral immune responses and autoimmunity.

BAFF-Receptor function in B cell survival and immune responses
Publications P 06:

Ntellas, P., Dardiotis, E., Sevdali, E., Siokas, V., Aloizou, A.M., Tsinti, G., Germenis, A.E., Hadjigeorgiou, G.M., Eibel, H., and Speletas, M. (2020). TNFRSF13C/BAFFR P21R and H159Y polymorphisms in multiple sclerosis. Mult. Scler. Relat. Disord. 37, 101422.

Sevdali, E., Katsantoni, E., Smulski, C.R., Moschovi, M., Palassopoulou, M., Kolokotsa, E.N., Argentou, N., Giannakoulas, N., Adamaki, M., Vassilopoulos, G., Polychronopoulou, S., Germenis, A.E., Eibel, H., and Speletas, M. (2019). BAFF/APRIL System Is Functional in B-Cell Acute Lymphoblastic Leukemia in a Disease Subtype Manner. Front. Oncol. 9, 594.

Smulski, C.R., and Eibel, H. (2018). BAFF and BAFF-Receptor in B Cell Selection and Survival. Front. Immunol. 9, 2285.

Smulski, C.R., Kury, P., Seidel, L.M., Staiger, H.S., Edinger, A.K., Willen, L., Seidl, M., Hess, H., Salzer, U., Rolink, A.G., Rizzi, M., Schneider, P., and Eibel, H. (2017). BAFF- and TACI-Dependent Processing of BAFFR by ADAM Proteases Regulates the Survival of B Cells. Cell Rep. 18, 2189-202.

Smulski, C.R., Decossas, M., Chekkat, N., Beyrath, J., Willen, L., Guichard, G., Lorenzetti, R., Rizzi, M., Eibel, H., Schneider, P., and Fournel, S. (2017). Hetero-oligomerization between the TNF receptor superfamily members CD40, Fas and TRAILR2 modulate CD40 signalling. Cell Death Dis. 8, e2601.

Keller, B., Cseresnyes, Z., Stumpf, I., Wehr, C., Fliegauf, M., Bulashevska, A., Usadel, S., Grimbacher, B., Rizzi, M., Eibel, H., Niesner, R., and Warnatz, K. (2017). Disturbed canonical nuclear factor of kappa light chain signaling in B cells of patients with common variable immunodeficiency. J. Allergy Clin. Immunol. 139, 220-31

Kienzler, A.K., and Eibel, H. (2016). Human B cell development and tolerance. Enzyclopedia of Immunobiology. M Ratcliffe, Elsevier Ltd. 1, 105-21.

Xu, H.C., Huang, J., Khairnar, V., Duhan, V., Pandyra, A.A., Grusdat, M., Shinde, P., McIlwain, D.R., Maney, S.K., Gommerman, J., Lohning, M., Ohashi, P.S., Mak, T.W., Pieper, K., Sic, H., Speletas, M., Eibel, H., Ware, C.F., Tumanov, A.V., Kruglov, A.A., Nedospasov, S.A., Haussinger, D., Recher, M., Lang, K.S., and Lang, P.A. (2015). Deficiency of the B cell-activating factor receptor results in limited CD169+ macrophage function during viral infection. J. Virol. 89, 4748-59.

Janda, A., Schwarz, K., van der Burg, M., Vach, W., Ijspeert, H., Lorenz, M.R., Elgizouli, M., Pieper, K., Fisch, P., Hagel, J., Lorenzetti, R., Seidl, M., Roesler, J., Hauck, F., Traggiai, E., Speckmann, C., Rensing-Ehl, A., Ehl, S., Eibel, H., and Rizzi, M. (2016). Disturbed B-lymphocyte selection in autoimmune lymphoproliferative syndrome. Blood 127, 2193-2202.