Prof. Dr. Lars Nitschke

Lehrstuhl für Genetik
Department Biologie
Friedrich-Alexander-Universität Erlangen-Nürnberg
Staudtstr. 5
91058 Erlangen 

Tel. +49 (0) 9131 85 28453
lars.nitschke@fau.de

Project summary:

The role of Siglec proteins in B cell activation and autoimmunity

B cells express inhibitory receptors on the cell surface, which can suppress responses of the B cell antigen receptor (BCR). These inhibitory receptors control the strength of B cell activation. This control may also be important to maintain B cell tolerance, as many BCRs are autoreactive and can potentially trigger autoimmune responses. CD22 and Siglec-G are inhibitory receptors of the Siglec family that can bind to cell surface expressed sialic acids in specific linkages (Fig.1). Since sialic acids are abundantly expressed in vertebrates, but usually not in microorganisms they may act as self ligands by binding to Siglecs and suppressing B cell activation. By generation of new mouse models with mutated CD22- or Siglec-G-ligand binding domains it will be studied how ligand-binding controls the inhibitory activity of these molecules. Siglec-G seems to be a B1-cell specific inhibitory receptor, as loss of Siglec-G only affects the B1 cell population. In this project the regulation and selection of precursor cells into the B1 cell pool will be studied. We will also study the role of CD22 and Siglec-G in autoimmunity by crossing CD22- and Siglec-G-deficient mice into autoimmune-prone mouse strains, which develop a SLE-like disease. We will also address the question whether higher expression of CD22 and Siglec-G can prevent autoimmunity by generating new mouse models overexpressing these two proteins. These planned experiments will show how these two inhibitory receptors are involved in generating B cell tolerance and preventing autoimmunity.

Fig.1 The inhibitory proteins CD22 and Siglec-G are expressed on the B cell surface and inhibit IgM-induced signalling by recruitment of the phosphatase SHP-1 to inhibitory ITIM sequences.
Publications P 04:

Brandl, C., Angermuller, S., and Nitschke, L. (2020). Humanized CD22 transgenic mouse model for in vivo analysis of anti-CD22-based immunotherapy. Eur. J. Immunol. doi: 10.1002/eji.202048636.

Meyer, S.J., Boser, A., Korn, M.A., Koller, C., Bertocci, B., Reimann, L., Warscheid, B., and Nitschke, L. (2020). Cullin 3 Is Crucial for Pro-B Cell Proliferation, Interacts with CD22, and Controls CD22 Internalization on B Cells. J. Immunol. 204, 3360-3374.

Fernandes, V.E., Ercoli, G., Benard, A., Brandl, C., Fahnenstiel, H., Muller-Winkler, J., Weber, G.F., Denny, P., Nitschke, L.*, and Andrew, P.W.* (2020). The B-cell inhibitory receptor CD22 is a major factor in host resistance to Streptococcus pneumoniae infection. PLoS Pathog. 16, e1008464.   * equal contribution

Robinson, M.J., Pitt, C., Brodie, E.J., Valk, A.M., O'Donnell, K., Nitschke, L., Jones, S., and Tarlinton, D.M. (2019). BAFF, IL-4 and IL-21 separably program germinal center-like phenotype acquisition, BCL6 expression, proliferation and survival of CD40L-activated B cells in vitro. Immunol. Cell Biol. 97, 826-839.

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

Setz, C.S., Khadour, A., Renna, V., Iype, J., Gentner, E., He, X., Datta, M., Young, M., Nitschke, L., Wienands, J., Maity, P., Reth, M. and Jumaa, H. (2019). Pten controls B-cell responsiveness and germinal center reaction by regulating the expression of IgD BCR. EMBO J 38. 192, 5406-5414.

Meyer, S.J., Linder, A.T., Brandl, C., and Nitschke, L. (2018). B Cell Siglecs-News on Signaling and Its Interplay With Ligand Binding. Front. Immunol. 9, 2820.

Özgör, L., Meyer, S.J., Korn, M., Terorde, K., and Nitschke, L. (2018). Sialic Acid Ligand Binding of CD22 and Siglec-G Determines Distinct B Cell Functions but Is Dispensable for B Cell Tolerance Induction. J. Immunol. 201, 2107-2116.

Gruber, S., Hendrikx, T., Tsiantoulas, D., Ozsvar-Kozma, M., Goderle, L., Mallat, Z., Witztum, J.L., Shiri-Sverdlov, R., Nitschke, L., and Binder, C.J. (2016). Sialic Acid-Binding Immunoglobulin-like Lectin G Promotes Atherosclerosis and Liver Inflammation by Suppressing the Protective Functions of B-1 Cells. Cell Rep. 14, 2348-2361.

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.