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AG Lars Nitschke

Focus of research: AG Lars Nitschke

The group of Professor Lars Nitschke is interested in proteins of the siglec family that, among other functions, modulate B cell receptor signalling.

Prof. Dr. Lars Nitschke

Professur für Genetik (Prof. Dr. Nitschke)

<< Staff of the Nitschke group >>

 

 

 

Fig. 1: The functions of CD22 and Siglec-G in the modulation of BCR-mediated signalling.

B lymphocytes (or B cells) are cells of the adaptive immune system, which induce an antibody-mediated humoral immune response.

We are interested in the signals, that regulate development and functionality of B cells. CD22 (Siglec-2) and Siglec-G are B cell transmembrane proteins that are associated with the B cell receptor (BCR) and interfere with its signalling cascade (Fig. 1). Both carry inhibitory ITIM motifs, which are phosphorylated after stimulation of the BCR. After phosphorylation, the ITIM motif recruits phosphatases such as SHP-1, which negatively regulate signalling.

We generated CD22-/- and Siglec-G-/- mice and could show that these mice exhibit greatly increased BCR signalling, as measured through Ca2+ influx into the B cell. CD22 inhibits BCR signalling in conventional B cells, while Siglec-G inhibits BCR signalling in the subpopulation of B1 cells, which are B cells with specific functions.

Inhibitory proteins like Siglecs are important to control B cell activation, because uncontrolled activation of B cells could lead to the emergence of autoimmune disease or to the development of B cell lymphomas or leukemias. Both Siglec-G-/- , as well as CD22-/- x Siglec-G-/-  double deficient mice develop an autoimmune disease which resembles systemic lupus erythematosus (SLE), characterized by autoantibodies and kidney pathology. As the inhibitory Siglec proteins are involved in preventing theses diseases, new treatment options targeting these proteins could be developed. This project is funded by the TRR130.

Fig. 2: Functional diversity of Siglec proteins – Siglec-H inhibits IFN-I signalling in plasmacytoid Dendritic Cells, whereas Siglec-15 plays a crucial role in osteoclast maturation.

Siglec-H is expressed in a very restricted fashion on plasmacytoid dendritic cells (pDCs), while Siglec-15 is expressed exclusively on osteoclasts (Fig.2). Siglec-H inhibits the type1 interferon (IFN-I) production in pDCs. IFN-I is important for anti-viral responses, but is also elevated in SLE patients. We could show, that Siglec-H-/- mice develop a very strong SLE-like autoimmune disease several weeks after a virus (CMV) infection. This shows that viral infections can trigger an autoimmune disease when IFN-I is not well controlled. Siglec-15 is crucial for osteoclast maturation and plays a role in bone erosion in arthritis, as we could show with Siglec-15-/- mice that we generated. This implies Siglec-15 as a potential new target in arthritis and also in osteoporosis. This project is funded by the CRC 1181.

Fig. 3: Sialic acids are commonly found modifications of cell membrane glycoproteins.

Sialic acids (Sia) are abundant carbohydrate structures on glycoproteins of cell membranes. On these glycoproteins Sia are the terminally expressed carbohydrates (Fig.3). Sia serve as ligands for Siglec proteins, regulating their inhibitory functions.

We generated mice lacking Sia either on B cells or T cells. Surprisingly, B cells and T cells without Sia cannot survive in immunological organs such as the spleen or lymph nodes.

This points to a more general role of Sia than just serving as Siglec ligands on lymphocytes. These functions will be addressed in our group in the future. This project is funded by the FOR 2953.

Lars Nitschke on Google Scholar

5 Key Publications

  1. Müller J, Nitschke L. (2014) The role of CD22 and Siglec-G in B-cell tolerance and autoimmune disease. Nat Rev Rheumatol. 10:422-8.
  2. Schmitt H, Sell S, Koch J, Seefried M, Sonnewald S, Daniel C, Winkler TH, Nitschke L. (2016) Siglec-H protects from virus-triggered severe systemic autoimmunity. J Exp Med. 213:1627-44
  3. Müller J, Obermeier I, Wöhner M, Brandl C, Mrotzek S, Angermüller S, Maity PC, Reth M, Nitschke L. (2013) CD22 ligand-binding and signaling domains reciprocally regulate B-cell Ca2+ signaling. Proc Natl Acad Sci U S A. 110:12402-7
  4. Ackermann J, Radtke D, Maurberger, A, Winkler TH, Nitschke L (2011) Grb2 regulates Bcell maturation, B cell memory responses and inhibits B cell Ca2+ signalling. EMBO J. 30:1621-1633
  5. Hoffmann A, Kerr S, Jellusova J, Zhang J, Weisel F, Wellmann U, Winkler TH, Kneitz B, Crocker PR, Nitschke L. (2007)  Siglec-G is a B1 cell-inhibitory receptor that controls expansion and calcium signaling of the B1 cell population. Nat Immunol. 8:695-704.

Primary Publications (since 2012)

  • Prescher H, Frank M, Gütgemann S, Kuhfeldt E, Schweizer A, Nitschke L, Watzl C, Brossmer R. (2017) Design, Synthesis, and Biological Evaluation of Small, High-Affinity Siglec-7 Ligands: Toward Novel Inhibitors of Cancer Immune Evasion. J Med Chem. 60: 941-956
  • Schmitt H, Sell S, Koch J, Seefried M, Sonnewald S, Daniel C, Winkler TH, Nitschke L. (2016) Siglec-H protects from virus-triggered severe systemic autoimmunity. J Exp Med. 213:1627-44
  • Radtke D, Lacher SM, Szumilas N, Sandrock L, Ackermann J, Nitschke L, Zinser E. (2016) Grb2 Is Important for T Cell Development, Th Cell Differentiation, and Induction of Experimental Autoimmune Encephalomyelitis. J Immunol. 196:2995-3005
  • Krzyzak L, Seitz C, Urbat A, Hutzler S, Ostalecki C, Gläsner J, Hiergeist A, Gessner A, Winkler TH, Steinkasserer A, Nitschke L. (2016) CD83 Modulates B Cell Activation and Germinal Center Responses. J Immunol. 196:3581-94
  • Özgör L, Brandl C, Shock A, Nitschke L. (2016) Epratuzumab modulates B-cell signaling without affecting B-cell numbers or B-cell functions in a mouse model with humanized CD22. Eur J Immunol. 46:2260-72
  • 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.
  • Gasparrini, F., Feest, C., Bruckbauer, A., Mattila, P.K., Muller, J., Nitschke, L., Bray, D., and Batista, F.D. (2016). Nanoscale organization and dynamics of the siglec CD22 cooperate with the cytoskeleton in restraining BCR signalling. EMBO J 35, 258-280.
  • Nitschke L. (2015) Siglec-G is a B-1 cell inhibitory receptor and also controls B cell tolerance. Ann N Y Acad Sci. 1362:117-21
  • Übelhart R, Hug E, Bach MP, Wossning T, Dühren-von Minden M, Horn AH, Tsiantoulas D, Kometani K, Kurosaki T, Binder CJ, Sticht H, Nitschke L, Reth M, Jumaa H. (2015) Responsiveness of B cells is regulated by the hinge region of IgD. Nat Immunol. 16:534-43
  • Ludwig J, Federico G, Prokosch S, Küblbeck G, Schmitt S, Klevenz A, Gröne HJ, Nitschke L, Arnold B. (2015) Dickkopf-3 acts as a modulator of B cell fate and function. J Immunol. 194:2624-34.
  • 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 Immunol195,51-60.
  • Engels N, König LM, Schulze W, Radtke D, Vanshylla K, Lutz J, Winkler TH, Nitschke L, Wienands J. (2014) The immunoglobulin tail tyrosine motif upgrades memory-type BCRs by incorporating a Grb2-Btk signalling module. Nat Commun. 5:5456.
  • Nitschke L. (2014) CD22 and Siglec-G regulate inhibition of B-cell signaling by sialic acid ligand binding and control B-cell tolerance. Glycobiology. 24:807-17.
  • Luo W, Mayeux J, Gutierrez T, Russell L, Getahun A, Müller J, Tedder T, Parnes J, Rickert R, Nitschke L, Cambier J, Satterthwaite AB, Garrett-Sinha LA. (2014) A balance between B cell receptor and inhibitory receptor signaling controls plasma cell differentiation by maintaining optimal Ets1 levels. J Immunol. 2014 Jul 15;193(2):909-20.
  • Simonetti G, Bertilaccio MT, Rodriguez TV, Apollonio B, Dagklis A, Rocchi M, Innocenzi A, Casola S, Winkler TH, Nitschke L, Ponzoni M, Caligaris-Cappio F, Ghia P. (2014) SIGLEC-G deficiency increases susceptibility to develop B-cell lymphoproliferative disorders. Haematologica. 99:1356-64.
  • Prescher H, Schweizer A, Kuhfeldt E, Nitschke L, Brossmer R. (2014) Discovery of multifold modified sialosides as human CD22/Siglec-2 ligands with nanomolar activity on B-cells. ACS Chem Biol. 9:1444-50.
  • Hutzler S, Özgör L, Naito-Matsui Y, Kläsener K, Winkler TH, Reth M, Nitschke L. (2014) The ligand-binding domain of Siglec-G is crucial for its selective inhibitory function on B1 cells. J Immunol. 192:5406-14.
  • Müller J, Nitschke L. (2014) The role of CD22 and Siglec-G in B-cell tolerance and autoimmune disease. Nat Rev Rheumatol. 10:422-8.
  • Bökers S, Urbat A, Daniel C, Amann K, Smith KG, Espéli M, Nitschke L. (2014) Siglec-G deficiency leads to more severe collagen-induced arthritis and earlier onset of lupus-like symptoms in MRL/lpr mice. J Immunol. 192:2994-3002.
  • Niedzielska M, Bodendorfer B, Münch S, Eichner A, Derigs M, da Costa O, Schweizer A, Neff F, Nitschke L, Sparwasser T, Keyse SM, Lang R. (2014) Gene trap mice reveal an essential function of dual specificity phosphatase Dusp16/MKP-7 in perinatal survival and regulation of Toll-like receptor (TLR)-induced cytokine production. J Biol Chem. 289:2112-26.
  • Naito-Matsui Y, Takada S, Kano Y, Iyoda T, Sugai M, Shimizu A, Inaba K, Nitschke L, Tsubata T, Oka S, Kozutsumi Y, Takematsu H. (2014) Functional evaluation of activation-dependent alterations in the sialoglycan composition of T cells. J Biol Chem. 289:1564-79.
  • Dütting S, Vögtle T, Morowski M, Schiessl S, Schäfer CM, Watson SK, Hughes CE, Ackermann JA, Radtke D, Hermanns HM, Watson SP, Nitschke L, Nieswandt B. (2014) Growth factor receptor-bound protein 2 contributes to (hem)immunoreceptor tyrosine-based activation motif-mediated signaling in platelets. Circ Res.114:444-53.
  • Nitschke L. (2013) Suppressing the antibody response with Siglec ligands. N Engl J Med. 369:1373-4.
  • Puttur F, Arnold-Schrauf C, Lahl K, Solmaz G, Lindenberg M, Mayer CT, Gohmert M, Swallow M, van Helt C, Schmitt H, Nitschke L, Lambrecht BN, Lang R, Messerle M, Sparwasser T. (2013) Absence of Siglec-H in MCMV infection elevates interferon alpha production but does not enhance viral clearance. PLoS Pathog. 9(9):e1003648.
  • Müller J, Obermeier I, Wöhner M, Brandl C, Mrotzek S, Angermüller S, Maity PC, Reth M, Nitschke L. (2013) CD22 ligand-binding and signaling domains reciprocally regulate B-cell Ca2+ signaling. Proc Natl Acad Sci U S A. 110:12402-7.
  • Wöhner M, Born S, Nitschke L. (2012) Human CD22 cannot fully substitute murine CD22 functions in vivo, as shown in a new knockin mouse model. Eur J Immunol.42: 3009-18
  • Schwab I, Seeling M, Biburger M, Aschermann S, Nitschke L, Nimmerjahn F. (2012) B cells and CD22 are dispensable for the immediate antiinflammatory activity of intravenous immunoglobulins in vivo. Eur J Immunol. 42:3302-9
  • Walker JA, Hall AM, Kotsopoulou E, Espeli M, Nitschke L, Barker RN, Lyons PA, Smith KG. (2012) Increased red cell turnover in a line of CD22-deficient mice is caused by Gpi1c: a model for hereditary haemolytic anaemia. Eur J Immunol. 42:3212-22
  • Schweizer A, Wöhner M, Prescher H, Brossmer R, Nitschke L. (2012) Targeting of CD22-positive B-cell lymphoma cells by synthetic divalent sialic acid analogues. Eur J Immunol. 42:2792-802.