Group Lars Nitschke


Differentiation, Activation and Signaltransduction of B-Lymphocytes

Research projects

B lymphocytes are cells of the adaptive immune system, which generate an antibody-dependent humoral immune response. We are interested in the signals which regulate the maturation and function of B lymphocytes(or B cells). In order to study the function of B cells in vivo we generate genetically-modified mouse lines in which proteins of B cells are deleted or mutated. The resulting “knockout” or “knockin” mice are model systems to study the normal function of the immune system, as well as pathological changes of the immune system associated with diseases.
CD22 is a B cell-specific transmembrane protein, which is associated to the B cell receptor (BCR) and which modulates BCR signalling (fig.1).

Figure 1: The function of CD22:  Inhibition of BCR-induced signalling and CD22 ligand-binding to alpha2,6-linked sialic acids (2,6Sia).

CD22 carries inhibitory ITIM motifs, which get tyrosine-phosphorylated after BCR stimulation. With these tyrosine phosphorylated ITIM motifs CD22 can recruit signalling proteins such as the tyrosine phosphatase SHP-1. CD22 knockout mice, which were generated by us, show an enhanced BCR signalling, as measured as Ca2+ influx into B cells. Thus, CD22 is an important inhibitor of BCR signalling, which prevents uncontrolled activation of B cells that potentially could lead to autoimmunity (Nitschke 2009).
CD22 is also an adhesion receptor. It binds to alpha2,6-linked sialic acids (2,6Sia) and can induce cell-cell adhesion. CD22 belongs to the family of Siglecs (Sialic acid binding Immunoglobulin-like lectins), a family of adhesion molecules, which all bind specifically to sialic acids as ligands (Fig.2). By analysis of CD22-deficient mice and subsequent work we could describe a new function of CD22. CD22 is probably a homing receptor for recirculating B cells which migrate back to the bone marrow (Nitschke 1999). We are also interested how ligand binding of CD22 regulated BCR signalling. We analyse this with genetically modified mice, which carry selective mutations in the ligand-binding domain or in the intracellular ITIM motifs.

Figure 2: The family of murine Siglecs, expression and specificities for sialic acids are shown.

Siglec-G is another B-cell specific co-receptor, the function of which was which was recently identified by our group.  Siglec-G acts as an inhibitory receptor  for a certain subclass of B cells, so-called B1 cells. Siglec-G deficient mice show a strongly increased number of B1 cells, enhanced Ca2+ signalling in B1 cells and enhanced production of IgM antibodies (Hoffmann 2007). Together with CD22, Siglec-G protects against autoimmunity, because Siglec-G x CD22 double-deficient mice show spontaneous autoimmunity, as characterized by autoantibody formation and glomerulonephritis (Jellusova 2010). The functional importance of CD22 and Siglec-G in prevention of autoimmunity will be determined in more detail in the future. The group is also interested in the biological function of other Siglec proteins and of signalling molecules in B cells.