Seminar: Lars Nitschke

Siglecs on B cells and dendritic cells: inhibiting signalling and preventing autoimmunity

Date:
11 May 2017 10:30 hrs. - 11:30 hrs.
Location:
Figdor Lecture Theatre, 8th floor RIMLS Building, Geert Grooteplein 26-28, route 289
Title:
Siglecs on B cells and dendritic cells: inhibiting signalling and preventing autoimmunity
Speaker(s):

Lars Nitschke, Division of Genetics, University of Erlangen, Germany

Host(s):

Gosse Adema, Radiotherapy & OncoImmunology lab, Dept. of Radiation Oncology

11-05-2017 10:30:0011-05-2017 11:30:00Europe/AmsterdamSiglecs on B cells and dendritic cells: inhibiting signalling and preventing autoimmunity Figdor Lecture Theatre, 8th floor RIMLS Building, Geert Grooteplein 26-28, route 289Rimlsrimls@radboudumc.nl

Remarks / more information:

undefinedCD22 (Siglec-2) and Siglec-G are two inhibitory receptors, which negatively regulate B-cell antigen receptor (BCR) signalling. Mice with mutated Siglec ligand binding domains showed that the association of the Siglec to the BCR regulates its inhibitory signalling function. Interestingly, loss of sialic acid binding in the CD22 protein led to stronger BCR signal inhibition, while the same mutation in Siglec-G led to a loss of the inhibitory function and stronger BCR signalling. We are addressing the regulation of the association of the Siglecs to the BCR by ligand-binding in more detail. Loss of the inhibitory receptors on B cells can lead to a higher susceptibility to a lupus-like autoimmune disease, as we could show in mouse models. Siglec-H is a Siglec with quite restricted expression on plasmacytoid dendritic cells (pDCs), a subpopulation of antigen-presenting dendritic cells. pDCs are known to produce most of the type1 interferon which is necessary for anti-viral responses. pDCs of Siglec-H-/- mice produced higher levels of type1 interferon in vitro or after cytomegalovirus (CMV) infection in vivo. Several weeks after a CMV infection Siglec-H-/- mice developed a strong lupus-like autoimmune disease, which was type1 interferon-dependent. These results show that Siglec-H is a receptor downregulating type1 interferon responses after virus infection. A defect in this pathway can cause the development of autoimmune diseases.

Key Publications

  • The role of CD22 and Siglec-G in B-cell tolerance and autoimmune disease. Nat Rev Rheumatol. 10:422-8, 2014
  • CD22 ligand-binding and signaling domains reciprocally regulate B-cell Ca2+ signaling. Proc NatlAcadSci U S A. 110:12402-7, 2013
  • Grb2 regulates Bcell maturation, B cell memory responses and inhibits B cell Ca2+ signalling. EMBO J., 30:1621-1633, 2011

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