Brigitte Kasper

FcγRIIA and FcγRIIIB are required for autoantibody-induced tissue damage in experimental human models of bullous pemphigoid.

Medina F, Segundo C, Campos-Caro A et al. (2002) The heterogeneity shown by human plasma cells from tonsil, blood and bone marrow reveals graded stages of increasing maturity, but local profiles of adhesion molecule expression. Blood 99: 2154–61 Odendahl M, Mei H, Hoyer BF et al. (2005) Generation of migratory antigen-specific plasma blasts and mobilization of resident plasma cells in a secondary immune response. Blood 105:1614–21

SH2-containing protein tyrosine phosphatases SHP-1 and SHP-2 are dramatically increased at the protein level in neutrophils from patients with severe congenital neutropenia (Kostmann’s syndrome)

Severe congenital neutropenia (SCN) or Kostmanns syndrome is characterized by a stop in differentiation of myeloid progenitor cells at the myelocytic or promyelocytic stage. The pathophysiology of SCN is still unclear. We previously showed that the tyrosine kinase JAK2 is phosphorylated and activated in neutrophils from patients with severe congential neutropenia. We investigated the role of tyrosine phosphatases in this disease. Expression of the SH2 domain-containing tyrosine phosphatases SHP-1 and SHP-2 was analyzed in myeloid cells from patients with SCN in comparison to healthy donors. We investigated tyrosine phosphatase expression in myeloid cells at the protein level by Western blot analysis using polyclonal antisera against SHP-1 and SHP-2. Whereas SHP-1 and SHP-2 were hardly detectable in neutrophils from healthy donors, neutrophils from patients with SCN revealed high amounts of these two proteins in Western blot analyses. Reverse transcriptase-polymerase chain reaction and Northern blot analyses demonstrated no dramatic differences of SHP-1 mRNA in neutrophils from congenital neutropenia patients as compared to healthy donors. SHP-2 mRNA was hardly detectable in the neutrophils from patients and in normal neutrophils. Increased expression of SHP protein correlated with elevated activity of both SHP-1 and SHP-2 in neutrophils of patients with SCN. Taken together, these data indicate differential regulation for SHP-1 and SHP-2 at the protein level in neutrophils from SCN patients in comparison to healthy donors. We suggest that overexpression of SHP-1 and SHP-2 protein in neutrophils and not in mononuclear cells from patients with SCN might be related to the disease, e.g., by defective dephosphorylation of proteins involved in intracellular signaling pathways.

Syntaxin 11 is required for NK and CD8? T-cell cytotoxicity and neutrophil degranulation.

Syntaxin 11 (STX11) controls vesicular trafficking and is a key player in exocytosis. Since Stx11 mutations are causally associated with a familial hemophagocytic lymphohistio‐cytosis, we wanted to clarify whether STX11 is functionally important for key immune cell populations. This was studied in primary cells obtained from newly generated Stx11−/− mice. Our data revealed that STX11 is not only widely expressed in different immune cells, but also induced upon LPS or IFN‐γ treatment. However, Stx11 deficiency does not affect macrophage phagocytic function and cytokine secretion, mast cell activation, or antigen presentation by DCs. Instead, STX11 selectively controls lymphocyte cytotoxicity in NK and activated CD8+ T cells and degranulation in neutrophils. Stx11−/− NK cells and CTLs show impaired degranulation, despite a comparable activation, maturation and expression of the complex‐forming partners MUNC18–2 and VTI1B. In addition, Stx11−/− CTLs and NK cells produce abnormal levels of IFN‐γ. Since functional reconstitution rescues the defective phenotype of Stx11−/− CTLs, we suggest a direct, specific and key role of STX11 in controlling lymphocyte cytotoxicity, cytokine production and secretion. Finally, we show that these mice are a very useful tool for dissecting the role of STX11 in vesicular trafficking and secretion.

Clinical implications of G-CSF receptor mutations

2. The physiology of mutated G-CSF receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 2.1. Frequency of G-CSF receptor point mutations in chronic neutropenia . . . . . . . . . . 2 2.2. The function of mutated G-CSF receptors in transfected cell lines . . . . . . . . . . . . 2 2.3. In vivo data on G-CSF receptor point mutations in patients . . . . . . . . . . . . . . . 3 2.4. Mutated G-CSF receptors and leukemogenesis . . . . . . . . . . . . . . . . . . . . . . . . 4