A role for brain-derived neurotrophic factor in B cell development Berit Schuhmann a , Alexander Dietrich b , Serdar Sel a , Christian Hahn a , Martin Klingenspor c , Marek Lommatzsch d , Thomas Gudermann b , Armin Braun e , Harald Renz a , Wolfgang Andreas Nockher a, T a Department of Clinical Chemistry and Molecular Diagnostics, University Hospital, Philipps-Universita ¨t, Baldingerstrasse, 35033 Marburg, Germany b Institute for Pharmacology and Toxicology, Philipps-Universita ¨t, 35043 Marburg, Germany c Animal Physiology, Department of Biology, Philipps-Universita ¨t, 35043 Marburg, Germany d Department of Pneumology, University Medical Clinics, 18055 Rostock, Germany e Department of Immunology and Allergology, Fraunhofer Institute of Toxicology and Experimental Medicine, 30625 Hannover, Germany Received 1 December 2004; received in revised form 31 January 2005; accepted 31 January 2005 Abstract In the present study, we demonstrated a significant reduction of B lymphocytes in the blood, spleen and bone marrow of BDNF deficient mice. The observed developmental block in bone marrow B cell development was linked specifically to the Pre-BII stage. B lymphocytes express the BDNF receptors p75 NTR and TrkB gp95 , while no BDNF expression was found. However, a strong BDNF expression was demonstrated in bone marrow stromal cells. An increase of intracellular free calcium [Ca 2+ ] i in B lymphocytes after BDNF application confirms a direct responsiveness of B lymphocytes to BDNF. In conclusion, these results suggest a role of BDNF for normal B lymphocyte development through paracrine effects in the bone marrow. D 2005 Elsevier B.V. All rights reserved. Keywords: Neurotrophins; Brain-derived neurotrophic factor; Hematopoesis; Bone marrow stromal cells; Neuroimmunology 1. Introduction Members of the neurotrophin (NT) family like nerve growth factor (NGF), brain derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3) and neurotrophin-4 (NT-4) are crucial mediators of neuronal development, survival and function (Lewin and Barde, 1996). However, they are now considered to be growth factors with a wide spectrum of functions outside the nervous system, including modulation and regulation of immune functions (Aloe, 2001; Vega et al., 2003; Nockher and Renz, 2003) leading to the paradigm change: bfrom neurotrophin to neurokineQ (Levi-Montalcini et al., 1996). Several lines of evidence suggest that, e.g. NGF is acting as a cytokine like factor in development and function of the immune system. The function of NGF on mast cell, B cell, T cell, macrophage and eosinophil function is already well described (Nilsson et al., 1997; Torcia et al., 2001; Braun et al., 1998; Nassenstein et al., 2003). However, much less information is available regarding the role of BDNF in the immune system and in contrast to NGF, BDNF has not been studied in B cell development. Biological effects of BDNF are mediated by two distinct classes of cell surface receptors, the high affinity receptor TrkB and the low affinity pan-neurotrophin receptor p75 NTR . In addition, there are two main variants of TrkB, the full length TrkB gp145 receptor and the truncated TrkB gp95 receptor lacking the intracellular signal transduction domain (Huang and Reichardt, 2003). It has been shown before that T lymphocytes express both TrkB 0165-5728/$ - see front matter D 2005 Elsevier B.V. All rights reserved. doi:10.1016/j.jneuroim.2005.01.023 Abbreviations: BDNF, brain derived neurotrophic factor; BMSC, bone marrow stromal cells; (Ca 2+ ) i , intracellular free calcium; BDNF À/À , BDNF knockout mice; IL-7, interleukin-7; MNC, mononuclear cell; NGF, nerve growth factor; wt, wildtype; Trk, tropomyosine related tyrosine kinase. T Corresponding author. E-mail address: nockher@med.uni-marburg.de (W.A. Nockher). Journal of Neuroimmunology 163 (2005) 15 – 23 www.elsevier.com/locate/jneuroim