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* Department of Clinical Chemistry and Molecular Diagnostics, Philipps-University Marburg, Marburg, Germany;
Division of Experimental Pneumology, Research Center Borstel, Leibniz-Center for Medicine and Biosciences, Borstel, Germany;
German Rheumatism Research Center, Berlin, Germany;
Department of Pediatrics, Philipps-University Marburg, Marburg, Germany; and
¶ Charité University Hospital Berlin, Allergy-Centrum-Charité, Berlin, Germany
Allergen-specific Abs play a pivotal role in the induction and maintenance of allergic airway inflammation. During secondary immune responses, plasma cell survival and Ab production is mediated by extrinsic factors provided by the local environment (survival niches). It is unknown whether neurotrophins, a characteristic marker of allergic airway inflammation, influence plasma cell survival in the lung. Using a mouse model of allergic asthma, we found that plasma cells from the lung and spleen are distinct subpopulations exhibiting differential expression patterns of neurotrophins and their receptors (Trks). In vitro, the nerve growth factor (NGF) and neurotrophin-3 (NT3) led to a dose-dependent increase in viability of isolated pulmonary plasma cells due to up-regulation of the antiapoptotic Bcl2 pathway. In parallel, the expression of transcription factors that stimulate the production of immunoglobulins (X-box binding protein 1 and NF-
B subunit RelA) was enhanced in plasma cells treated with NGF and NT3. These findings were supported in vivo. When the NGF pathway was blocked by intranasal application of a selective TrkA inhibitor, sensitized mice showed reduced numbers of pulmonary plasma cells and developed lower levels of allergen-specific and total serum IgE in response to OVA inhalation. This suggests that in the allergic airway inflammation, NGF/TrkA-mediated pulmonary IgE production contributes significantly to serum-IgE levels. We conclude that the neurotrophins NGF and NT3 act as survival factors for pulmonary plasma cells and thus are important regulators of the local Ab production in the allergic airway disease.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 Supported by the Deutsche Forschungsgemeinschaft Re737/14-1 (to M.A., M.W., V.F., S.S., E.O.L., A.R., and H.R.) and Transregio 22 Pulmonary Allergies; Project A17 (to M.Z.) and Project Z2 (to H.R.).
2 H.R. and M.Z. contributed equally to this work.
3 Address correspondence and reprint requests to: Dr. Michael Zemlin, Philipps University Marburg, Department of Pediatrics, Baldingerstr. 1, 35033 Marburg, Germany. E-mail address: zemlin{at}staff.uni-marburg.de
4 Abbreviations used in this paper: PC, plasma cell; ASC, Ab-secreting cell; BAL, bronchoalveolar lavage; ER, endoplasmic reticulum; i.n., intranasal; MNC, mononuclear cell; NGF, nerve growth factor; SAC, Staphylococcus aureus cells; siRNA, small interfering RNA; qPCR, quantitative PCR; UPR, unfolded protein response; 7-AAD, 7-aminoactinomycin D; XBP-1, X-box binding protein-1.
5 The online version of this article contains supplemental material.
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