Nerve Growth Factor (NGF) vermitteltes Überleben pulmonaler Plasmazellen in der Atemwegsentzündung des murinen allergischen Asthma bronchiale

Die humorale Immunantwort spielt eine essentielle Rolle in der Pathogenese chronischer Entzündungen. Innerhalb des allergischen Asthma bronchiale, einer chronischen Entzündung der Atemwege, spielt die Bildung Allergen-spezifischer Antikörper bei der Initiierung des allergischen Entzündungsprozesses...

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Bibliographic Details
Main Author: Abram, Melanie
Contributors: Bölker, Michael (Prof.) (Thesis advisor)
Format: Doctoral Thesis
Published: Philipps-Universität Marburg 2009
Online Access:PDF Full Text
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Allergen-specific antibodies play a pivotal role in the induction and maintenance of allergic airway inflammation. During secondary immune responses, plasma cell survival and antibody production is mediated by extrinsic factors provided by the local environment (survival niches). It is unknown if neurotrophins, a characteristic marker of the 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-kB 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 ovalbumin 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 antibody production in the allergic airway disease.