Das IgE-Repertoire von Kindern und Jugendlichen mit allergischem Asthma bronchiale

Das allergische Asthma bronchiale ist eine chronisch entzündliche Erkrankung der Atemwege und mit einer Prävalenz von ca. 10% in Deutschland die häufigste chronische Erkrankung im Kindesalter. Die Erkenntnislage bezüglich der Ursachen allergischer Erkrankungen und insbesondere ihrer Zunahme in westl...

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Bibliographic Details
Main Author: Strücker, Benjamin
Contributors: Maier, Rolf Felix (Prof. Dr.) (Thesis advisor)
Format: Doctoral Thesis
Published: Philipps-Universität Marburg 2011
Online Access:PDF Full Text
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Allergic asthma is a chronic inflammatory disease of the respiratory system and the most frequent chronic disorder in childhood. Although the pathogenesis of allergic asthma remains unclear, Immunoglobulin E (IgE) can be considered as a central effector molecule of the immediate allergic reaction. Bound to the surface of mast cells IgE generates an interface between allergens and the immune system. The nature of the IgE response is still under debate. The objective of our study was to clarify whether the IgE repertoire in the circulation of allergic children represents a classical Ag-driven and oligoclonal B cell response, a superantigen-like activation of a subset of B cells, or a polyclonal B-1 cell expansion. By establishing a highly sensitive RT-PCR method we amplified, cloned, and sequenced IgE H chain transcripts from 13 children aged from 3 – 16 years suffering from allergic asthma. In total we gained 1.366 functional IgE sequences which currently represent the most extensive collection of human IgE transcripts. As a reference we gained 308 functional IgM transcripts of the same children. Interestingly in contrast to several recent studies the analysis of the VH-family usage was not indicative of a superantigen-like activation of B cells. The pattern of VH-family usage corresponded to germline complexity of these genes, making VH3 the most frequently used family in IgE (56%) and IgM (55%). Compared to IgM (43 ± 9,8 bp) IgE sequences (48 ± 13bp) showed a 5bp longer CDR-H3 (p < 0,001). The somatic mutation rate was significantly enhanced in IgE transcripts (21% versus 72%; p < 0.001), which renders a polyclonal B-1 response unlikely. Whilst only 9% of IgM sequences displayed a significantly enhanced Ag selection, 29% of IgE transcripts were indicative of a classical Ag-driven immune response with affinity maturation (p < 0.001). In summary IgE transcripts in the circulation of children with allergic asthma reflect a classical adaptive B-2 cell response. This study provides reference data for a better characterization of the IgE response under immunomodulating therapies, such as anti-IgE therapy or allergen-specific immunotherapy.