Dokument

Zusammenfassung:
Die Hygiene-Hypothese identifizierte vor über 20 Jahren u. a. humanpathogene Helminthen als möglichen Schutzfaktor gegenüber dem Auftreten allergischer Erkrankungen. Viele epidemiologische Studien zeigten eine inverse Korrelation zwischen dem Vorhandensein einer Helminthen-Infektion und der Prävalenz allergischer Erkrankungen, wie z. B. Asthma bronchiale. In den letzten Jahren wurden zunehmend Mausmodelle eingesetzt, um wichtige Faktoren, die für das antiallergische und immunmodulatorische Potential von Helminthen verantwortlich sind, zu identifizieren. Die durch eine chronische Helminthen-Infektion induzierte Immunantwort wird auch als alternative TH2-Antwort bezeichnet (Yazdanbakhsh et al., 2002). Meist liegt – ähnlich wie bei allergischen Erkrankungen - eine starke TH2-Antwort mit hohen systemischen IgE-Konzentrationen vor, jedoch fehlt jegliche Pathologie und Symptomatik. Dieses „Helminthen-Paradoxon“ (Smits et al., 2010) und insbesondere die Rolle der IgE-Antikörper-Antwort gilt es zu entschlüsseln. Hierfür wurden BALB/c-Mäuse mit L. sigmodontis über den Biss des natürlichen Vektors - der Tropischen Rattenmilbe (O. bacoti) - infiziert. Der Phänotyp der Mäuse wurde anschließend in einem etablierten Modell der akuten allergischen Atemwegsentzündung untersucht und mit nicht infizierten Mäusen verglichen. Fraglich war, ob die Wurm-Infektion im verwendeten Modell vor Asthma schützen würde und welche Auswirkungen sie auf den Prozess der allergischen Sensibilisierung und den Charakter des IgE-Antikörper-Repertoires haben würde. Die vorliegende Arbeit charakterisiert erstmals das IgE-Repertoire von Helminthen-infizierten Tieren in einem murinen Asthmamodell. Hierfür wurde splenische RNA extrahiert, umgeschrieben und mit einer RT-PCR amplifiziert. Das Produkt wurde in ein Plasmid ligiert, welches wiederum in kompetente E. coli-Zellen transferiert und kloniert wurde. Das monoklonale DNA-Amplifikat, das für die variable Region der schweren Kette des IgE-Moleküls kodierte, wurde von einem kommerziellen Anbieter sequenziert und anschließend durch einen etablierten Algorithmus analysiert. Zudem wurden Antikörper-Serumkonzentrationen mittels ELISA bestimmt, splenische B-Zellen mittels Durchflusszytometrie differenziert und als Indikator der allergischen Atemwegsentzündung der Influx eosinophiler Granulozyten in die Lunge mittels maschineller und mikroskopischer Zelldifferenzierung. gemessen. Während nicht infizierte Tiere einen starken Influx an eosinophilen Granulozyten in die Lunge zeigten, waren L. sigmodontis-infizierte Tiere - analog zu der erweiterten Hygiene-Hypothese - vor allergischer Atemwegsentzündung geschützt. Sie zeigten eine robuste TH2-wendige Immunantwort, viel stärker als bei nicht infizierten OVA-sensibilisierten Tieren. Die Immunantwort auf OVA wurde von der Helminthen-Infektion moduliert. Das IgE-Repertoire unterschied sich von dem Repertoire nicht infizierter Tiere in der CDR-H3-Komposition, durch längere CDR-H3, vermehrte Nutzung von gestreckten CDR-H3-Basisstrukturen und durch höhere Variabilität. Es konnten erhöhte somatische Mutationsraten und Anzeichen für Antigenselektion nachgewiesen werden. Dies spricht für eine oligoklonale Immunantwort, hervorgerufen durch klassische Affinitätsreifung. Es zeigt sich demnach, dass eine Infektion mit L. sigmodontis in dem hier genutzten Mausmodell vor Asthma bronchiale schützt und das IgE-Repertoire in Struktur und Funktion beeinflusst. Die Ergebnisse sind kompatibel mit der „IgE-Blocking-Hypothese“, welche postuliert, dass Helminthen-spezifische IgE-Antikörper durch Kreuz-Reaktion mit Allergen-spezifischem IgE oder Kompetition um den FcɛR1 eine Effektorzell-Degranulation verhindern.

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