Dokument

Zusammenfassung:
Neurotrophine sind lösliche, nicht kovalent gebundene Homodimerpeptide, die initial im Zentralnervensystem von Vertebraten detektiert worden sind. Sie vermitteln dort in erster Linie anti-apoptotische Effekte wie Proliferation, Differenzierung, Überleben der Zelle und Schutz vor zytotoxischen Zellschaden; daneben sind auch nicht-topische Effekte wie Induktion von Chemotaxis zur regelrechten Axonsprossung bekannt. Hauptvertreter sind NGF, BDNF, NT-3 und NT-4/5. Dabei werden Neurotrophine nicht nur die Zielzelle umgebenen Zellen sezerniert, sondern auch durch die Zielzelle selbst im Sinne autokriner Mechanismen. Die Effekte der Neurotrophine werden durch zwei Familien von Neurotrophine-Rezeptoren vermittelt: die Tyrosinkinase-Glykoprotein-Rezeptoren binden nur bestimmte Neurotrophine mit hoher Affinität und vermitteln anti-apoptotische Effekte. Sie werden in 3 Klassen unterschieden: trkA, trkB und trkC. Dabei werden durch die Zielzelle durch alternatives Splicing verschiedene Isoformen dieser Rezeptoren exprimiert, darunter auch solche die keine katalytische Tyrosinkinase-Domäne beinhalten. Ein weiterer Rezeptor ist der Pan-Neurotrophin-p75-Rezeptor, der alle Neurotrophine mit gleicher Affinität bindet. Er vermittelt bivalente Funktionen: bei Anwesenheit von trk-Rezeptoren antia-apoptotische Effekte, bei Abwesenheit von trk-Rezeptoren pro-apoptototische Effekte. In den letzten 20 Jahren wurde etraneuronal insbesondere auf Immunzellen Neurotrophin-Synthese und Neurotrophin-Rezeptor-Expression detektiert. Hinsichtlich der B-Zellen zeigen sich jedoch divergente Angaben. Einige Autoren belegen, daß die B-Zelle alle Neurotrophine und deren Rezeptoren exprimiert, andere Autoren belegen lediglich eine Expression von trkA und p75. Dabei sind in diesen Arbeiten einige Limitationen offensichtlich: Verwendung von malignen B-Zellen bzw- EBV-transformierten B-Zellen und Verwendung immunhistochemischer Nachweisverfahren. In dieser Arbeit wurde mittels molekularbiologischer Methodik eine umfassende Charakterisierung der unreifen B-Zellen des Knochenmarks und reifer B-Zellen (exemplarisch in der Milz) in einer Wildtyp-Maus verwirklicht. Dabei zeigt sich, daß reife wie unreife B-Zellen alle bekannten Neurotrophine und deren Rezeptoren exprimiert. Eine Ausnahme besteht jedoch hinsichtlich des trkB-Rezeptors; dieser wird nur in einer Isoform exprimiert, die keine katalytische Tyrosinkinase-Domäne besitzt (trkBgp95). In der quantitativen real-time-PCR zeigt sich, daß BDNF das dominante Neurotrophin der unreifen B-Zelle im Knochenmark und NT-3 und NGF das dominante Neurotrophin der reifen B-Zelle ist. Hinsichtlich der Neurotrophin-Rezeptoren gibt es keine quantitativen Unterschiede, lediglich der Neurotrophin-Rezeptor trkC wird geringradig mehr durch die unreifen B-Zellen des Knochenmarks exprimiert.

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