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Asthma pp 33-57 | Cite as

Mononuclear cells in the pathogenesis of bronchial asthma

  • St. J. Lane
  • T. H. Lee

Summary

In conclusion, there is increasing evidence implicating the central role of cells of monocyte/macrophage lineage in the pathogenesis of bronchial asthma. This evidence comes from studies on peripheral blood monocytes, BAL fluid and cells and more recently, airway immunohistochemistry. Elucidation of the mechanisms of macrophage interactions may eventually lead to novel approaches in anti-asthma therapy.

Keywords

Alveolar Macrophage Idiopathic Pulmonary Fibrosis Allergy Clin Immunol Peripheral Blood Monocyte Beclomethasone Dipropionate 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Zusammenfassung

Mononukleäre Zellen bei der Pathogenese des Asthma bronchiale. Unsere Untersuchungen zielen auf die Erforschung der Effekte der von Monozyten und Makrophagen gebildeten Zellprodukte ab, welche auch die Funktion der Granulozyten und T-Zellen beeinflussen, aufgrund der erwiesenen Aktivierung von Monozyten und Makrophagen beim Asthma.

Monozyten des peripheren Blutes von Asthma-Patienten weisen eine gesteigerte Expression von FCeR2 und Komplementrezeptoren auf, welche mittels der Rosettentechnik auf Monozyten von Asthma-Patienten nach Allergenprovokation erfaßt werden kann.

Die Alveolarmakrophagen von Patienten mit Asthma zeigen eine gesteigerte Fähigkeit zur Produktion von Eicosanoidmediatoren und Superoxydanion. Weiters tragen diese Zellen FC£R2 auf ihrer Oberfläche und können damit zur Freisetzung von Mediatoren durch IgE- abhängige Ereignisse angeregt werden.

Die Analyse der bronchoalveolaren Lavageflüssigkeit von Patienten mit Asthma nach Antigenprovokation zeigte, daß die sekretorischen Prozesse der Makrophagen durch die Allergenprovokation aktiviert wurden.

Der Überstand einer Zellkultur aus peripheren mononukleären Zellen von atopischen Asthmatikern erhielt mehr Überlebenssteigemde Aktivität für Eosinophile als der von nicht atopischen Individuen. Dieser Faktor wurde als GM-CSF ausgewiesen. Die Gegenwart von GM-CSF in der Lunge dürfte eine wichtige Rolle bei der Amplifikation der eosinophilen Entzündung spielen.

In den Bronchialbiopsien von 16 asthmatischen Patienten und 6 Normalpersonen zeigte sich, daß bei den Asthmatikern die Gesamtzahl der infiltrierenden Makrophagen gesteigert war, wobei viele dieser Zellen die phänotypischen Charakteristika der Monozyten des peripheren Blutes aufwiesen. HLA II Antigen wurde von den infiltrierenden Zellen und den Atemwegsepithelien exprimiert. Es fand sich bei den Asthmatikern eine signifikante Steigerung der aktivierten Eosinophilen, aber nicht der Neutrophilen, femer eine signifikante Steigerung der Zahl der T-Lymphozyten mit sehr wenigen B-Lymphozyten. Diese Resultate lassen vermuten, daß die Lungenmakrophagen eine Rolle bei der Entstehung der chronischen immunmediierten Entzündung spielen, und daß eine Heterogenität von Makrophagensubpopulationen vorliegt. Wir haben zeigen können, daß die Zahl der GM-CSF bildenden Zellen in der Schleimhaut von Asthmatikem 7 x größer ist als bei Normalpersonen, wofür hauptsächlich die deutlich vermehrten Makrophagen verantwortlich sind. Zusätzlich zur GM-CSF-Exprimierung der Entzündungszellen der Schleimhaut findet sich eine sehr starke Expression dieses Zytokins auch aus den Epithelzellen.

Wenn Beclomethason in einer Dosis von 1000 μg täglich durch 8 Wochen verabreicht wurde, resultierte dies in einer signifikanten Verminderung der GM-CSF Expression im Epithel, welche überdies mit einer Steigerung des FEV1 bzw. einer Zunahme der Carbachol-Provokationsschwelle korrelierte.

Eosinophile, die mit dem Überstand von Alveolarmakrophagenkulturen der Asthmatiker inkubiert und dann mit A23187 stimuliert wurden, zeigten eine Steigerung ihrer Fähigkeit, LTC4 zu sezemieren (mittlere Steigerung 169 ± 37%, n = 31).

Die Hauptkomponente, die hier aktiv war, war offensichtlich eng verwandt mit dem GM-CSF.

GM-CSF und Interferon-Gamma (IFN-Gamma) steigern die Expression von HLA Klasse II Molekülen und die Antigenpräsentation. Autologe T-Zellen wurden in vitro bei normalen und asthmatischen Individuen untersucht. Die Monozyten von normalen und atopischen Personen präsentierten Recall-Antigene gegenüber T-Zellen besser als gegenüber Makrophagen.

Die gesteigerte Fähigkeit von Atemwegsmakrophagen, die T-Zellen von Asthmatikern zu aktivieren, spricht für das Vorhandensein einer unreifen Makrophagenpopulation in den Atemwegen. Es fand sich auch eine Korrelation zwischen der Lymphozytose in der BAL und der relativen Fähigkeit der Alveolarmakrophagen von Asthmatikern, Recall-Antigene zu präsentieren.

Kortikosteroide sind eine wirksame Therapie für das Bronchialasthma. Sie versagen aber bei einer kleinen Gruppe von Patienten, die zu schwerem Asthma neigen, in der Regel für längere Zeitabschnitte arbeitsunfähig sind und in der Langzeittherapie beträchtliche Schwierigkeiten bereiten. Die Steroidresistenz ist verquickt mit einer reduzierten Bindungsaffinität des Glukokortikoidrezeptors (GR) an DNA und eine verminderte Zahl von translozierten Kern-GRs, die für die DNA-Bin- dung verfügbar sind. Zusätzlich ist sie in vitro und in vivo mit einem Defekt in der Funktion der mononukleären Zellen verquickt.

Die Funktion der mononukleären Zellen beim Asthma kann an Monozyten des peripheren Blutes, an Alveolarmakrophagen, an der bronchialen Histologie und bei Untersuchung von Patienten mit Kortikosteroidresistenz studiert werden.

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Copyright information

© Springer-Verlag/Wien 1995

Authors and Affiliations

  • St. J. Lane
    • 1
  • T. H. Lee
    • 1
  1. 1.Department of Allergy and Allied Respiratory DisordersGuy’s HospitalLondonUK

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