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Pulmonary sarcoidosis: The role of alveolar macrophages in pathogenesis and their modulation with therapy

Spiteri, Monica Ann; (1990) Pulmonary sarcoidosis: The role of alveolar macrophages in pathogenesis and their modulation with therapy. Doctoral thesis (Ph.D), University of London, Royal Free Hospital School of Medicine. Green open access

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Abstract

Pulmonary sarcoidosis is a clinical disorder that arises as a result of a granuloma-forming mechanism, driven by aberrant immunological reactions within the lung interstitium, in response to an as yet unknown stimulus. Extensive work identifying changes within the lymphocyte population and mediator release in sarcoidosis, does not fully explain the outcome of this granulomatous response; in particular its insidious progression to fibrosis, with ultimate irreversible tissue damage in ~ 15% of patients. As it is now recognised that macrophages are intimately involved in T-cell stimulation and granuloma formation, the studies in this thesis test the hypothesis that aberrations within the alveolar macrophage (AM) population contribute to the pathogenesis of pulmonary sarcoidosis. AM were obtained from the lungs of a total of 62 normal volunteers, and 115 biopsy- proven sarcoid patients by means of bronchoalveolar lavage (BAL), (the technique of which was standardized prior to formal studies). As the AM population is known to be heterogeneous, use was made of specific monoclonal antibody probes that discriminate subpopulations of macrophages. Initial studies identified 3 phenotypically distinct macrophage subpopulations in both normal and sarcoid BAL. The latter consistently contained a high proportion of macrophages with the phenotype of dendritic cells. Much of this increase was accounted for by the emergence of AM expressing the surface phenotype of both dendritic cells and 'classic' macrophages. To test the possibility that relative changes within these AM subsets may directly influence lymphocyte inductive capacity, experiments were set up to isolate them from BAL. A combination of techniques involving cell adherence, metrizamide density gradients and antibody-conjugated magnetic beads were used. This enabled a detailed analysis of their individual phenotypic, physiological and functional characteristics. All 3 AM subsets isolated from normal volunteers displayed distinctive features. In addition, individual cell phenotype could be related to specific functional capacity. It was clearly demonstrated that within the AM pool, besides T-cell inducer macrophages and 'classic phagocytic macrophages', there existed a double phenotype macrophage subset capable of actively down-regulating T-cell responsiveness. With the advent of disease, changes in the proportion of these AM subpopulations were accompanied by sarcoid-related differences in phenotype, physiology and function. In particular, double phenotype AM from active sarcoid patients expressed a separate antigen, which identifies epithelioid cells, and showed an intense reaction for fibronectin. The T-cell suppressive action of this AM subset was also noted to be enhanced in sarcoidosis. The above cellular aberrations in the lower respiratory tract of sarcoid patients do not seem to be pathognomonic to the disease itself. Current studies have shown that besides overlapping clinical features, both sarcoidosis and primary biliary cirrhosis share the same underlying mechanisms of macrophage- T-cell interaction, at least in the lung. Finally, these local immune responses could be directly manipulated by therapeutic regimes. In an 18-month placebo-controlled study, it was seen that both inhaled and systemic corticosteriods were capable of altering the aberrant cellular profiles (including function), possibly through an influence on the AM population. Such immune modulation was accompanied by clinical improvement. The information in this thesis bears testimony to the hypothesis that the changes observed within the AM population in the sarcoid lung are partly controlled by factors arising in the local milieu. Such changes are finely balanced, and as such are critical to the outcome of the cellular immune response in pulmonary sarcoidosis.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: Pulmonary sarcoidosis: The role of alveolar macrophages in pathogenesis and their modulation with therapy
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Thesis digitised by ProQuest.
Keywords: Health and environmental sciences
URI: https://discovery.ucl.ac.uk/id/eprint/10121257
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