Tomlinson, G.S. (2012) Inflammatory responses by monocytes and macrophages in pulmonary sarcoidosis and infection. Doctoral thesis, UCL (University College London).
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Inflammatory responses by macrophages are essential for host defense, but also underpin the pathogenesis of numerous diseases. I adopted a systems biology approach using transcriptional profiling to investigate monocyte and macrophage inflammatory responses in relation to pulmonary sarcoidosis and infection, to compare alveolar macrophages (AM) and monocyte derived macrophages (MDM), and to probe integrated innate and adaptive immunological responses within the tuberculin skin test (TST). In sarcoidosis I established the importance of prostaglandin endoperoxide synthase (PTGS)2 promoter haplotypes in determining susceptibility to disease across two genetically dissimilar ethnic groups, UK Whites and Afro-Caribbeans, but found no functional effect of promoter haplotype on PTGS2 gene expression, in mononuclear phagocytic cells. In contrast to the widely held view that AM have an anti-inflammatory bias, I show that freshly isolated AM have a striking pro-inflammatory profile that may confound the study of their responses to innate immune stimulation. In human immunodeficiency virus (HIV)/Mycobacterium tuberculosis (Mtb) co-infection I show that HIV-1 infection of macrophages leads to augmented inflammatory responses to Mtb, accompanied by enhanced viral replication, due to deficient induction of anti-inflammatory IL10, via attenuation in mitogen activated protein kinase (MAPK) signalling pathways downstream of TLR2 and dectin-1. These changes were not evident in HIV-1/Streptococcus pneumoniae co-infected macrophages, and the specificity of the effect in Mtb co-infection was mirrored by lower IL10 and higher pro-inflammatory IL1β in HIV-infected patients with pulmonary tuberculosis compared with non-tuberculous infection. Finally, I show that the TST is characterised by Th1 polarised and cytotoxic T cell responses. Distinct innate immune and IFNγ-stimulated gene expression signatures under NFκB and STAT1 transcriptional control and highly enriched for chemokines and MHC class II molecules, provide a mechanism for paracrine amplification of inflammatory responses in the TST. Strikingly, identical responses of lower magnitude were also detectable in clinically negative TST subjects.
|Title:||Inflammatory responses by monocytes and macrophages in pulmonary sarcoidosis and infection|
|Additional information:||Permission for digitisation not received|
|UCL classification:||UCL > School of Life and Medical Sciences > Faculty of Medical Sciences > Medicine (Division of)|
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