Cytokines and tuberculosis : an investigation of tuberculous lung tissue and a comparison with sarcoidosis

[摘要] The formation of granulomas at the site of antigen presentation in both tuberculosis andsarcoidosis is an essential component of host immunity for controlling inflammation.Granuloma formation is a complex process that also requires recruitment and activation oflymphocytes and macrophages to the site of infection and arrangement into a granuloma. Itis dependant on the activation of especially IFNγ secreting CD4+ T cells, resulting in a Th1profile. However, it is suggested that a persistently high IFNγ is responsible for the damagecaused by granulomatous disease and that moderating cytokines, resulting in a Th0 profile,are necessary to down-regulate the IFNγ response to more appropriate levels later in thedisease process, after the antigen has been effectively contained.I propose that: 'Cytokine profiles determine clinical and histopathological phenotypes ofdisease. This thesis tests the hypothesis that it will be reflected by cytokine expressionprofiles in granulomas in different forms of tuberculosis and in sarcoidosis. To examinethis, biopsy tissue was obtained from patients with pulmonary cavitary tuberculosis, pleuraltuberculosis in HIV sero-negative and sero-positive patients, and sarcoidosis. The diagnosisof tuberculosis or sarcoidosis was confirmed, granulomas were characterised as necrotic ornon-necrotic, sarcoidosis cases were graded histologically and in situ hybridisation wasperformed for IL-12-, IFNγ-, TNFα- and IL-4-mRNA.In all patients with pleural tuberculosis, a Th0 profile was noted, while necrotic granulomaswere more evident in HIV positive than HIV negative patients. There was a clearassociation between TNFα and necrosis in tuberculous granulomas that may be ascribed tothe increased apoptotic activity of TNFα. An increase in IFNγ correlated with an increasein necrosis, supporting the theory that high IFNγ levels later in disease is detrimental. Thiseffect may be enhanced by a strong presence of TNFα positive cells. An increase in bothTh1 and Th2 cytokine mRNA in HIV positive patients supports the theory that anoverproduction of cytokines may be a mechanism to compensate for the failure of anotherimmune effector mechanism. Findings in pulmonary tuberculosis were similar to those inpleural tuberculosis.In all sarcoidosis cases the presence of a very strong Th1 and TNFα, but no Th0 responsewas confirmed. None of the differences in either the histological grading, or the clinicaloutcome of patients were reflected in the cytokine profile. It is possible that this profiledoes not reflect the histological grade of disease or that it may reflect various stages ofdisease. These findings support the theory that a strong Th1 presence later in disease, inconjunction with TNFα may induce fibrosis, as most of these cases showed signs of at leastfocal fibrosis.Numerous aspects, including a T helper response are involved in granulomatousinflammation. The earlier dogma of good, beneficial (Th1) versus evil, detrimental (Th2),is an oversimplification of a very complex process. It is clear that the effect of a cytokinedepends at least partially on the stage of disease. The balance between the variouscytokines, and the levels of these cytokines contribute to their role in resolution or diseaseprogression. An early, pure Th1 response may be beneficial if effectively clearing thegranuloma-inducing antigen. At this stage, a Th2 presence will be harmful as clearing ofthe antigen will not be as effective. In chronic disease where failure to remove the antigenresults in progression of granulomas with subsequent necrosis and/or fibrosis, a proinflammatoryTh1 response may be detrimental and minimising of this effect is needed. Anoverly strong presence of the various cytokines may also be detrimental, while lower levelswill be beneficial.

[发布机构] Stellenbosch University