Thesis (PhD (Pathology. Anatgomical Pathology))--University of Stellenbosch, 2005. / The formation of granulomas at the site of antigen presentation in both tuberculosis and
sarcoidosis is an essential component of host immunity for controlling inflammation.
Granuloma formation is a complex process that also requires recruitment and activation of
lymphocytes and macrophages to the site of infection and arrangement into a granuloma. It
is dependant on the activation of especially IFNγ secreting CD4+ T cells, resulting in a Th1
profile. However, it is suggested that a persistently high IFNγ is responsible for the damage
caused 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 the
disease process, after the antigen has been effectively contained.
I propose that: “Cytokine profiles determine clinical and histopathological phenotypes of
disease. This thesis tests the hypothesis that it will be reflected by cytokine expression
profiles in granulomas in different forms of tuberculosis and in sarcoidosis.” To examine
this, biopsy tissue was obtained from patients with pulmonary cavitary tuberculosis, pleural
tuberculosis in HIV sero-negative and sero-positive patients, and sarcoidosis. The diagnosis
of tuberculosis or sarcoidosis was confirmed, granulomas were characterised as necrotic or
non-necrotic, sarcoidosis cases were graded histologically and in situ hybridisation was
performed for IL-12-, IFNγ-, TNFα- and IL-4-mRNA.
In all patients with pleural tuberculosis, a Th0 profile was noted, while necrotic granulomas
were more evident in HIV positive than HIV negative patients. There was a clear
association between TNFα and necrosis in tuberculous granulomas that may be ascribed to
the increased apoptotic activity of TNFα. An increase in IFNγ correlated with an increase
in necrosis, supporting the theory that high IFNγ levels later in disease is detrimental. This
effect may be enhanced by a strong presence of TNFα positive cells. An increase in both
Th1 and Th2 cytokine mRNA in HIV positive patients supports the theory that an
overproduction of cytokines may be a mechanism to compensate for the failure of another
immune effector mechanism. Findings in pulmonary tuberculosis were similar to those in
pleural tuberculosis.
In all sarcoidosis cases the presence of a very strong Th1 and TNFα, but no Th0 response
was confirmed. None of the differences in either the histological grading, or the clinical
outcome of patients were reflected in the cytokine profile. It is possible that this profile
does not reflect the histological grade of disease or that it may reflect various stages of
disease. These findings support the theory that a strong Th1 presence later in disease, in
conjunction with TNFα may induce fibrosis, as most of these cases showed signs of at least
focal fibrosis.
Numerous aspects, including a T helper response are involved in granulomatous
inflammation. 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 cytokine
depends at least partially on the stage of disease. The balance between the various
cytokines, and the levels of these cytokines contribute to their role in resolution or disease
progression. An early, pure Th1 response may be beneficial if effectively clearing the
granuloma-inducing antigen. At this stage, a Th2 presence will be harmful as clearing of
the antigen will not be as effective. In chronic disease where failure to remove the antigen
results in progression of granulomas with subsequent necrosis and/or fibrosis, a proinflammatory
Th1 response may be detrimental and minimising of this effect is needed. An
overly strong presence of the various cytokines may also be detrimental, while lower levels
will be beneficial.
| Identifer | oai:union.ndltd.org:netd.ac.za/oai:union.ndltd.org:sun/oai:scholar.sun.ac.za:10019.1/1453 |
| Date | 12 1900 |
| Creators | Bezuidenhout, Juanita |
| Contributors | Walzl, G., University of Stellenbosch. Faculty of Health Sciences. Dept. of Pathology. Anatomical Pathology. |
| Publisher | University of Stellenbosch. Faculty of Health Sciences. Dept. of Biomedical Sciences. |
| Source Sets | South African National ETD Portal |
| Language | English |
| Detected Language | English |
| Type | Thesis |
| Rights | University of Stellenbosch |
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