Seah, Geok Teng; (2000) Type-2 cytokines in the immunopathology of tuberculosis. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Immune correlates of protective and deleterious host responses in human tuberculosis are not well understood, but this knowledge is central to the design of new immunotherapeutic and vaccination strategies. Interest was focused on type-2 cytokines in the immunopathology of human tuberculosis in this work because exacerbation of disease coincides temporally with the emergence of type-2 responses in murine tuberculosis, but the human data had been inconclusive. A novel, sensitive method of measuring low copy number cytokines with a 5-log detection range was developed and validated for studying type-2 cytokine messenger ribonucleic acid (mRNA) production in unstimulated human cells, then applied to a clinical tuberculosis study. When compared to healthy tuberculin-positive tuberculosis contacts, tuberculosis patients expressed significantly higher levels of interleukin (IL)-4 and IL-13 mRNA which correlated with the radiographic extent of disease and serum immunoglobulin E levels, and did not always decline following treatment. Expression of the IL-4 splice-variant (IL4δ2) was also studied for the first time in this disease, and found to be bimodally distributed within the study population. Observations on human peripheral blood lymphocyte in vitro responses to M. tuberculosis sonicate (MtbS) antigens suggested that MtbS-activated lymphocytes were more susceptible to cytotoxic effects of TNF-α in the presence of IL-4. Lymphocytes expressing CD30 were particularly susceptible, and such cells had diminished levels of TNF-receptor-associated factor 2 (TRAF2) expression. TRAF2 mediates cytoprotective signalling pathways downstream of both TNF-α receptors and CD30. The levels of CD30 expression and IL-4 mRNA expression in MtbS-reactive lymphocytes were significantly higher than those in lymphocytes responding to M. vaccae sonicate antigens. CD30 expression was found to be IL-4-dependent in this model. A pathway linking apoptosis of MtbS-reactive lymphocytes to IL-4 production was proposed, and hence a potential mechanism by which type-2 cytokines may contribute to pathologic host responses in human tuberculosis.

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