Molecular Biology and Human Genetics

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Browsing Molecular Biology and Human Genetics by browse.metadata.advisor "Beyers, Nulda"

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    Immune responses in a community with a high incidence of tuberculosis
    (Stellenbosch : Stellenbosch University, 2004-03) Adams, Joanita Frances Ann; Beyers, A. D.; Van Helden, P. D.; Beyers, Nulda; Stellenbosch University. Faculty of Medicine & Health Sciences. Dept. of Biomedical Sciences. Molecular Biology and Human Genetics.
    ENGLISH ABSTRACT: It is estimated that about one third of the world's population is infected with Mycobacterium tuberculosis (M. tuberculosis). Of those infected, only 10 % will develop disease of which 3-5 % will relapse after completion of treatment. Susceptibility to M tuberculosis or relapse following treatment, may be due to environmental influences such as poverty-related factors including intestinal parasites (helminths), and/or genetic factors, all of which can influence the immune response to M. tuberculosis. In the current study, the epidemiology of mycobacterial infection and helminths was studied in two adjacent suburbs of Cape Town, South Africa. These communities had a tuberculosis notification rate of over 1 000/100 000 population with rampant infestations by helminths such as Ascaris lumbricoides and Trichuris trichiura. M. tuberculosis infection and Bacille Calmette Guerin (BCG) vaccination induce a Thl (type 1) immune response, while a Th2 (type 2) immune response is required for expulsion of intestinal parasites. Type 1 and type 2 responses negatively cross regulate each other in vitro and in experimental models. The interaction of these two immune responses in the study community, were investigated. It was hypothesised that susceptibility to M. tuberculosis and progression to disease may be increased in individuals mounting prominent type 2 immune responses, manifested by high serum IgE levels. Furthermore it is proposed that that poverty-related factors and intestinal parasites, specifically those trafficking through the lungs, could further augment the type 2 dominance in the study community. Results presented show that serum IgE concentrations, surrogate marker for type 2 activation, were high among healthy adults, confirming the dominance of type 2 responses. When characterised in census blocks or enumerator sub-districts (ESDs), IgE levels correlated with the tuberculosis notification rate per ESD. The notification rate of tuberculosis also correlated with the socio-economic status, female literacy and population density of the study population. Although these correlations do not necessarily imply a causal relationship, these factors are associated with susceptibility to M. tuberculosis. It was also shown that IgE concentrations decreased significantly after successful treatment of tuberculosis, showing that IgE concentrations in humans can be down-regulated under these circumstances, presumably due to enhancement of a type 1 response. Furthermore, as a reason for the high serum IgE concentrations in the study population, the helminth burden was subsequently measured in all primary school children in the study community. Results show that more than 50 % of the children recruited were infected with A. lumbricoides and/or T. trichiura. Schools situated in the poorest areas with the highest tuberculosis notification rates, presented with the highest prevalences of helminths. All the children, irrespective of their helminth status or their participation in the study, subsequently received ant-helminthic treatment. The BCG vaccination scar status and Mantoux skin test responses were available on a sub-sample of the above-mentioned school children. Although it is assumed that most children receive BCG vaccination in the neonatal period, only two thirds of the children had evidence of a BCG scar. The results show that the prevalence of BCG scar positivity, while independent of age, was lower in children around 11 years of age. In contrast to the broad constancy of BCG scar expression, the percentage of children showing Mantoux reactivity increased with age, from 13 % at 6 years to 65 % at mid teenage. The time course of Mantoux conversion with age indicated that any tuberculin sensitivity, induced by the BCG, waned within the first few years of life and that PPD responsiveness thereafter was induced by environmental exposure to M. tuberculosis. Contrary to the ThllTh2 paradigm, the prevalence of helminth infection in children with a BCG scar was marginally lower than in those without one. A relatively weak positive correlation was found between tuberculin responsiveness and helminth infection and this correlation was most marked in children without a BCG scar. In this subgroup, children who were infected with helminths were more likely to be PPD responsive than those who were not infected. The data showed that conversion to PPD sensitivity predisposed to helminth infection. The results suggest that the effect of helminth infection on the development of clinical tuberculosis is such that those with large worm burdens and who make good PPD responses are likely to be resistant whereas those who deal very effectively with these parasites and who make weaker PPD responses are more likely to be susceptible. The data also indicate that the BCG vaccine used in this study does not give rise to a latent infection whereas the pathogenic M. tuberculosis does so and repeatedly stimulates an immune response to it. In a separate study, it was demonstrated how the host response to M. tuberculosis differs in patients at risk for developing tuberculosis after successful completion of treatment, compared to those who have protective immunity. Individuals participating in the study were also interviewed to understand their social and economic background and how it relates to the disease. Purified protein derivative (PPD) and M. tuberculosis-induced cytokine responses were determined in the study groups. The results show that single immunological marker of susceptibility could not be distinguished, but rather immunological patterns of susceptibility were observéd. Individuals who have had tuberculosis once before and who had been cured, presented with an immuno-suppressive profile, which included high concentrations of IL-lO, TGF-13 as well as high IgE levels. This type of profile suggests that although these individuals have had tuberculosis once before, they have not acquired protective immunity and would be susceptible to reinfection and progression to disease. Furthermore, the interviews conducted showed that most of the people included in this study were poor, unemployed, undernourished and lived in overcrowded conditions. It seems inevitable that those individuals with the immuno-suppressed profile living in poverty would present with a second episode of tuberculosis in the near future. We conclude that in the study community, which has a typical third world setting, poverty-related factors including helminths, could contribute to a dominant type 2 immune response which in tum, would down-regulate the protective type I response, resulting in an enhanced susceptibility to M. tuberculosis and progression to disease.