Thesis (PhD)--Stellenbosch University, 2004 / 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. / AFRIKAANSE OPSOMMING:
Dit word beraam dat ongeveer een derde van die wêreld se populasie geïnfekteer is met
Mycobacterium tuberculosis (M. tuberculosis). Van diegene wat wel geïnfekteer is, sal
slegs 10 % siekte ontwikkel met 3-5 % wat 'n relaps episode sal ervaar na voltooiing van
behandeling. Vatbaarheid vir M. tuberculosis of 'n relaps episode gevolg na behandeling,
mag toegeken word aan armoede-verwante faktore wat intestinale parasiete (helminte)
asook genetiese faktore, insluit. Hierdie faktore het die vermoë om die immuun respons
teen M. tuberculosis te beïnvloed. In die huidige studie, is die epidemiologie van die
mikobakteriele infeksie en helminte bestudeer in twee aangrensende voorstede van
Kaapstad, Suid Afrika. Hierdie gemeenskappe het 'n tuberkulose aanmeldings koers van
1 000/1 00 000 populasie met verpreide infestasies met helminte soos Ascaris
lumbricoides and Trichuris trichiura. Infeksie met M tuberculosis en vaksinasie met
Bacille Calmette Guerin (BeG), induseer 'n Th1 (tipe 1) immuun respons, terwyl 'n Th2
immuun respons benodig word vir die eliminasie van intestinale parasiete. Die interaksie
tussen die twee immuun response was in die huidige studie populasie bestudeer. Dit word
gepostuleer dat persone met 'n sterk tipe 2 immuun respons, gemanifesteer deur hoë
serum IgE vlakke, vatbaar is vir infeksie met M. tuberculosis en progressie tot siekte.
Verder was dit voorgestel dat armoede-verwante faktore en intestinal parasiete, veral
parasiete wat deur die longe beweeg, 'n dominante tipe 2 respons verder kan versterk.
Die resultate voorgestel, wys daarop dat serum IgE konsentrasies, 'n surrogaat merker vir
tipe 2 aktivering, hoog was in gesonde volwassenenes. Dit het die siening van 'n
dominante tipe 2 respons bevestig. IgE vlakke was bereken vir elke sensus blok of
enumerator sub-distrik (ESD) en het gekorreleer met die tuberkulose annmeldings koers
per ESD. Die aanmeldings koers het ook gekorreleer met die sosio-ekonomiese status,
vroulike geletterdheid en populasie digtheid. Alhoewel hierdie korrelasies nie
noodwending dui op 'n oorsaak en gevolg verhouding nie, is dit duidelik dat hierdie
faktore kan bydra tot vatbaarheid vir M. tuberculosis. Dit was ook getoon dat IgE
konsentrasies beduidend afneem na suksesvolle behandeling van tuberkulose. Dit wys
daarop dat IgE konsentrasies in mense afgeruleer kan an waarskynlik dui op 'n
verhoogde tipe 1 respons. Verder, as 'n rede vir die hoë IgE konsentrasies in die studie populasie, is die helmint ladings gevolglik in alle prim ere skool kinders in die studie
populasie, gemeet. Die resultate dui daarop dat meer as 50 % van die kinders ingesluit,
geïnfekteer was met A. lumbricoides en/of T. trichiura. Skole in areas met die hoogste
armoede syfer en tuberkulose annmeldings koers, het ook die hoogste prevalensie van
helminte gehad. Alle kinders, ongeag hulle helmint status of hulle deelname in die studie,
het gevolglik anti-helmintiese behandeling ontvang.
BeG vaksinasie littekens en Mantoux vel toets response was beskikbaar op 'n subpopulasie
van die bogenoemde skool kinders. Alhoewel dit aanvaar word dat die
meerderheid van kinders BeG vaksinasie in die neonatale periode ontvang het, het slegs
twee derdes van die kinders 'n BeG litteken getoon. Die resulatate dui daarop dat die
prevalensie van BeG litteken positiwiteit, onafhanklik van ouderdom, laer was in kinders
rondom die ouderdom van 11 jaar. In kontras met die konstante uitdrukking van BeG
littekens, het die persentasie van Mantoux reaktiwiteit verhoog met ouderdom vanaf 13
% by 6 jaar tot 65 % teen 15 jarige ouderdom. Die tyd koers van Mantoux omskakeling
met ouderdom dui daarop dat tuberkulin sensitiwiteit, geïnduseer deur BeG, afneem
binne die eerste paar jaar van lewe en dat PPD responsiwiteit daarna deinduseer word
deur omgewings blootstelling aan M. tuberculosis. In kontras met die ThllTh2
paradigma, was die prevalensie van helmint infeksies in kinders met 'n BeG litteken
marginaal laer teenoor hulle sonder 'n litteken. 'n Relatiewe swak posititiewe korrelasie
was gevind tussen tuberkulin responsiwiteit en helmint infeksie. Hierdie korrelasie was
meer beduidend in kinders sonder 'n litteken. In hierdie sub-groep, was die helmintgeïnfekteerde
kinders meer geneig om PPD responsief te wees teenoor hulle wat nie
geïnfekteer was nie. Die data wys daarop dat omskakeling na PPD sensiwiteit kan lei tot
infeksie met helminte. Die resultate stel voor dat die effek van helmint infeksie op die
ontwikkeling van kliniese tuberkulose van so 'n aard is dat diegene met groot wurm
ladings en wat goeie PPD response toon, meer geneig sal wees om weerstandig te wees.
Diegene egter wat die parasiete beter kan beheer and wat goeie PPD response toon, sal
meer geneig wees om vatbaar te wees vir tuberkulose. Die data dui ook daarop dat die
BeG vaksien wat in die studie gebruik was, nie lei tot latente infeksie nie, terwyl
patogene M tuberculosis dit wel doen en herhaardelik die immuun respons sal stimuleer.
In 'n aparte studie, was dit gedemonstreer dat die gasheer-respons teen M. tuberculosis in
pasiënte wat die gevaar loop om na suksesvolle voltooiing van behandeling, weer
tuberkulose te ontwikkel, verskil van diegene wat beskermende immuniteit het.
Onderhoude was ook gevoer met indiwidue wat deelgeneem het aan die studie, om ten
einde hul sosiale en ekonomiese agtergrond te verstaan en hoe dit gekoppel is aan die
siekte. Purified protein derivative (PPD) en M. tuberculosis-geinduseerde sitokien
response was in die studie groepe bepaal. Die resultate wys daarop dat alhoewel 'n enkele
immunologiese merker nie geidentifiseer kon word nie, was immunologiese patrone vir
vatbaarheid welopgemerk. Indiwidue wat reeds een episode van tuberkulose gehad het
en suksesvolle behandeling ontvang het, het 'n onderdrukte immuun profiel getoon. Dit
het ingesluit hoë vlakke van die sitokiene, IL-lO en TGF-J3 asook hoë vlakke van serum
IgE. Hierdie tipe profiel stel voor dat ten spyte van die vorige tuberkulose episode,
hierdie persone nie beskermende immunitiet ontwikkel nie en dus vatbaar is vir herinfeksie
en progressie tot siekte. Die onderhoude het getoon dat die meerderheid van
mense in die studie populasie onder armoedige oorbevolkte omstandighede lewe, wat
werkloosheid en ondervoeding insluit. Die studie het verder getoon dat hierdie indiwidue
met die onderdrukte immuun profiel en wat in armoede lewe, in die nabye toekoms
vatbaar is vir 'n tweede episode van tuberkulose.
In die studie gemeenskap, met 'n tipiese derde wêreld opset, is daar gewys dat armoedeverwante
faktore en helminte, mag bydra tot 'n dominante tipe 2 immuun respons wat op
sy beurt, die beskermende tipe 1 response sal af-reguleer. Dit sal uiteindelik lei tot
verhoogde vatbaarheid vir M. tuberculosis en uiteindelik progressie tot siekte
(tuberkulose).
| Identifer | oai:union.ndltd.org:netd.ac.za/oai:union.ndltd.org:sun/oai:scholar.sun.ac.za:10019.1/49985 |
| Date | 03 1900 |
| Creators | Adams, Joanita Frances Ann |
| Contributors | Beyers, A. D., Van Helden, P. D., Beyers, N., Stellenbosch University. Faculty of Medicine & Health Sciences. Dept. of Biomedical Sciences. Molecular Biology and Human Genetics. |
| Publisher | Stellenbosch : Stellenbosch University |
| Source Sets | South African National ETD Portal |
| Language | en_ZA |
| Detected Language | English |
| Type | Thesis |
| Format | 334 p. : ill. |
| Rights | Stellenbosch University |
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