The influence of age on the cellular immune response in patients with tuberculosis and healthy controls

Schölvinck, Elisabeth Henriëtte (2002)

Thesis (PhD) -- Stellenbosch University, 2002.

Thesis

ENGLISH ABSTRACT: Children and adults may differ in their immune function. An adequate function of the individual's immune system is crucial to the risk for development of tuberculosis (TB) after infection with Mycobacterium tuberculosis (Mtb). Epidemiological evidence suggests an age-related incidence of TB. Furthermore, the prevailing clinical expression t ' of TB varies between age groups. -The aims of this study were to characterise the cellular immune response at different ages in TB patients and healthy individuals living in a region highly endemic for TB and to relate the findings to the clinical expression of TB in different age groups. A total of 150 persons of different ages were included in this study: 50 TB patients, (identified on the basis of clinical, radiological and microbiological characteristics), 49 healthy Mantoux positive (~15mm) and 51 healthy Mantoux negative (<15mm) subjects. All patients <12yrs were identified as having primary TB and postprimary TB was only diagnosed in patients ~12yrs. Haematologic indices were obtained from all the included subjects and found to be agerelated. With the exception of the absolute lymphocyte counts, all indices were significantly different in TB patients when compared to healthy controls. Whole blood was cultured and stimulated with PHA, PPD and ESAT -6 to measure lymphocyte proliferation and IFN-y, TNF-a, IL-2 and IL-10 production in the supernatants of the cultures. After stimulation with PHA, the production of IFN-y, TNF-a and IL-10 as well as lymphocyte proliferation were all age-related. After stimulation with PPD, age correlated positively with IFN-y production in healthy Mantoux positive subjects< 12yrs. In the age groups <20 yrs, patients produced similar amounts of IFN-y when compared to healthy age-related Mantoux positive controls. TNF-a and IL-2 production were not different between patients and controls. In this whole blood system, measuring any of these cytokines on their own did not differentiate patients from controls at all ages. The ratio of PPD stimulated IFN-y to TNF-a production was significantly less in patients with primary TB and postprimary TB when compared to Mantoux positive controls, irrespective of age. These findings indicate that calculated ratios between several cytokines may be useful markers of disease at all ages. ESA T -6 stimulated IFN -y production did not result in any significant correlation with age, but was significantly less in healthy Mantoux positive subjects ~12 yrs when compared to healthy Mantoux positive subjects <12 yrs and TB patients of all ages. This finding suggests that a positive immune response to ESAT -6 is indicative of recent immunological contact with Mtb. Total IgE was measured in serum. In children <12 yrs these values correlated with age and were highest in healthy Mantoux positive controls, thereby not confirming any inverse correlation between IgE and TB. Age should be recognised as a significant variable in quantitative measurements of cellular immune responses.

AFRIKAANSE OPSOMMING: Die immuunsisteem van kinders en volwassenes kan verskillend wees. Die mate van immuniteit van 'n individu is deurslaggewend vir die risiko om tuberkulose (TB) na infeksie met die Mycobacterium tuberculosis (M tb) te ontwikkel. Epidemiologiese bevindings suggereer dat die insidensie van TB ouderdomgebonde mag wees. V erder verskil die voorkomende kliniese beeld van TB ook tussen ouderdomsgroepe. Die doelstellings van hierdie studie was om die sellulere immuunrespons op verskillende ouderdomme by TB-pasiente en gesonde individue wat in 'n streek met hoogs endemiese TB-insidensie woon te vergelyk. Die doel was ook om vas te stel hoe hierdie bevindings by die kliniese beeld van TB by verskillende ouderdomsgroepe inpas. Daar is l50 persone van verskillende ouderdomme in hierdie studie ingesluit: 50 TBpasiente (geidentifiseer op grond van kliniese, radiologiese en mikrobiologiese karakteristieke), 49 gesonde Mantoux -positiewe (:2':l5mm) en 5l gesonde Mantouxnegatiewe (<l5mm) persone. Alle pasiente <l2 jaar is gediagnoseer met primere TB. Postprimere TB is alleenlik gediagnoseer in pasiente :2':l2 jaar. Daar is aangetoon dat. hematologiese indekse van al die persone in hierdie studie ouderdomsverwant was. Daar was n beduidende verskil in alle indekse van TB-pasiente in vergelyking met die gesonde kontroles met die uitsondering van die absolute limfosiettellings. Kulture van volbloed is gedoen en gestimuleer met behulp van PHA, PPD en ESAT -6 om limfosiet-proliferasie, IFN-y-, TNF-a-, IL-2- en IL-l0-produksie in die supematante van die kulture te meet. Na stimulasie met PHA was die produksie van IFN-y, TNF-a en IL-l0, asook die limfosiet-proliferasie ouderdomsverwant Na stimulasie met PPD het ouderdom positief gekorreleer met IFN-y produksie in gesonde Mantoux-positiewe persone <l2 jaar. In die ouderdomsgroep <20 jaar het pasiente dieselfde hoeveelhede IFN-y geproduseer as gesonde, ouderdomsverwante Mantoux-positiewe kontroles. Daar was geen verskil tussen die produksie van TNF -a. en IL-2 tussen pasiente en kontroles nie. In hierdie volbloed-sisteem het die meet van nie een van hierdie sitokiene op sigself 'n verskil getoon tussen pasiente en kontroles van aile ouderdomme nie. Die verhouding van PPD-gestimuleerde IFN-y- tot TNF-a.-produksie was betekenisvol minder in pasiente met primere TB en postprimere TB in vergelyking met Mantouxpositiewe kontroles, ongeag ouderdom. Hierdie bevindings toon dat berekende verhoudings tussen verskillende sitokiene waardevoile merkers van 'n siektetoestand {TB) by aile ouderdomme kan wees. ESAT-6 gestimuleerde IFN-y-produksie het geen betekenisvoile korrelasie met ouderdom getoon nie. Daar was egter betekenisvol minder produksie in gesonde Mantoux-positiewe persone ~l2 jaar as in gesonde Mantoux-positiewe persone <l2 jaar, asook in vergelyking met TB-pasiente van aile ouderdomme. Hierdie bevinding kan daarop dui dat 'n positiewe immuun respons op ESAT -6 'n aanduiding van onlangse immunologiese kontak met M tb is. Totale IgE was in serum bepaal. In kinders <l2 jaar het hierdie waardes gekorreleer met ouderdomme en die waardes was die hoogste in gesonde Mantoux-positiewe kontroles. Hierdeur is daar nie bevestig dat daar 'n omgekeerde korrelasie tussen IgE en TB is nie. Ouderdom behoort dus as 'n belangrike veranderlike gesien te word in die kwantitatiewe meting van die sellulere immuunrespons.

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