Decreased IFN- gamma and increased IL-4 production by human CD8(+) T cells in response to Mycobacterium tuberculosis in tuberculosis patients.

To investigate the role of MHC class I restricted CD8(+) T cells in host defense to M. tuberculosis, peripheral blood mononuclear cells (PBMC) from healthy BCG-vaccinated donors and untreated pulmonary tuberculosis (TB) patients in The Gambia were stimulated for 6 days with M. bovis BCG or M. tuberculosis and the CD8(+) T cell response analyzed. Intracellular FACS analysis of cytokine production by CD8(+) T cells showed that IFN- gamma and TNF- alpha production were greatly reduced in TB patients compared to healthy controls. IL-4-producing CD8(+) T cells were detected in TB patients, a phenotype absent in controls. Collectively, these data suggest that an alteration in the type 1/type 2 cytokine balance occurs in CD8(+) T cells during clinical tuberculosis, and that this may provide a surrogate marker for disease.

Clinical and radiological presentation of 340 adults with smear-positive tuberculosis in The Gambia.

SETTING: Four clinics in The Gambia. OBJECTIVE: To document clinical and radiographic presentations of sputum smear-positive tuberculosis in adults. DESIGN: Newly diagnosed acid-fast bacilli (AFB) smear, culture-positive tuberculosis patients aged > or = 15 years were interviewed and examined, and underwent tuberculin skin testing, HIV testing and chest X-ray reviewed by a chest physician using set criteria. RESULTS: Of 340 patients enrolled (median age 29 years; males 73%), 8.3% were HIV-positive. One-third reported haemoptysis, > 90% reported weight loss and fever, and wasting was the most common sign (69%). Crepitations were the most frequent auscultatory finding (41%). The most common radiological lesion was a patchy infiltrate (> 90%). Cavitation was present in 206 patients (60.6%), most frequently occurred in the upper lung fields, was associated with increasing bacterial load in the sputum, and was less prevalent in HIV-positive patients (45% vs. 62%; P = 0.07). Auscultatory and chest X-ray findings matched only one-third of the time. CONCLUSION: In our setting, wasting is the most common clinical sign of sputum smear-positive tuberculosis. Auscultatory findings correlate poorly with radiological abnormalities. Cavitation is associated with increasing bacterial load in the sputum, and is therefore a strong indicator for early treatment.

Traditional healers participate in tuberculosis control in The Gambia.

SETTING: Twenty-three Gambian villages. OBJECTIVE: To evaluate the feasibility of involving traditional healers in tuberculosis diagnosis and treatment in The Gambia. DESIGN: Twenty-eight traditional healers were educated in the recognition of signs and symptoms of tuberculosis and indications for referral. They administered medications to confirmed cases, and were revisited after 1 year to assess knowledge retention. RESULTS: Over 6 months, the traditional healers referred 66 suspects, from whom eight cases were diagnosed. All were successfully treated. Twenty-three of 24 traditional healers re-interviewed retained appropriate knowledge; 16 continued to refer suspects. CONCLUSIONS: Traditional healers can play a positive role in tuberculosis control.

Surveillance of drug-resistant Mycobacterium tuberculosis in The Gambia.

To determine the rates of drug-resistant tuberculosis in The Gambia, Mycobacterium tuberculosis isolates obtained from 225 patients during a nationwide survey were tested against isoniazid, rifampicin, ethambutol and streptomycin using the resistance ratio method. Only nine (4%) of the patients had strains that were resistant to one or more drugs. None of the patients with drug-resistant M. tuberculosis had previously been treated for tuberculosis. Drug-resistant tuberculosis is, as yet, not common in The Gambia. Periodic surveys for drug-resistant tuberculosis are recommended to monitor changes that may emerge over time.

The TB pandemic: an old problem seeking new solutions.

Tuberculosis (TB) continues to kill more than 2 million people globally each year. Annual TB case notification rates have risen up to fourfold since the mid-1980s, with the highest rate of 1000/100,000 around Cape Town, South Africa. There is an urgent need for novel diagnostic methods and preventive vaccines to control this epidemic. The rising incidence of TB has been attributed to HIV co-infection especially in developing countries. The threat of drug resistance arising from ineffective TB treatment programmes is looming and could potentially lead to loss of any gains made in controlling the disease globally.

FOXP3 gene expression in a tuberculosis case contact study.

Regulatory T lymphocytes (T(regs)) that express FOXP3 are involved in the beneficial attenuation of immunopathology, but are also implicated in down-regulation of protective responses to infection. Their role in tuberculosis (TB) is unknown. We classified 1272 healthy TB contacts according to their tuberculin skin test (TST) and interferon (IFN)-gamma enzyme-linked immunospot (ELISPOT) results and 128 TB cases, and studied the expression of FOXP3 and interleukin (IL)-10 in blood samples. Compared to the uninfected contact group (TST(-), ELISPOT(-)), we observed higher levels of FOXP3 mRNA in blood from TB patients (< 0.001), but IL-10 expression was slightly lower (P = 0.04). In contrast, FOXP3 expression levels were significantly lower (P = 0.001) in the recently infected contacts (TST(+), ELISPOT(+)) but there was no difference for IL-10 (P = 0.74). We hypothesize that during early/subclinical TB, most of which will become latent, FOXP3(+) T(regs) may be sequestered in the lungs, but when TB becomes progressive, FOXP3 reappears at increased levels in the periphery. While these findings do not reveal the role, beneficial or harmful, of T(regs) in TB, they emphasize the probable importance of these cells.

Plasmodium falciparum infection of the placenta affects newborn immune responses.

The effects of exposure to placental malaria infection on newborn immunological responses, in particular Th1/Th2 cytokines and antigen-presenting cell (APC) function, were compared between cord blood mononuclear cells (CBMC) from parasitized and non-parasitized placentas of Gambian women. Cells were analysed in vitro for their ability to respond to mitogens [phorbol myristate acetate (PMA)/ionomycin, phytohaemagglutinin (PHA)], a malaria-unrelated test antigen [purified protein derivative of Mycobacterium tuberculin[purified protein derivative (PPD)] and Plasmodium falciparum schizont extracts. Mitogens induced strong proliferation and secretion of high concentrations of both IL-13 and sCD30 in CBMC from both groups. Conversely, significantly lower amounts of IFN-gamma were induced in the parasitized group in response to low doses of PHA. Protein antigens induced very low amounts of all tested cytokines, in particular IFN-gamma. However, a significantly higher release of sCD30 was observed in response to schizont extracts in the parasitized group. Addition of LPS to activate APC to low doses of PHA or schizont extracts increased the IFN-gamma production in both groups but levels remained lower in CBMC from the parasitized group. This result correlates with the lower production of IL-12 found following lipopolysaccharide (LPS) stimulation in this group. Taken together, these data show that placental infection with P. falciparum affects Th1 differentiation and sCD30 priming of neonatal lymphocytes and that the probable mode of action is via APC.

T cell responses to vaccines in infants: defective IFNgamma production after oral polio vaccination.

The immaturity of the neonatal immune system is associated with an increased susceptibility to infections. Studies in mice indicate that neonatal immune responses are biased towards the T helper 2 type, but little is known about helper T cell responses in human newborns. In this study, the oral polio vaccine was used as a model of early immunization to investigate the capacity of young infants to develop cellular immune responses. We show that neonatal immunization with oral polio vaccine induces the production of high titres of neutralizing antibodies but reduced proliferative and IFNgamma responses to polio antigens compared to immune adults. These data suggest that specific strategies will be required to immunize newborns against pathogens controlled by Th1 type immune responses.

Absence of association between delayed type hypersensitivity to tuberculin and atopy in children in The Gambia.

BACKGROUND: An inverse association between delayed type hypersensitivity to tuberculin and atopy has been observed in children, suggesting that exposure to mycobacteria may influence the immune response to allergens. OBJECTIVE: To investigate the relationship between tuberculin responses and atopy in children living in three different environments in The Gambia. METHODS: In this cross-sectional study a total of 507 school-aged children were recruited from rural, urban poor or urban affluent communities. They were assessed for skin responses to five common allergens and tuberculin, presence of bacille Calmette-Guérin (BCG) scar, presence of intestinal parasites, and total serum IgE. Atopy was defined as the presence of a skin prick test response > or = 3 x 3 mm to at least one allergen. RESULTS: The overall prevalence of atopy was 33% but there was a significant variation among the three study groups. The prevalence of atopy was 22% in urban poor, 36% in urban affluent, and 43% in rural children. Controlling for potential confounding factors, children in the rural community had a significantly higher odds ratio, 3.3 (95% confidence interval 1.8-6.0) of being atopic than children from the urban poor community. No association between atopy and tuberculin response or BCG scar was observed in any of the three groups. Serum IgE levels were higher among children of the urban poor group but were not associated with tuberculin response or BCG scar in any of the groups. CONCLUSION: Environmental factors have an important influence on the development of atopy in children in The Gambia but delayed type hypersensitivity to tuberculin is not a protective factor.

No association between interferon-gamma receptor-1 gene polymorphism and pulmonary tuberculosis in a Gambian population sample.

BACKGROUND: Tuberculosis (TB) is a major global cause of mortality and morbidity, and host genetic factors influence disease susceptibility. Interferon-gamma mediates immunity to mycobacteria and rare mutations in the interferon-gamma receptor-1 gene (IFNGR1) result in increased susceptibility to mycobacterial infection, including TB, in affected families. The role of genetic variation in IFNGR1 in susceptibility to common mycobacterial diseases such as pulmonary TB in outbred populations has not previously been investigated. METHODS: The association between IFNGR1 and susceptibility to pulmonary TB was investigated in a Gambian adult population sample using a case-control study design. The coding and promoter regions of IFNGR1 were sequenced in 32 patients with pulmonary TB, and the frequencies of six common IFNGR1 polymorphisms were determined using PCR based methods in 320 smear positive TB cases and 320 matched controls. Haplotypes were estimated from the genotype data using the expectation-maximisation algorithm. RESULTS: There was no association between the IFNGR1 variants studied and TB in this Gambian population sample. Three common haplotypes were identified within the study population, none of which was associated with TB. CONCLUSIONS: These data represent an important negative finding and suggest that, while IFNGR1 is implicated in rare Mendelian susceptibility to mycobacterial disease, the common variants studied here do not have a major influence on susceptibility to pulmonary TB in The Gambian population.

Febrile response in malnutrition

The febrile response to a standard dose of triple (DPT) vaccine was assessed in sixteen malnourished children before and after recovery. The increase in temperature was significantly lower in the malnourished children (p < 0.005)