Abstract
Evidence from genetic association and twin studies indicates that susceptibility to tuberculosis (TB) is under genetic control. One gene implicated in susceptibility to TB is that encoding interleukin-10 (IL10). In a group of 2010 Ghanaian patients with pulmonary TB and 2346 healthy controls exposed to Mycobacterium tuberculosis, among them 129 individuals lacking a tuberculin skin test (PPD) response, we genotyped four IL10 promoter variants at positions −2849 , −1082 , −819 , and −592 and reconstructed the haplotypes. The IL10 low-producer haplotype −2849A/−1082A/−819C/−592C, compared to the high-producer haplotype −2849G/−1082G/−819C/−592C, occurred less frequent among PPD-negative controls than among cases (OR 2.15, CI 1.3–3.6) and PPD-positive controls (OR 2.09, CI 1.2–3.5). Lower IL-10 plasma levels in homozygous −2849A/−1082A/−819C/−592C carriers, compared to homozygous −2849G/−1082G/−819C/−592C carriers, were confirmed by a IL-10 ELISA (p = 0.016). Although we did not observe differences between the TB patients and all controls, our results provide evidence that a group of individuals exposed to M. tuberculosis transmission is genetically distinct from healthy PPD positives and TB cases. In these PPD-negative individuals, higher IL-10 production appears to reflect IL-10-dependent suppression of adaptive immune responses and sustained long-term specific anergy.
Highlights
Innate and adaptive defense mechanisms contribute to antiMycobacteriuM. tuberculosis immunity
After uptake of the pathogen by alveolar macrophages, i) the pathogen may be destroyed in a first line of defence without inducing adaptive T-cell immune responses (PPD negativity), or ii) infection establishes and adaptive T-cell responses result in containment of bacteria (PPD positivity), or iii) innate and adaptive immune responses fail, allowing for outgrowth and spread of bacteria
No significant results were obtained when stratifying TB cases for whom genotyping results were available (n = 1587) for the three mycobacterial species M. tuberculosis (n = 1097; 69.1%), M. africanum (n = 480, 30.3%) and M. bovis (n = 10; 0.6%) that were identified after culturing of mycobacteria
Summary
Innate and adaptive defense mechanisms contribute to antiMycobacteriuM. tuberculosis immunity. Most contacts of tuberculosis (TB) patients develop a delayed-type hypersensitivity reaction to tuberculin and are, if remaining healthy, considered protected from active TB. As the skin papule indicating PPD positivity contains reactive T lymphocytes, protection is believed to result from acquired T-cell-mediated immunity. PPD negativity can result from either lack of previous exposure, anergy due to overwhelming TB, or from any form of immunosuppression. PPD negativity may indicate innate immunity after exposure without induction of adaptive mechanisms. After uptake of the pathogen by alveolar macrophages, i) the pathogen may be destroyed in a first line of defence without inducing adaptive T-cell immune responses (PPD negativity), or ii) infection establishes and adaptive T-cell responses result in containment of bacteria (PPD positivity), or iii) innate and adaptive immune responses fail, allowing for outgrowth and spread of bacteria (disease). A firm molecular basis of the three scenarios remains to be defined
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