Polymorphism in tumor necrosis factor genes associated with mucocutaneous leishmaniasis

Department of Medicine, University of Cambridge Clinical School, Addenbrooke's Hospital, United Kingdom.
Journal of Experimental Medicine (Impact Factor: 12.52). 12/1995; 182(5):1259-64.
Source: PubMed


Recent studies have shown that mucocutaneous leishmaniasis (MCL), a severe and debilitating form of American cutaneous leishmaniasis (ACL) caused by Leishmania braziliensis infection, is accompanied by high circulating levels of tumor necrosis factor (TNF)-alpha. Analysis of TNF polymorphisms in Venezuelan ACL patients and endemic unaffected controls demonstrates a high relative risk (RR) of 7.5 (P < 0.001) of MCL disease in homozygotes for allele 2 of a polymorphism in intron 2 of the TNF-beta gene, especially in females (RR = 9.5; P < 0.001) compared with males (RR = 4; P < 0.05). A significantly higher frequency (P < 0.05) of allele 2 at the -308-basepair TNF-alpha gene polymorphism was also observed in MCL patients (0.18) compared with endemic control subjects (0.069), again associated with a high relative risk of disease (RR = 3.5; P < 0.05) even in the heterozygous condition. Because both the TNF-alpha and TNF-beta polymorphisms have previously been linked with functional differences in TNF-alpha levels, these data suggest that susceptibility to the mucocutaneous form of disease may be directly associated with regulatory polymorphisms affecting TNF-alpha production.

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    • "MCL pathology is associated with chronic hyper-inflammation, concomitant with a modulation of T helper cytokines and cytotoxic T cell activity [3]–[7]. Studies have shown that host genetic polymorphisms (such as a single base pair substitution in the IL-6 and TNF-α promoters) [8]–[10], immune-status, and parasite derived virulence factors [11] are associated with the development of clinical MCL. "
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    ABSTRACT: Infections with Leishmania parasites of the Leishmania Viannia subgenus give rise to both localized cutaneous (CL), and metastatic leishmaniasis. Metastasizing disease forms including disseminated (DCL) and mutocutaneous (MCL) leishmaniasis result from parasitic dissemination and lesion formation at sites distal to infection and have increased inflammatory responses. The presence of Leishmania RNA virus (LRV) in L. guyanensis parasites contributes to the exacerbation of disease and impacts inflammatory responses via activation of TLR3 by the viral dsRNA. In this study we investigated other innate immune response adaptor protein modulators and demonstrated that both MyD88 and TLR9 played a crucial role in the development of Th1-dependent healing responses against L. guyanensis parasites regardless of their LRV status. The absence of MyD88- or TLR9-dependent signaling pathways resulted in increased Th2 associated cytokines (IL-4 and IL-13), which was correlated with low transcript levels of IL-12p40. The reliance of IL-12 was further confirmed in IL12AB-/- mice, which were completely susceptible to infection. Protection to L. guyanensis infection driven by MyD88- and TLR9-dependent immune responses arises independently to those induced due to high LRV burden within the parasites.
    Full-text · Article · May 2014 · PLoS ONE
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    • "TNFα is secreted by activated macrophages and has been implicated in neutrophil and monocyte recruitment to inflammatory sites [23,24,25,26,27]. Spontaneous or PGF2α-induced luteolysis are associated with a significant rise in intraluteal TNFα as shown in previous studies by using a CL microdialysis system [28]. Moreover, TNFα induces apoptotic death of steroidogenic and endothelial cells in vitro [11, 29, 30]. "
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    Full-text · Article · Mar 2013 · Journal of Reproduction and Development
    • "Also the polymorphism in the human TNF-α may be important in the susceptibility or severity of diseases and in other inflammatory conditions. Another study showed that -308A allele was associated with the most severe outcome, mucocutaneous leishmaniasis.[53] In multiple-injured patients with severe sepsis the TNF-α allele acts as a predictor of severe post-traumatic sepsis and increased level of circulating TNF-α.[54] "
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