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.
    PLoS ONE 05/2014; 9(5):e96766. DOI:10.1371/journal.pone.0096766 · 3.23 Impact Factor
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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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    ABSTRACT: Prostaglandin F2α (PGF2α) induces luteolysis in cows and causes infiltration of immune cells, which resembles inflammatory immune response. Since the general immune response is mediated by the lymphatic system, we hypothesized that luteolysis is associated with generation of an immune response that involves lymphatic vessels in the bovine corpus luteum (CL). The CL was obtained from Holstein cows at the mid-luteal phase (days 10-12, ovulation = day 0) by ovariectomy at various time points after PGF2α injection. Lymphatic endothelial cell (LyEC) marker, endothelial hyaluronan receptor 1 (LYVE1), levels decreased significantly 12 h after PGF2α injection. Podoplanin, another LyEC marker, decreased from 15 min after PGF2α injection. PGF2α also diminished mRNA expression of lymphangiogenic factors, such as vascular endothelial growth factor (VEGF) C, VEGFD and VEGF receptor 3 (VEGFR3). During PGF2α-induced luteolysis, the levels of mRNA expression of tumor necrosis factor α (TNFα; the major pro-inflammatory cytokine) and chemokine (C-X-C motif) ligand 1 (neutrophil chemokine) were increased. On the other hand, chemokine (C-C motif) ligand 21, which regulates outflow of immune cells from tissues via the lymphatic vessels during an immune response, was decreased. This study demonstrated that the lymphatic network in the CL is disrupted during luteolysis and suggests that during luteolysis, immune cells can induce a local immune response in the CL without using the lymphatic vessels.
    Journal of Reproduction and Development 03/2013; 59(3). DOI:10.1262/jrd.2012-090 · 1.52 Impact Factor
    • "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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    ABSTRACT: Febrile convulsions (FCs), occurring between 6 months and 6 years of age is the most common seizure disorder during childhood. The febrile response is thought to be mediated by the release of pyrogenic cytokines, such as tumor necrosis factor and interleukin-1 (IL-1). There is a significant relationship between genetic components for susceptibility of FCs and different report mutation. We investigated association between two polymorphisms in the tumor necrosis factor (TNF)-α promoter region (G-308A, C-850T) and FCs in the southwest area of Iran. In this matched case-control study, 100 patients with febrile convulsion as case group and 130 healthy children as control group were enrolled in the study. Peripheral blood samples were collected and DNA was extracted by standard phenol-chloroform method. The genotype and allele frequencies of TNF- α polymorphisms in case and control groups were determined by using PCR-RFLP (polymerase chain reaction restriction fragment length polymorphism) method. Statistical analysis was done using Chi-square test. The average age of case and control groups were 3.4 ± 1.4 and 3.4 ± 1.2 years, respectively. There was no significant difference between age and sex in both the groups (P > 0.05). A family history of febrile convulsion was detected in 44% of patients. Moreover, the simple febrile convulsion was detected in 85% of the case group. RFLP analysis of TNF- α promoter region polymorphisms, considering P = 0.146 and P = 0.084 for G-308A and C-850T, respectively, showed no correlation between TNF- α polymorphisms and predisposition to simple febrile, based on the kind of convulsion (atypical and simple febrile convulsion). We found a significant relation between genotype distribution of G-308A and atypical febrile convulsion in case group (P = 0.04). A significant correlation between genotype distribution of G-308A and atypical febrile convulsion in the case group was found, but there was no correlation between TNF- α polymorphisms at positions of -308A, and 850T and predisposition to simple febrile convulsion. Further studies are needed to understand clinical usefulness of this correlation.
    12/2012; 1(1):85. DOI:10.4103/2277-9175.105167
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