Genetic polymorphisms in TNF genes and tuberculosis in North Indians

<p>Abstract</p> <p>Background</p> <p>Pulmonary tuberculosis, the most common clinical form of mycobacterial diseases, is a granulomatous disease of the lungs caused by <it>Mycobaterium tuberculosis</it>. A number of genes have been identified in studies of diverse origins to be important in tuberculosis. Of these, both tumor necrosis factor α (TNF-α) and lymphotoxin α (LT-α) play important immunoregulatory roles.</p> <p>Methods</p> <p>To investigate the association of <it>TNF </it>polymorphisms with tuberculosis in the Asian Indians, we genotyped five potentially functional promoter polymorphisms in the <it>TNFA </it>gene and a <it>LTA_NcoI </it>polymorphism (+252 position) of the <it>LTA </it>gene in a clinically well-defined cohort of North-Indian patients with tuberculosis (N = 185) and their regional controls (N = 155). Serum TNF-α (sTNF-α) levels were measured and correlated with genotypes and haplotypes.</p> <p>Results</p> <p>The comparison of the allele frequencies for the various loci investigated revealed no significant differences between the tuberculosis patients and controls. Also, when the patients were sub-grouped into minimal, moderately advanced and far advanced disease on the basis of chest radiographs, TST and the presence/absence of cavitary lesions, none of the polymorphisms showed a significant association with any of the patient sub-groups. Although a significant difference was observed in the serum TNF-α levels in the patients and the controls, none of the investigated polymorphisms were found to affect the sTNF-α levels. Interestingly, it was observed that patients with minimal severity were associated with lower log sTNF-α levels when compared to the patients with moderately advanced and far advanced severity. However, none of these differences were found to be statistically significant. Furthermore, when haplotypes were analyzed, no significant difference was observed.</p> <p>Conclusions</p> <p>Thus, our findings exclude the <it>TNF </it>genes as major risk factor for tuberculosis in the North Indians.</p

Genetic and Functional Role of TNF-alpha in the Development Trypanosoma cruzi Infection

TNF-alpha plays an important role in trypanocidal mechanisms and is related to tissue injury. This cytokine has been detected in the heart of human chagasic patients where it is associated with tissue damage. This study investigated whether TNF-alpha levels and the presence of genetic polymorphisms are associated with the presence of T. cruzi infection and/or with the development of the cardiac form in chronic chagasic patients. Genomic DNA of 300 subjects from an endemic area was extracted and analyzed by PCR using specific primers. TNF-alpha was assayed in culture supernatants by ELISA. An association was observed between the absence of the TNF-238A allele and negative serology. Furthermore, seropositive individuals carrying the TNF-238A allele produced significantly higher TNF-alpha levels without stimulation (p = 0.04) and after stimulation with LPS (p = 0.007) and T. cruzi antigens (p = 0.004). The present results suggest that the polymorphism at position -238 influences susceptibility to infection and that this allele is associated with higher TNF-alpha production in seropositive individuals

Reducing Crowding by Weakening Inhibitory Lateral Interactions in the Periphery with Perceptual Learning

We investigated whether lateral masking in the near-periphery, due to inhibitory lateral interactions at an early level of central visual processing, could be weakened by perceptual learning and whether learning transferred to an untrained, higher-level lateral masking known as crowding. The trained task was contrast detection of a Gabor target presented in the near periphery (4°) in the presence of co-oriented and co-aligned high contrast Gabor flankers, which featured different target-to-flankers separations along the vertical axis that varied from 2λ to 8λ. We found both suppressive and facilitatory lateral interactions at target-to-flankers distances (2λ - 4λ and 8λ, respectively) that were larger than those found in the fovea. Training reduces suppression but does not increase facilitation. Most importantly, we found that learning reduces crowding and improves contrast sensitivity, but has no effect on visual acuity (VA). These results suggest a different pattern of connectivity in the periphery with respect to the fovea as well as a different modulation of this connectivity via perceptual learning that not only reduces low-level lateral masking but also reduces crowding. These results have important implications for the rehabilitation of low-vision patients who must use peripheral vision to perform tasks, such as reading and refined figure-ground segmentation, which normal sighted subjects perform in the fovea

Immunoregulatory function of IL-27 and TGF-β1 in cardiac allograft transplantation.

BACKGROUND: Deciphering the mechanisms of tolerance represents a crucial aim of research in transplantation. We previously identified by DNA chip interleukin (IL)-27 p28 and transforming growth factor (TGF)-β1 as overexpressed in a model of rat cardiac allograft tolerance mediated by regulatory CD4CD25 T cells. The role of these two molecules on the control of the inflammatory response remains controversial. However, both are involved in the regulation of the T helper 17/Treg axis, suggesting their involvement in tolerance. METHODS: We analyzed regulation of IL-27 and TGF-β1 expression in allograft response and their role in tolerance by using blocking anti-TGF-β antibody and by generating an adeno-associated virus encoding IL-27. RESULTS: Here, we confirmed the overexpression of IL-27 and TGF-β1 in tolerated cardiac allografts in two different rodent models. We observed that their expression correlates with inhibition of T helper 17 differentiation and with expansion of regulatory CD4CD25 T cells. We showed in a rat model that anti-TGF-β treatment abrogates infectious tolerance mediated by the transfer of regulatory CD4CD25 T cells. Moreover, overexpression of IL-27 by adeno-associated virus administration in combination with a short-term immunosuppression allows prolongation of cardiac allograft survival and one tolerant recipient. We found that IL-27 overexpression did not induce Foxp3CD4CD25 T-cell expansion but rather IL-10-expressing CD4 T cells in the tolerant recipient. CONCLUSIONS: Taken together, these data suggest that both TGF-β1 and IL-27 play a role in the mechanisms of tolerance. However, in contrast to TGF-β1, IL-27 seems not to be involved in regulatory CD4CD25 T-cell expansion but rather in their mode of action

Tmem176B and Tmem176A are associated with the immature state of dendritic cells.

DCs play a central role in the development of innate and adaptive immunity but also in the induction and maintenance of immune tolerance. Identification of factors that govern DC activation, their maturation state, and their capacity to induce proinflammatory or tolerogeneic responses therefore represents a crucial aim of research. We previously identified a new molecule, Tmem176B (which we named TORID initially), as highly expressed in a model of allograft tolerance in the rat. We showed that its overexpression in rat DCs blocked their maturation, suggesting a role for this molecule in the maturation process. To characterize the function of Tmem176B further, we used a split-ubiquitin yeast, two-hybrid system to identify interacting partners and found that Tmem176B associated with itself but also with Tmem176A, a membrane protein similar to Tmem176B. Interestingly, these two molecules showed similar mRNA expression patterns among various murine tissues and immune cells and were both down-regulated following DC maturation. In addition, we showed that in using RNAi, these molecules are both involved in the maintenance of the immature state of the DCs. Taken together, these data suggest that Tmem176B and Tmem176A associate to form multimers and restrain DC maturation. Therefore, these two molecules may represent valid targets to regulate DC function

Early and late factors impacting patient and graft outcome in pediatric liver transplantation: summary of an ESPGHAN Monothematic Conference

As pediatric liver transplantation comes of age, experts gathered to discuss current paradigms and define gaps in knowledge warranting research to further improve patient and graft outcomes. Identified areas ripe for collaborative research include understanding the molecular and cellular mechanisms of tolerance and the role of donor-specific antibodies, considering ways to expand donor pool, minimizing long term side effects of immunosuppression, and fine-tuning surgical techniques to minimize biliary and vascular complications