TNF-α and TNF-β Gene Polymorphism in Saudi Rheumatoid Arthritis Patients

Background Tumor necrosis factor (TNF)-α and -β are cytokines with a wide range of inflammatory, apoptotic and immunomodulatory activities. TNF-α promoter –308 G < A polymorphism has been reported to be associated with rheumatoid arthritis (RA) with inconsistent results. Objective The aim of this study is to elucidate a possible association of TNF-α (G–308A) and TNF-β (A+252G) polymorphisms with the susceptibility of RA in Saudi patients. Patients and Methods This case control study consisted of 232 Saudi subjects including 106 RA patients and 126 matched controls. Genomic DNA was extracted using QIAamp R DNA mini kit (Qiagen CA, USA). TNF-α and TNF-β genes were amplified using Arms primers. Results The frequencies of TNF-α (–308) allele G and genotype GG were significantly higher in RA patients as compared to controls while allele A and genotype AA were predominant in control group. On the other hand the frequency of TNF-β (+252) GG and AA genotypes were significantly higher in RA patients as compared to controls while GA genotype was predominant in controls. It was inferred that genotype GG positive individuals at position –308 of TNF-α were susceptible to RA while genotype AA might has a protective effect on RA susceptibility in Saudis. Whereas GG and AA genotype of TNF-β at +252 position might exert additive susceptibility to RA and GA might be refractory. However, there was no significant association between duration of morning stiffness, RF positivity and number of joints involved and distribution of alleles/genotypes of TNF-α (–308) or TNF-β (+252) polymorphism. It may be concluded that the TNF-α (–308) and TNF-β (+252) polymorphisms might influence the susceptibility to RA in Saudi population. These results might have prognostic value for future clinical observations

Tumour necrosis factor gene polymorphism: a predictive factor for the development of post-transplant lymphoproliferative disease

Epstein–Barr virus-positive post-transplant lymphoproliferative disease (PTLD) is a potentially lethal complication of iatrogenic immunosupression after transplantation. Predicting the development of PTLD allowing early and effective intervention is therefore of importance. Polymorphisms within cytokine genes are implicated in susceptibility to, and progression of, disease however the published data are often conflicting. We undertook investigation of polymorphic alleles within cytokine genes in PTLD and non-PTLD transplant cohorts to determine risk factors for disease. &lt;br/&gt; Methods: SSP-PCR was used to analyse single nucleotide polymorphism within tumour necrosis factor (TNF)-α, interleukin- 1, -6, -10 and lymphotoxin-α genes. The TNF-α levels were measured by standard enzyme-linked immuno-absorbant assay. &lt;br/&gt; Results: We show an association between variant alleles within the TNF-α promoter (−1031C (&lt;i&gt;P&lt;/i&gt;=0.005)); −863A (&lt;i&gt;P&lt;/i&gt;=0.0001) and TNF receptor I promoter regions (−201T (&lt;i&gt;P&lt;/i&gt;=0.02)); −1135C (&lt;i&gt;P&lt;/i&gt;=0.03) with the development of PTLD. We also show an association with TNF-α promoter haplotypes with haplotype-3 significantly increased (&lt;i&gt;P&lt;/i&gt;=0.0001) and haplotype-1 decreased (P=0.02) in PTLD patients compared to transplant controls. Furthermore, we show a significant increase (&lt;i&gt;P&lt;/i&gt;=0.02) in the level of TNF-α in PTLD patient plasma (range 0–97.97 pg ml&lt;sup&gt;−1&lt;/sup&gt;) compared to transplant controls (0–8.147 pg ml&lt;sup&gt;−1&lt;/sup&gt;), with the highest levels found in individuals carrying the variant alleles. &lt;br/&gt; Conclusion: We suggest that genetic variation within TNF-α loci and the level of plasma cytokine could be used as a predictive risk factor for the development of PTLD

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

African Trypanosomiasis-associated anemia : the contribution of the interplay between parasites and the mononuclear phagocyte system

African trypanosomosis (AT) is a chronically debilitating parasitic disease of medical and economic importance for the development of sub-Saharan Africa. The trypanosomes that cause this disease are extracellular protozoan parasites that have developed efficient immune escape mechanisms to manipulate the entire host immune response to allow parasite survival and transmission. During the early stage of infection, a profound pro-inflammatory type 1 activation of the mononuclear phagocyte system (MPS), involving classically activated macrophages (i.e., M1), is required for initial parasite control. Yet, the persistence of this M1-type MPS activation in trypanosusceptible animals causes immunopathology with anemia as the most prominent pathological feature. By contrast, in trypanotolerant animals, there is an induction of IL-10 that promotes the induction of alternatively activated macrophages (M2) and collectively dampens tissue damage. A comparative gene expression analysis between M1 and M2 cells identified galectin-3 (Gal-3) and macrophage migration inhibitory factor (MIF) as novel M1-promoting factors, possibly acting synergistically and in concert with TNF-alpha during anemia development. While Gal-3 enhances erythrophagocytosis, MIF promotes both myeloid cell recruitment and iron retention within the MPS, thereby depriving iron for erythropoiesis. Hence, the enhanced erythrophagocytosis and suppressed erythropoiesis lead to anemia. Moreover, a thorough investigation using MIF-deficient mice revealed that the underlying mechanisms in AT-associated anemia development in trypanosusceptible and tolerant animals are quite distinct. In trypanosusceptible animals, anemia resembles anemia of inflammation, while in trypanotolerant animals' hemodilution, mainly caused by hepatosplenomegaly, is an additional factor contributing to anemia. In this review, we give an overview of how trypanosome-and host-derived factors can contribute to trypanosomosis-associated anemia development with a focus on the MPS system. Finally, we will discuss potential intervention strategies to alleviate AT-associated anemia that might also have therapeutic potential

The Role of Inflammatory Mediators in the Pathogenesis of Otitis Media and Sequelae

This review deals with the characteristics of various inflammatory mediators identified in the middle ear during otitis media and in cholesteatoma. The role of each inflammatory mediator in the pathogenesis of otitis media and cholesteatoma has been discussed. Further, the relation of each inflammatory mediator to the pathophysiology of the middle and inner ear along with its mechanisms of pathological change has been described. The mechanisms of hearing loss including sensorineural hearing loss (SNHL) as a sequela of otitis media are also discussed. The passage of inflammatory mediators through the round window membrane into the scala tympani is indicated. In an experimental animal model, an application of cytokines and lipopolysaccharide (LPS), a bacterial toxin, on the round window membrane induced sensorineural hearing loss as identified through auditory brainstem response threshold shifts. An increase in permeability of the blood-labyrinth barrier (BLB) was observed following application of these inflammatory mediators and LPS. The leakage of the blood components into the lateral wall of the cochlea through an increase in BLB permeability appears to be related to the sensorineural hearing loss by hindering K+ recycling through the lateral wall disrupting the ion homeostasis of the endolymph. Further studies on the roles of various inflammatory mediators and bacterial toxins in inducing the sensorineumral hearing loss in otitis media should be pursued

[Photograph 2012.201.B1126.0194]

Photograph used for a story in the Daily Oklahoman newspaper. Caption: "Reynolds, Dick - Norman - Candidate for City Commission, office 4

Norman

Photograph used for a story in the Oklahoma Times newspaper. Caption: "Hollywood has moved to Main Street, Oklahoma's top movie maker says.

[Photograph 2012.201.B1126.0195]

Photograph used for a newspaper owned by the Oklahoma Publishing Company. Caption: "Reynolds, Dick - Norman - Candidate for City Commission, office 4