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Dittrich N.,Charite - Medical University of Berlin | Berrocal-Almanza L.C.,Charite - Medical University of Berlin | Thada S.,Charite - Medical University of Berlin | Thada S.,Bhagwan Mahavir Medical Research Center | And 12 more authors.
Tuberculosis | Year: 2015

Background Tuberculosis (TB), a disease caused by Mycobacterium tuberculosis (MTB) infection, is still a global public health problem. TB susceptibility varies greatly in infected individuals, and mycobacterial recognition by the innate immune system likely affects disease course and outcome. This research describes a single nucleotide polymorphism in the Toll-like receptor (TLR) 1 gene that functionally alters the innate immune response to MTB and is associated with TB susceptibility in India. Methods 206 TB patients and 239 healthy controls from Hyderabad, India were analyzed for SNPs in the TLR1 and TLR2 genes, which were subsequently correlated to TB susceptibility. To test individual responses to MTB lysates, we stimulated PBMCs from genotyped healthy German individuals, as well as HEK cells transfected with TLR1/2 variants. TNF production and NF-kB activation were assessed respectively. Results Cohort analysis associated the TLR1-248N SNP (RS4833095) with TB protection. TLR1-248N expressing PBMCs from healthy controls exhibited an increased TNF response to MTB lysates. In addition to this, functional studies using HEK cell lines transfected with TLR1-248N and stimulated with MTB showed an increased NF-kB activation. Conclusion SNP TLR1-248N is associated with TB protection in an Indian population and exhibits an increased immune response to MTB lysate in vitro. © 2015 Elsevier Ltd. Source

Joshi L.,Bhagwan Mahavir Medical Research Center | Ponnana M.,Bhagwan Mahavir Medical Research Center | Sivangala R.,Bhagwan Mahavir Medical Research Center | Chelluri L.K.,Global Hospital | And 5 more authors.
PLoS ONE | Year: 2015

Background Household contacts of diagnostically established tuberculosis (TB) patients are highly susceptible to disease development. It is surmised that cytokines perhaps play a synergistic and a prognostic role in the activation of the otherwise latent infection in these house hold contacts. Evaluation of the cytokines and any of their inherent polymorphisms might provide a useful diagnostic tool in evaluating the immune regulation and the progression of the disease. The cytokines thus released in a paracrine manner in serum may also provide an indirect measure of the cytokine function. Objective The present study was aimed to evaluate the levels of TNF-α, IL-10 & IL-6 cytokines and their correlation with genotype variants amongst tuberculosis patients and their household contacts. Methods The cytokine levels were estimated in serum by enzyme-linked immunosorbent assay (ELISA) and their polymorphisms were studied by amplification refractory mutation system polymerase chain reaction (ARMs PCR) in active pulmonary tuberculosis patients (APTB = 150), household contacts (HHC = 190), and healthy controls (HC = 150). Results The median values of TNF-α cytokine were significantly high among APTB and HHC compared to HCs (P< 0.0001 and 0.0001). IL-6 levels also were elevated among APTB compared to HHC and HC, and a significant difference was observed between APTB and HHC at P<0.0001; APTB & HC at P< 0.04; HHC & HC at P< 0.01. The IL-10 levels were low in APTB compared to HHC and HCs and no significant difference was observed. TNF-α/IL-10 ratio was significant and indicated Th1 predominance in APTB and HHC. IL-6/IL-10 showed pronounced Th1 expression in APTB and Th2 in HHC and HC. The ROC analysis indicated that both IL-10 and IL-6 can be used to decide the risk of exposed individual to a disease. The results of multivariate analysis indicate that IL-10 (-1082) GA genotype was significantly associated with p<0.028 in APTB. No significant association was observed between genotypes, other serum cytokine levels and clinical characteristics between APTB, HHC and HCs. Conclusion Large sample size with follow-up at different time points may further illuminate the role of IL-10 and IL-6 cytokines as a prognostic marker in house hold contacts. © 2015 Joshi et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Source

Visser L.H.,St Elisabeth Hospital | Jain S.,CODEWEL Nireekshana ACET | Lokesh B.,Narayana Medical College | Suneetha S.,CODEWEL Nireekshana ACET | Subbanna J.,Blue Peter Public Health and Research Center
Muscle and Nerve | Year: 2012

Introduction: From histopathological studies of peripheral nerves in leprosy, it is known that the epineurium can be thickened. We measured the epineurial thickness of the ulnar nerve by high resolution sonography (HRUS). Methods: The epineurium of the ulnar nerve was measured above the elbow on transverse scan in 25 healthy controls and 26 leprosy patients. Results: The mean epineurial thickness was 0.77 mm (95% confidence interval [CI] 0.66-0.88) in symptomatic ulnar nerves (n = 20), 0.58 mm (CI 0.51-0.65) in asymptomatic nerves (n = 30), and 0.49 mm (CI 0.44-0.54) in healthy controls (n = 25) (P = 0.0001). This thickening was related to the cross-sectional area of the ulnar nerve, but not with increased blood flow. Conclusions: The epineurium of the ulnar nerve can be measured with the use of HRUS, and it is often strikingly thickened in leprosy patients, especially in those with ulnar involvement. © 2012 Wiley Periodicals, Inc. Source

Pydi S.S.,Blue Peter Public Health and Research Center | Sunder S.R.,Blue Peter Public Health and Research Center | Venkatasubramanian S.,University of Texas Health Science Center at Tyler | Kovvali S.,Southern Regional Center | And 2 more authors.
Human Immunology | Year: 2013

NK cells are vital components of innate immune system and are the first cells which come into picture mediating resistance against intracellular pathogens. NK cell cytotoxicity is modulated by a wide variety of cell surface receptors that recognize and respond towards infected cells. Activation of NK cells are controlled by both inhibitory and activating receptors, encoded by KIR genes and bind to HLA ligands. Not much is known about KIR genes and their influence on the pathogenesis with M. tuberculosis infection. Our study aimed at detecting the presence of 14 KIR genes, their distribution and their association with tuberculosis. Total 77 different genotype combinations were observed which belonged to B-haplotype. Fifteen genotypes were similar to those reported in other world populations while remaining 62 were unique to this study group. Inhibitory genes KIR3DL1, KIR2DL3 and activating genes KIR2DS1, KIR2DS5 conferred susceptibility towards TB either individually or in haplotype combinations. The complimentary MHC ligands need to be tested for the functional relevance of the associated genes. © 2012 American Society for Histocompatibility and Immunogenetics. Source

Shinde V.,Blue Peter Public Health and Research Center | Marcinek P.,University of Tubingen | Rani D.S.,CSIR - Central Electrochemical Research Institute | Sunder S.R.,Blue Peter Public Health and Research Center | And 6 more authors.
Human Immunology | Year: 2013

The heterodimeric transporter associated with antigen processing (. TAP) gene loci is known to play a vital role in immune surveillance. We investigated a possible association of gene polymorphisms both in TAP1 and TAP2 in a cohort of clinically classified leprosy patients (. n=. 222) and in ethnically matched controls (. n=. 223). The TAP1 and TAP2 genes were genotyped for four single nucleotide polymorphisms TAP1 (rs1057141 Iso333Val and rs1135216 Asp637Gly) and TAP2 (rs2228396 Ala565Thr and rs241447 Ala665Thr) by direct sequencing and ARMS-PCR. The minor allele of TAP1 637G contributes to an increased risk to leprosy compared to controls (OR: 1.68, 95% CI 1.2-2.36, P=. 0.0057). An increased risk for the variant minor allele of the TAP1 637G to multibacillary (BL. +. LL) or paucibacillary (BT. +. TT) infections was also observed [multibacillary vs. controls (OR: 1.56, 95% CI 1.07-2.28, P=. 0.054); paucibacillary vs. controls (OR: 1.92, 95% CI 1.21-3.01, P=. 0.013)]. In the dominant model, the genotypes of the TAP1 rs1135216AG. +. GG additionally contributed to an increased risk. Overall our findings demonstrate that the TAP1 gene variant (rs1135216 Asp637Gly) influences the susceptibility to clinically classified leprosy patients in Indian population. © 2013 American Society for Histocompatibility and Immunogenetics. Source

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