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Scollard D.M.,HRSA | Chaduvula M.V.,Society Blue Peter Research Center | Chaduvula M.V.,Institute of Pathology | Martinez A.,Fundacao Oswaldo Cruz | And 7 more authors.
Clinical and Vaccine Immunology | Year: 2011

Type 1 reaction (T1R) is a systemic inflammatory syndrome causing substantial morbidity in leprosy. T1R results from spontaneously enhanced cellular immunity in borderline types of leprosy, but there are no established laboratory markers for the reaction. Preliminary studies have identified elevated circulating CXC ligand 10 (CXCL10) during T1R. Correlation of CXCL10 with clinical T1R was studied in repeated serum specimens obtained before, during, and after T1R. CXCL10 gene expression was assessed in biopsy specimens taken before and during T1R, and sections were stained for the cytokine using monoclonal antibodies. Sequential serum specimens revealed elevation of circulating CXCL10 associated with episodes of T1R (P = 0.0001) but no evidence of an earlier, predictive change in the level of the chemokine. Reverse transcriptase (RT)-PCR revealed elevated expression of CXCL10 transcripts during T1R, but not in patients who did not have T1R. No significant correlation between CXCL10 and gamma interferon (IFN-γ) mRNA levels was observed. Immunohistochemical staining of the skin biopsy specimens suggested an overall increase in CXCL10 but did not identify a particular strongly staining population of leukocytes. Increased CXCL10 in lesions and serum is characteristic of T1R. CXCL10 measurement offers new possibilities for laboratory diagnosis and monitoring of T1R. Studies of the regulation of CXCL10 may provide insight into the mechanisms of T1R and identify potential new drug targets for treatment. Copyright © 2011, American Society for Microbiology. All Rights Reserved.

Gaddam S.L.,Bhagwan Mahavir Medical Research Center | Priya V.H.S.,Bhagwan Mahavir Medical Research Center | Srikanth Babu B.M.V.,Osmania University | Joshi L.,Bhagwan Mahavir Medical Research Center | And 3 more authors.
Genetic Testing and Molecular Biomarkers | Year: 2012

Aim: Allergic diseases are increasing alarmingly worldwide affecting >30% of the population, including India. Allergy is the result of interaction of the epitopes on the protein with the immunoglobulin E (IgE). T helper cell-2 cytokines promote allergen-specific IgE antibody and induce eosinophil-dominated inflammatory tissue responses. Interleukin-10 (IL-10), an antiinflammatory cytokine, plays a major role in the development of the allergy. The cytokine gene polymorphism of -592C→A (rs1800872) and -1082G→A (rs1800896) of IL-10 may influence the expression of the protein. Hence, the current study was aimed to evaluate the persistent association between these variants in the susceptibility of the disease. Methods: The allelic and genotype frequencies corresponding to IL-10 (-592C→A; -1082G→A) were determined in 94 allergic patients and 100 controls. Genomic typing was performed with polymerase chain reaction with sequence-specific primers. Result: The genotype AA at -592 position (p<0.000; odds ratio [OR] 9.92; 95% confidence interval [CI]=5.06-19.42) and GG at IL-10-1082 position (p<0.04; OR=2.47; 95% CI=1.003-4.96) was associated significantly in patients compared with controls. A considerable frequency of A-A haplotype in the patients and C-A, C-G haplotypes in controls was observed. A highly noteworthy difference was found in diplotype frequencies of A/A-A/A and A/A-G/A in patients and A/C-G/G and A/C-G/A in the controls. Conclusion: Our results indicate that haplotype and diplotype frequencies of the IL-10 locus may confer susceptibility to allergic patients. © Copyright 2012, Mary Ann Liebert, Inc.

Sreejit G.,DNA Diagnostics Center | Ahmed A.,DNA Diagnostics Center | Parveen N.,DNA Diagnostics Center | Jha V.,DNA Diagnostics Center | And 3 more authors.
PLoS Pathogens | Year: 2014

ESAT-6, an abundantly secreted protein of Mycobacterium tuberculosis (M. tuberculosis) is an important virulence factor, inactivation of which leads to reduced virulence of M. tuberculosis. ESAT-6 alone, or in complex with its chaperone CFP-10 (ESAT-6:CFP-10), is known to modulate host immune responses; however, the detailed mechanisms are not well understood. The structure of ESAT-6 or ESAT-6:CFP-10 complex does not suggest presence of enzymatic or DNA-binding activities. Therefore, we hypothesized that the crucial role played by ESAT-6 in the virulence of mycobacteria could be due to its interaction with some host cellular factors. Using a yeast two-hybrid screening, we identified that ESAT-6 interacts with the host protein beta-2-microglobulin (β2M), which was further confirmed by other assays, like GST pull down, co-immunoprecipitation and surface plasmon resonance. The C-terminal six amino acid residues (90–95) of ESAT-6 were found to be essential for this interaction. ESAT-6, in complex with CFP-10, also interacts with β2M. We found that ESAT-6/ESAT-6:CFP-10 can enter into the endoplasmic reticulum where it sequesters β2M to inhibit cell surface expression of MHC-I-β2M complexes, resulting in downregulation of class I-mediated antigen presentation. Interestingly, the ESAT-6:β2M complex could be detected in pleural biopsies of individuals suffering from pleural tuberculosis. Our data highlight a novel mechanism by which M. tuberculosis may undermine the host adaptive immune responses to establish a successful infection. Identification of such novel interactions may help us in designing small molecule inhibitors as well as effective vaccine design against tuberculosis. © 2014 Sreejit et al.

Abraham P.R.,DNA Diagnostics Center | Latha G.S.,Bhagwan Mahavir Medical Research Center | Valluri V.L.,Bhagwan Mahavir Medical Research Center | Valluri V.L.,Society Blue Peter Research Center | Mukhopadhyay S.,DNA Diagnostics Center
Infection, Genetics and Evolution | Year: 2014

Tuberculosis (TB) is one of the most important diseases of humans and major public health problem worldwide. Early and accurate diagnosis of TB is necessary for the treatment, prevention, and control of TB. Therefore, it is important to identify suitable antigens that can differentiate active tuberculosis patients from BCG-vaccinated individuals. In the present study, we have used Rv0256c (PPE2) protein of Mycobacterium tuberculosis to screen the sera of infected patients belonging to different clinical TB presentations, and BCG-vaccinated clinically healthy individuals by enzyme immunoassay. Our results demonstrated that Rv0256c displayed stronger and specific immunoreactivity against the sera obtained from clinically active tuberculosis patients compared to PPD and ESAT-6 and could differentiate the TB-patients from the BCG-vaccinated controls. Importantly, Rv0256c was also found to detect even the extrapulmonary and smear-negative pulmonary cases which often are tedious and difficult to detect using conventional diagnostic methods. This study suggests that Rv0256c can be used as a potential marker for the serodiagnosis of tuberculosis patients. © 2013 Elsevier B.V.

Grozdanovic Z.,Charite - Medical University of Berlin | Berrocal Almanza L.C.,Charite - Medical University of Berlin | Berrocal Almanza L.C.,Jena University Hospital | Goyal S.,Charite - Medical University of Berlin | And 11 more authors.
PLoS ONE | Year: 2015

Background Existing reading schemes for chest X-ray (CXR) used to grade the extent of disease severity at diagnosis in patients with pulmonary tuberculosis (PTB) are often based on numerical scores that summate specific radiographic features. However, since PTB is known to exhibit a wide heterogeneity in pathology, certain features might be differentially associated with clinical parameters of disease severity. Objective We aimed to grade disease severity in PTB patients at diagnosis and after completion of DOTS treatment by developing a reading scheme based on five different radiographic manifestations and analyze their association with the clinical parameters of systemic involvement and infectivity. Methods 141 HIV-negative adults with newly diagnosed sputum smear-positive PTB were enrolled in a prospective observational study in Hyderabad, India. The presence and extent on CXRs of five radiographic manifestations, i.e., lung involvement, alveolar infiltration, cavitation, lymphadenopathy and pleural effusion, were classified using the new reading scheme by using a four-quadrant approach. We evaluated the inter-reader reliability of each manifestation, and its association with BMI and sputum smear positivity at diagnosis. The presence and extent of these radiographic manifestations were further compared with CXRs on completion of DOTS treatment. Results At diagnosis, an average lung area of 51.7% +/- 23.3%was affected by radiographic abnormalities. 94% of the patients had alveolar infiltrates, with 89.4%located in the upper quadrants, suggesting post primary PTB and in 34.8% of patients cavities were found. We further showed that the extent of affected lung area was a negative predictor of BMI (β value -0.035, p 0.019). No significant association of BMI with any of the other CXR features was found. The extent of alveolar infiltrates, along with the presence of cavitation, were strongly associated with sputum smear positivity. The microbiological cure rate in our cohort after 6 months of DOTS treatment was 95%. The extent of the affected lung area in these patients decreased from 56.0% +/- 21.5%to 31.0 +/- 20% and a decrease was also observed in the extent of alveolar infiltrates from 98.4%to 25.8% in at least one quadrant, presence of cavities from 34.8% to 1.6%, lymphadenopathy from 46.8% to 16.1%, and pleural effusion from 19.4% to 6.5%. Conclusions We established a new assessment scheme for grading disease severity in PTB by specifically considering five radiographic manifestations which were differently associated with the BMI and sputum smear positivity, changed to a different extent after 6 months of treatment and exhibited an excellent agreement between radiologists. Our results suggest that this reading scheme might contribute to the estimation of disease severity with respect to differences in disease pathology. Further studies are needed to determine a correlation with short and long-term pulmonary function impairment and whether there would be any benefit in lengthening or modulating therapy based on this CXR severity assessment. Copyright: © 2015 Grozdanovic et al.

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