Narayanan Pr

Cytokine gene polymorphisms and cytokine levels in pulmonary tuberculosis

Polymorphisms in the cytokine genes are known to influence cytokine levels and may be associated with outcome of infections. We investigated the polymorphisms in the cytokine genes namely IFN-gamma (+874 and +5644), IL-2 (-330 and +160), IL-4 (VNTR), IL-6 (-174), IL-10 (-1082 and -819) and IL-12B (+1188) in 188 normal healthy subjects (NHS) and 166 pulmonary tuberculosis patients (PTB) using polymerase chain reaction-based methods. To study the influence of cytokine gene polymorphisms on cytokine levels, phytohaemagglutinin and culture filtrate antigen of Mycobacterium tuberculosis-induced cytokine levels were measured by ELISA from 72-h-old peripheral blood mononuclear cell culture supernatants. Significantly decreased frequency of TT genotype of IL-2 -330 polymorphism (p=0.024, odds ratio (OR) 0.53, 95% CI 0.31-0.92) was observed in patients compared to NHS. The genotype frequencies of other polymorphisms were not different between patients and NHS. IL-12p40 levels were significantly decreased among NHS with AA genotype of IL-12B gene polymorphism compared to NHS with AC genotype (p<0.05). Increased levels of IL-12p40 were observed among patients with CC genotype of IL-12B gene compared to patients with other genotypes (p<0.01). The present study suggests that the TT genotype of IL-2 -330 polymorphism may be associated with the protection to PTB in south India. Further, +1188 polymorphism of IL-12B gene either alone or in combination with closely linked genes may regulate IL-12p40 production and may play a major role on acquired immunity to tuberculosis.

Nutritional Status of Persons with HIV Infection, Persons with HIV Infection and Tuberculosis, and HIV-Negative Individuals from Southern India

We compared the nutritional status of individuals with human immunodeficiency virus (HIV) infection alone, individuals with HIV infection and tuberculosis (after completion of antituberculosis treatment), and HIV-negative individuals and found that malnutrition, anemia, and hypoalbuminemia were most pronounced among HIV-positive patients with tuberculosis. Weight loss was associated with loss of fat in female patients and with loss of body cell mass in male patients.

Nutritional supplementation in HIV-infected individuals in South India: a prospective interventional study.

BACKGROUNDnMalnutrition in human immunodeficiency virus (HIV)-infected individuals is associated with faster disease progression, higher mortality rates, and suboptimal response to antiretroviral therapy (ART).nnnMETHODSnWe conducted a prospective interventional study to evaluate the effects of an oral macronutrient supplement among HIV-infected adults in South India. Patients attending Tuberculosis Research Centre clinics from June 2005 through December 2007 had baseline nutritional assessment and laboratory investigations performed. Patients at 1 center received nutritional counseling and standard care, whereas patients at 2 centers additionally received a macronutrient providing 400 cal and 15 g of protein daily. Study outcomes were changes in anthropometry, body composition, blood chemistry, and immune status at 6 months.nnnRESULTSnIn total, 636 ART-naive patients were enrolled in the study; 361 completed 6 months of follow-up (282 received supplements and 79 received standard care). Mean age +/- standard deviation (SD) was 31 +/- 7 years, mean weight +/- SD was 50 +/- 10 kg, and 42% were male. Significant increases in body weight, body mass index, midarm circumference, fat-free mass, and body cell mass were observed in the supplement group but not in the control group at 6 months; gains were greater in patients with CD4 cell counts <200 cells/microL. No changes were observed in lipid levels, whereas the CD4 cell count decreased in the control group. However, after adjusting for baseline differences, these changes were not statistically significantly different between the groups.nnnCONCLUSIONSnMacronutrient supplementation did not result in significantly increased weight gain compared with standard care (including nutritional counseling) among patients with moderately advanced HIV disease. The effect of supplementation on specific subsets of patients and on preserving immune function needs further research.

Regulatory role of promoter and 3' UTR variants of vitamin D receptor gene on cytokine response in pulmonary tuberculosis

Vitamin D receptor (VDR) gene variants are shown to regulate immune response in tuberculosis. We studied the influence of VDR promoter (Cdx-2 and A1012G), 3′ untranslated region (Apa I, Bsm I, and Taq I) and start codon (Fok I) polymorphisms on 1,25(OH)2D3-modulated IL-12p40, IFN-γ, IL-10, and IL-5 response to live Mycobacterium tuberculosis and its culture filtrate antigen (CFA) in 60 normal healthy subjects and 51 pulmonary tuberculosis patients. In peripheral blood mononuclear cell cultures with CFA and 1,25(OH)2D3, IL-12p40, and IFN-γ levels were significantly decreased (pu2009<u20090.05) and IL-10 levels were significantly increased (pu2009<u20090.05) in patients with GG genotype. The extended genotype bbaaTT (baT haplotype) was associated with decreased IL-12p40 and IFN-γ levels and significantly increased IL-10 levels (pu2009<u20090.05). The Cdx-2 GG genotype and baT haplotype are associated with a suppressed Th1 and increased IL-10 response, which suggests that 1,25(OH)2D3 probably through the VDR polymorphic variants augments the anti-inflammatory response at the site of M. tuberculosis infection.

HLA-DQB1 and -DPB1 allele profile in HIV infected patients with and without pulmonary tuberculosis of south India.

We made an attempt to find out whether Human Leucocyte Antigen (HLA)-DQB1 and -DPB1 alleles are associated with susceptibility or resistance to Human Immunodeficiency Virus (HIV) infection and development of pulmonary tuberculosis (PTB) in HIV infected patients. The allelic profile of HLA-DQB1 and -DPB1 was studied among HIV patients without pulmonary tuberculosis (HIV+PTB-) (n = 115), HIV patients with pulmonary TB (HIV+PTB+) (n = 59), HIV negative PTB patients (HIV-PTB+) (n = 110) and healthy controls (n=112) by polymerase chain reaction and sequence specific oligonucleotide probe method. Increased frequency of HLA-DQB1*050301 was observed in HIV+PTB- [p = 0.024, Odds Ratio (OR) 2.30, 95% Confidence Interval (CI) 1.11-4.90] and HIV+PTB+ patients (p = 0.044, OR 2.41, 95% CI 1.01-5.73) compared to healthy controls, suggesting that DQB1*050301 may be associated with susceptibility to HIV infection as well as development of PTB in HIV patients. Underrepresentation of HLA-DPB1*1501 was observed in HIV-PTB+ (p = 0.002, Pc = 0.034) and HIV+PTB+ (p = 0.036) patients compared to healthy controls, suggesting that DPB1*1501 may be associated with protection against PTB development both in HIV positive and negative subjects. Analysis on the amino acid variation in the peptide binding pocket at beta69 position of HLA-DPB1 molecules revealed that the beta69 arginine containing HLA-DPB1 alleles and the genotype lysine/arginine were underrepresented in HIV-PTB+ (allele: p = 0.003, Pc = 0.009; genotype: p = 0.0002, Pc = 0.001) and HIV+PTB+ (allele: p = 0.016, Pc = 0.048; genotype: p = 0.026). This suggests that HLA-DPB1 alleles with arginine may be associated with protection against development of PTB in both HIV infected as well as uninfected individuals. Further, the haplotypes HLA-DRB1*1502-DPB1*0201 and HLA-DQB1*0601-DPB1*0201 (Pc < 0.001) and HLA-DRB1*1502-DQB1*0601-DPB1*0201 (p = 0.006, OR 5.09, 95% CI 1.42-22.66) were significantly overrepresented in HIV+PTB+ patients compared to healthy controls suggesting that genetic susceptibility to PTB development in HIV patients may be modulated by interplay between HLA class II alleles, besides HLA class I alleles.

A Comparison of Costs to Patients with Tuberculosis Treated in a DOTS Programme with Those in a Non-DOTS Programme in South India

Tuberculosis is a curable disease, yet it is the largest single infectious cause of death among adults in the world. India accounts for one-third of the global TB burden. Its economic burden in India is enormous as it perpetuates and exacerbates poverty. The revised national Tuberculosis Control Programme (the DOTS Strategy) is currently being implemented in India. The purpose of this study was to compare the costs to tuberculosis patients treated in a DOTS Programme with the costs to patients treated in a non-DOTS Programme in south India. Patients registered between June and December 2000 (455 in DOTS area, 441 in non-DOTS area) in Tiruvallur district were interviewed, collecting information on demographics, socio-economic characteristics of patients, expenditure incurred due to illness, and effect of illness on employment. Results showed that in the DOTS area, treatment success rate was higher, patient costs were less, and patients returned to work early. These findings establish the economic benefits to patients treated under DOTS and lend support to rapid expansion of the programme, particularly in low-income countries.

Comparative Evaluation of Cytokines, T‐Cell Apoptosis, and Costimulatory Molecule Expression in Tuberculous and Nontuberculous Pleurisy

In this study, we compared several immune parameters in tuberculosis (TB) and nontuberculosis (NTB) pleurisy to gain an understanding of the mechanism behind enhanced Th1 apoptosis that occurs at sites of active Myobacterium tuberculosis (M. tuberculosis) infection. An initial evaluation of the accumulated cytokines in pleural fluid (PF) demonstrated that both TB and NTB pleurisy were associated with prointflammatory cytokines, while only TB pleurisy had augmented expression of interferon (IFN)‐γ and soluble Fas ligand (sFASL). Despite enhanced expression of the apoptosis‐inducing molecule in TB pleurisy, T cells derived from both types of pleurisy exhibited significant apoptosis. In both groups, T‐cell apoptosis correlated with low expression of CD80 on PF‐derived macrophages and elevated accumulation of TGF‐β in the PF. A causative correlation between TGF‐β and low CD80 expression in the two groups was established by in vitro studies demonstrating TGF‐β inhibition of CD80 upregulation in a macrophage cell line. Together, the findings allude to the possibility that activation in the absence of appropriate CD80 costimulation is the mechanism that leads to T‐cell apoptosis at sites of active M. tuberculosis infection. Furthermore, the findings also indicate that T‐cell apoptosis is perhaps a host regulatory mechanism to limit inflammation, rather than a pathogen‐induced immune deviation.