Biomedical subjects

Narinder K Mehra

Publications and source records attributed to Narinder K Mehra.

8 recordsLinked to original sources

PubMed2004

Human leukocyte antigen class I supertypes influence susceptibility and severity of tuberculosis.

Although both differential susceptibility to Mycobacterium tuberculosis infection and disease pathogenesis depend on a multitude of factors, elucidation of specific host genetic markers, particularly those in the human major histocompatibility complex, is important. The present study is an attempt to delineate human leukocyte antigen (HLA) class I association in tuberculosis (TB) on the basis of a shared sequence motif in peptide-binding pockets of HLA molecules. In patients with pulmonary TB and miliary/disseminated TB, we observed significantly increased frequencies of A3-like supertypes and decreased frequencies of A1-like supertypes. These 2 positively and negatively associated supertypes (allele groups) share a similar peptide-binding motif, except for residues in pocket F of the HLA class I molecules. In addition, the HLA-Cw specificities that are major ligands for killer cell immunoglobulin-like (inhibitory) receptors (KIRs), particularly KIR2DL1 (Cw2, Cw4, and CW5) and KIR2DL2 (Cw1, Cw3, and Cw7), were found more frequently among patients with TB, which suggests a possible inhibition of natural killer cell activity against the infected target cells. The results of the present study suggest that the frequent occurrence of HLA class I specificities comprising an A3-like peptide-binding motif and the increased occurrence of ligands for KIR2DL in TB together may influence the outcome of TB.

Cohort Studies↗

PubMed2004

HLA haplotypes associated with type 1 diabetes mellitus in North Indian children.

Human leukocyte antigen (HLA) encoded susceptibility to develop type 1 diabetes mellitus (T1DM) has been investigated in children from North India. The results revealed significantly increased prevalence of HLA-A26, -B8, and -B50 among patients and strong positive association of the disease with DRB1*0301 (82.1% vs 13.9%, chi2=71.3, odds ratio [OR]=28.3) and a negative association with DRB1*02 (chi2=12.2, PF=38.5). HLA-DQB1*0201 occurred in 96.4% of the patients, whereas the heterodimer DQA1*0501-DQB1*0201 was present in 82.1% of patients (60.7% in single dose and 21.4% in double dose) and revealed significant deviation from the healthy controls (chi2=74.1, pc=6.0E-10). In addition to DRB1*03, positive association was also observed with DRB1*09 (14.3% vs 1.3%, chi2=13.4) and DRB1*04 (39.3% vs 15.6%, chi2=8.39). No HLA association was observed in relation to residual pancreatic beta-cell function or associated thyroid autoimmunity. Family analysis revealed involvement of multiple DR3+ve haplotypes with T1DM in North Indian children with A26-B8-DRB1*03 (25% vs 3.5%, chi2=16.9, p=3.96E-05) and Ax-B50-DRB1*03 (25% vs 0.7%, chi2=44.7, p=9.88E-11) being the most frequent haplotypes encountered among patients. The classical Caucasian haplotype A1-B8-DRB1*03 was infrequent (7.2%) among the diabetic children. The study highlights the race specificity of HLA association and disease associated HLA haplotypes in T1DM among North Indian children.

Adolescent↗

PubMed2003

MHC-based vaccination approaches: progress and perspectives.

The major histocompatibility complex (MHC) harbours genes whose primary function in regulating immune responsiveness to infection is to present foreign antigens to cytotoxic T lymphocytes (CTLs) and T helper cells. In the case of infection by human immunodeficiency virus (HIV), defining the optimal HIV epitopes that are recognised by CTLs is important for vaccine design, and this in turn will depend on the characteristics of the predominant infecting virus. Moreover, the particular MHC human leukocyte antigens (HLAs) expressed by a geographical population is important since these are likely to determine which HIV epitopes are immunodominant in the anti-HIV immune response. Consideration of these aspects has lead to the dawn of a new era of MHC-based vaccine design, in which the CTL epitopes are selected on the basis of the frequency of restricting MHC alleles. This article reviews data on the distribution patterns of molecular subtypes of HLA class I and class II extended haplotypes, discussing distribution among Asian Indians but with reference to global distributions. These data provide a genetic basis for the possible predisposition and fast progression of HIV infections in the Indian population. Since there is selective predominance of different HLA alleles and haplotypes in different populations, a dedicated screening effort is required at the global level to develop MHC-based vaccines against infectious diseases. It is hoped that this might lead to the development of multivalent, poly-epitope, subtype-specific HIV vaccines that are specific for the target geographical location.

AIDS Vaccines↗

PubMed2003

Human leukocyte antigen-DR alleles influence the clinical course of pulmonary sarcoidosis in Asian Indians.

Host genetic factors are known to contribute to disease susceptibility and course in sarcoidosis. They may also be important in defining the pattern of disease presentation and progression, as well as its overall prognosis. We have studied human leukocyte antigen (HLA) class I (n = 31) and class II alleles (n = 56) in a cohort of Indian patients with sarcoidosis and 275 healthy control subjects from north India. Although no specific HLA class I allele association was found among sarcoidosis, the functional classification of HLA-A, -B, and -Cw alleles into supertypes revealed an increased frequency of group 2 ligands (Cw2, Cw4, Cw5) for the Killer cell Ig-like receptors (KIR2DL1) in the patient group as compared with control subjects. Among class II alleles, positive association of DRB1*11, DRB1*14, DQA1*0101/4, and DQB1*0503 alleles with the disease was noticed. Clinical follow-up of the patient cohort up to a 5-yr period showed a predominant occurrence of DRB1*14 and its linked DQ alleles in patients with insidious onset, advanced disease on chest radiographs, and chronic course with frequent relapses on tapering off the prednisolone treatment. Further, multivariate logistic regression analysis revealed that the presence of DRB1*11(odds ratio [OR] 9) and DRB1*14 (OR 7), and absence of DRB1*07 (OR 63 and DQB1*0201(OR 3) alleles, were independent predictors of sarcoidosis. The present findings imply that HLA-associated genetic factors influence the risk for the development of sarcoidosis and disease progression.

Adult↗

PubMed2002

Evaluation of clinical and immunogenetic risk factors for the development of hepatotoxicity during antituberculosis treatment.

Though several risk factors for the development of hepatotoxicity due to antituberculosis drugs have been suggested, involvement of genetic factors is not fully established. We have studied the major histocompatibility complex (MHC) class II alleles and clinical risk factors for the development of hepatotoxicity in 346 North Indian patients with tuberculosis undergoing antituberculosis treatment. Of these, 56 patients developed drug-induced hepatotoxicity (DIH group), whereas the remaining 290 patients did not (non-DIH group). The DIH group was comparatively older, had lower pretreatment serum albumin, and a higher frequency of moderately/far advanced disease radiographically than the latter. Further, patients with high alcohol intake had threefold higher odds of developing hepatotoxicity. In multivariate logistic regression analysis, older age (odds ratio [OR] 1.2), moderately/far advanced disease (OR 2.0), serum albumin < 3.5 g/dl (OR 2.3), absence of HLA-DQA1*0102 (OR 4.0), and presence of HLA-DQB1*0201 (OR 1.9) were independent risk factors for DIH. Our results suggest that the risk of hepatotoxicity from antituberculosis drugs is influenced by clinical and genetic factors.

Adolescent↗

PubMed2002

Distinctive KIR and HLA diversity in a panel of north Indian Hindus.

HLA and KIR are diverse and rapidly evolving gene complexes that work together in human immunity mediated by cytolytic lymphocytes. Understanding their complex immunogenetic interaction requires study of both HLA and KIR diversity in the same human population. Here a panel of 72 unrelated north Indian Hindus was analyzed. HLA- A, B, C, DRB1, DQA1, and DQB1 alleles and their frequencies were determined by sequencing or high-resolution typing of genomic DNA; KIR genotypes were determined by gene-specific typing and by allele-level DNA typing for KIR2DL1, 2DL3, 2DL5, 3DL1, and 3DL2. From HLA analysis, the north Indian population is seen to have several characteristics shared either with Caucasian or East Asian populations, consistent with the demographic history of north India, as well as specific features, including several alleles at high frequency that are rare or absent in other populations. A majority of the north Indian KIR gene profiles have not been seen in Caucasian and Asian populations. Most striking is a higher frequency of the B group of KIR haplotypes, resulting in equal frequencies for A and B group haplotypes in north Indians. All 72 members of the north Indian panel have different HLA genotype and different KIR genotype.

Alleles↗

PubMed2002

Heterogeneity of HLA-DRB1*04 and its associated haplotypes in the North Indian population.

HLA-DR4 has been implicated in several diseases including rheumatoid arthritis (RA) and type I diabetes, the strength of associations being ethnically variable. Unusually high level of heterogeneity in DR4-DQB1 haplotypes has been reported in the Indian population. The present study is an attempt to determine the genetic diversity of the HLA-DR4 allelic family and its associated DQA1-DQBI haplotypic combinations in the healthy North Indian population. Using PCR-SSP and PCR-SSOP techniques, nine subtypes of DR4 were encountered of which DRB1*0403 was the most predominant allele (34.8%) followed by *0404 (27%), *0401 (14.6%), and *0405 (11%). No examples of *0402, *0409, *0411, *0413-*0417, and *0419-23 were encountered, although a few other subtypes, *0410 (three examples), *0406 and *0418 (two examples each), and *0407, *0408, and *0412 (single example each) occurred infrequently in a cohort of 85 HLA-DR4 positive samples studied. Most of these subtypes occurred in combination with DQA1*03-DQB1*0302 (69.5%). DRB1*0403 and *0404 exhibited maximum heterogeneity of DQB1 combinations. Haplotype data revealed the presence of 15 different DR4-DQ haplotypes, four of which were found to be "unique" to Asian Indians, not reported in any other population. These results help to explain the observed variability in DR4 associations in autoimmune diseases in Asian Indians and provide support for scientific and historical documentation of extensive admixture in the Indian subcontinent.

Alleles↗

PubMed2002

Cytokine polarization in miliary and pleural tuberculosis.

Cytokines were measured in patients with pleural effusion and miliary tuberculosis (TB). Patients with pleural effusion had significantly higher interferon-gamma (IFN-gamma) levels (P < 0.001) in their pleural fluid as compared to that of peripheral blood of the same patients, thus exhibiting localization of predominantly Th1-type immunity in the pleural fluid. On the contrary, patients with miliary TB had higher IFN-gamma levels in the peripheral blood as compared to their bronchoalveolar lavage fluid. Moreover, the median IFN-gamma: IL-4 ratio in the peripheral blood of miliary TB patients was two-fold higher as compared to bronchoalveolar lavage fluid, suggesting that the cytokine profile at the disease site is skewed toward a Th2-like bias. Further, flow cytometry data revealed a significantly higher (P < 0.001) percentage of CD4+ pleural fluid lymphocytes expressing IFN-gamma, whereas in the miliary TB, a nine-fold higher percentage of lymphocytes in bronchoalveolar lavage fluid expressed IL-4 in comparison with their peripheral CD4 T cells. Our data indicate, respectively, a Th1-like and Th2-like response in tuberculous pleural effusion and miliary TB, suggesting that these clinical forms of extrapulmonary tuberculosis probably reflect the extreme ends of a Th1-Th2 spectrum of the disease.

Adult↗