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HLA antigen profile in pulmonary tuberculosis patients & their spouses
Abstract
HLA-A, -B, -DR and -DQ antigen profile was studied in pulmonary tuberculosis patients (n = 209) and their spouses (family contacts; n = 50) and healthy volunteers (n = 72). An increased frequency of HLA-A-10, B7, B15, DR2 and DQ1 was seen in the pulmonary-TB (PTB) patients when compared to the total control subjects (n = 122). However, a significant increase was seen only with HLA-DR2 (P < 0.001; Pc < 0.01; Relative Risk 2.3) and -DQ1 (P < 0.005; Pc < 0.015; Relative Risk 2.8). Among the spouses and the corresponding patients, a similar increase of HLA-DR2 was seen. A decreased frequency of HLA-A19, B8, B17, B35, DR5 and DR6 were seen in PTB as compared to control groups. The present study suggested that HLA-DR2 and DQ1 genes/gene products may be associated with the susceptibility to tuberculosis either alone or in combination with other HLA or non-HLA genes.
... No [15] Bsm(Exon) Meta-analysis(Africa) No [16] Folk1(Exon) Tanzania No [15] Taq1(Exon) ...
... No [15] Bsm(Exon) Meta-analysis(Africa) No [16] Folk1(Exon) Tanzania No [15] Taq1(Exon) ...
... The Gambia Yes [17] Tanzania No [15] FOLKI Bsm1-Apal-Taq1 West Africa Yes [18] Haplotype South Africa Yes [19] SP-A1 307G/A, 776C/T(Exon) Ethiopia Yes [20] SP-A2 355C/G, 751A/C(Exon) Ethiopia Yes [ ...
Tuberculosis remains a global health concern, with substantial mortality rates worldwide. Genetic factors play a significant role in influencing susceptibility to tuberculosis. This review examines the current progress in studying polymorphisms within immune genes associated with tuberculosis susceptibility, focusing on African populations. The roles of various proteins, including Toll-like receptors, Dendritic Cell-Specific Intercellular Adhesion Molecule-3 Grabbing Non-Integrin, vitamin D nuclear receptor, soluble C-type lectins such as surfactant proteins A and D, C-type Lectin Domain Family 4 Member E, and mannose-binding lectin, phagocyte cytokines such as Interleukin-1, Interleukin-6, Interleukin-10, Interleukin-12, and Interleukin-18, and chemokines such as Interleukin-8, monocyte chemoattractant protein 1, Regulated upon activation, normal T-cell expressed and secreted are explored in the context of tuberculosis susceptibility. We also address the potential impact of genetic variants on protein functions, as well as how these findings align with the genetic polymorphisms not associated with tuberculosis. Functional studies in model systems provide insights into the intricate host-pathogen interactions and susceptibility mechanisms. Despite progress, gaps in knowledge remain, highlighting the need for further investigations. This review emphasizes the association of Single Nucleotide Polymorphisms with diverse aspects of tuberculosis pathogenesis, including disease detection and Mycobacterium tuberculosis infection.
... [19][20][21] Di beberapa negara di dunia (Cina, India, Korea dan Iran) hubungan HLA kelas II khususnya HLA-DRB telah dibuktikan berhubungan dengan kerentanan penyakit tuberkulosis paru. [22][23][24][25][26][27][28] Sebuah studi meta analisis telah membuktikan bahwa kerentanan terhadap tuberkulosis paru sebagai akibat dari modulasi antigen HLA baik kelas I maupun kelas II. 29 Dijelaskan bahwa variasi mekanisme modulasi dari ekspresi gen dan sistem regulasi dari MHC kelas II berperan di dalam keadaan resistensi suatu penyakit. ...
... Berdasarkan penelitian-penelitian sebelumnya telah menyebutkan hubungan HLA-DRB dengan tuberkulosis paru. [22][23][24][25][26][27][28] Penelitian bertujuan menganalisis bagaimana hubungan HLA-DRB dengan tuberkulosis paru khususnya pada proses pengobatan DOTS. ...
... Pemeriksaan Lebih tingginya secara signifikan alel HLA-DR2 pada penderita tuberkulosis paru dibanding kontrol sehat telah dibuktikan oleh peneliti-peneliti lain. [21][22][23][24][25][26][27][28] Disimpulkan bahwa HLA-DR2 secara sendiri atau berkombinasi dengan gen HLA lain atau non HLA berhubungan dengan kerentanan terhadap tuberkulosis paru. ...
... In addition to bacterial virulence, it is likely that socio-economic status, family size, crowding , malnutrition, and limited access to health care or effective treatment influence transmission (Chapman and Dyerly, 1964; Nardell and Piessens, 2000). Many genetic factors are implicated in susceptibility and resistance to M. tuberculosis infection ( Bothamley et al., 1993; Goldfeld et al., 1998; Hill, 1998; Kramnik et al., 2000; Meyer et al., 1998; Rook et al., 1986; Selvaraj et al., 1998; Wilkinson et al., 1999). These factors include key elements of the immune system responsible for presenting antigen from foreign pathogens to immune effector cells (Bothamley et al., 1993; Goldfeld et al., 1998; Meyer et al., 1998; Selvaraj et al., 1998), the vitamin D receptor ( Rook et al., 1986), and macrophage proteins associated with natural resistance ( Hill, 1998). ...
... Many genetic factors are implicated in susceptibility and resistance to M. tuberculosis infection ( Bothamley et al., 1993; Goldfeld et al., 1998; Hill, 1998; Kramnik et al., 2000; Meyer et al., 1998; Rook et al., 1986; Selvaraj et al., 1998; Wilkinson et al., 1999). These factors include key elements of the immune system responsible for presenting antigen from foreign pathogens to immune effector cells (Bothamley et al., 1993; Goldfeld et al., 1998; Meyer et al., 1998; Selvaraj et al., 1998), the vitamin D receptor ( Rook et al., 1986), and macrophage proteins associated with natural resistance ( Hill, 1998). A particular allele (HLA-DR2) is highly correlated with susceptibility to TB disease in India and is present in 30% of that population (Bothamley et al., 1989; Brahmajothi et al., 1991; Mehra et al., 1986; Rajalingam et al., 1996; Selvaraj et al., 1998; Singh et al., 1983; Subramanian et al., 1995). ...
... These factors include key elements of the immune system responsible for presenting antigen from foreign pathogens to immune effector cells (Bothamley et al., 1993; Goldfeld et al., 1998; Meyer et al., 1998; Selvaraj et al., 1998), the vitamin D receptor ( Rook et al., 1986), and macrophage proteins associated with natural resistance ( Hill, 1998). A particular allele (HLA-DR2) is highly correlated with susceptibility to TB disease in India and is present in 30% of that population (Bothamley et al., 1989; Brahmajothi et al., 1991; Mehra et al., 1986; Rajalingam et al., 1996; Selvaraj et al., 1998; Singh et al., 1983; Subramanian et al., 1995). In caucasoid populations of Western Europe and the USA, the allele is present in only 8–15% of the population (Awad et al., 1987; Zachary et al., 1996). ...
Global eradication of tuberculosis (TB) is an international agenda. Thus understanding effects of treatment of TB in different settings is crucial. In previous work, we introduced the framework for a mathematical model of epidemic TB in demographically distinct, heterogeneous populations. Simulations showed the importance of genetic susceptibility in determining endemic prevalence levels. In the work presented here, we include treatment and investigate different strategies for treatment of latent and active TB disease in heterogeneous populations. We illustrate how the presence of a genetically susceptible subpopulation dramatically alters effects of treatment in the same way a core population does in the setting of sexually transmitted diseases. In addition, we evaluate treatment strategies that focus specifically on this subpopulation, and our results indicate that genetically susceptible subpopulations should be accounted for when designing treatment strategies to achieve the greatest reduction in disease prevalence.
... [7][8][9] Por otro lado, los antígenos clase II HLA-DR y -DQ han presentado una mayor consistencia en la asociación. 7,[9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25] A su vez, en algunos estudios se ha encontrado asociación negativa de la TbP con los antígenos HLA-DR y -DQ. 12,15,[24][25][26] Desde el punto de vista clínico, se ha sugerido que el conocimiento detallado y amplio de estos marcadores genéticos en los pacientes con TbP, permite evaluar rápidamente la naturaleza de un proceso tuberculoso, definir su pronóstico y bajo estas bases, elegir el tratamiento adecuado que debe consistir en una quimioterapia más agresiva y específica en aquellos pacientes con antígenos HLA que predisponen a un cuadro clínico más severo. ...
... 15 Selvaraj y colaboradores demostraron que los genes/productos génicos de HLA-DR2 (antígeno paterno de DR16) pueden estar asociados con un papel regulador en el mecanismo de la susceptibilidad a enfermedad en la tuberculosis. 21 Difiere a lo observado en otro estudio en población mexicana, donde la TbP ha sido asociada al antígeno HLA-DR15(2) (DRB1*1501). 23 Los resultados respecto al antígeno DR11(5) incrementado significativamente en casos, indicando asociación positiva o mayor riesgo para padecer TbP en este grupo, están de acuerdo con los de Dovgaliuk y colaboradores, quienes encontraron incrementado a su antígeno paterno DR5. 9 ...
SUMMARY Background: Genetic susceptibility to pulmonary tuberculosis (PTb) has been associated with the HLA (Antigens of the Human Leukocytes) system of the MHC (Major Histocompatibility Complex), mainly with HLA-DR and-DQ antigens. Based on this assumption we carried out a case control study to determine the association of PTb with the HLA-DR and-DQ antigens among a sample of patients attending a medical unit belonging to the Mexican Social Security System (IMSS). Methods: HLA system phenotypes from cases (n=50) and controls (n=417), were defined serologically using a complement dependent microlymphocytotoxic assay. B lymphocytes were obtained using immunobeads. The allele and haplotype frequencies were determined using the Arlequin version 3.01 computer software. Relative risk (RR) was calculated with the Epimax Table Calculator. Results: The alelles HLA-DR11(5), -DR16(2) and -DQ7(3) and haplotypes /DR11(5)-DQ7(3), /DR14(6)-DQ5(1) and /DR16(2)- DQ7(3) had a higher frequency in cases than in controls (RR>1, p
... Since HLA-DR2 is associated with susceptibility to pulmonary tuberculosis (Selvaraj et al ., 1998) as well as HIV and HIV-TB (Selvaraj et al ., 2006), we have attempted to find out the HLA-DR2 subtypes and the possible HLA-A/B/DRB1 haplotypes that involve HLA-A11, -B40 and -DR2 subtypes in the context of genetic susceptibility or resistance to HIV and HIV-PTB in south Indian population. ...
... Our earlier study revealed the association of HLA-A11 with resistance and -B40 and -DR2 with susceptibility to HIV and HIV-TB in south Indian population (Selvaraj et al., 2006). We have also shown the association of HLA-DR2 with susceptibility to PTB (Selvaraj et al., 1998) and specifically HLA-DRB1*1501 (Sriram et al., 2001) in south Indian population. The findings reported here are based on our extended investigation and analysis with subtyping of HLA-DR2 at the allelic level and haplotype analysis. ...
We have shown earlier the association of human leucocyte antigen (HLA)-A11 with resistance and HLA-B40 and -DR2 with susceptibility to HIV and HIV-TB. In the present study, we have attempted to find out the HLA-DR2 subtypes and the possible HLA-A/-B/-DRB1 haplotype combinations that are associated with susceptibility or resistance to HIV and HIV with pulmonary tuberculosis (HIV+PTB+). HLA-DR2 subtyping was carried out by polymerase chain reaction-based sequence-specific oligonucleotide probe method. Overrepresentation of HLA-DRB1*1501 in HIV-positive PTB-negative (HIV+PTB-) patients (P = 0.004, P(c) = 0.06) and -DRB1*1502 in HIV-positive PTB-positive (HIV+PTB+) patients (P = 0.019) was observed as compared to healthy controls. Haplotype analysis revealed an increased frequency of HLA-A2-DRB1*1501 haplotype in HIV+PTB- patients (P = 0.008) and HLA-A2-DRB1*1502 among HIV+PTB+ patients (P = 0.01) compared to healthy controls. The haplotypes B40-DRB1*1501 and B40-DRB1*04 were found to be moderately increased in HIV+PTB(-) and HIV+PTB+ patients (P < 0.05). The study suggests that HLA-A2-DRB1*1501 haplotype may be associated with HIV infection while HLA-A2-DRB1*1502 haplotype might be associated with susceptibility to PTB in HIV patients. Moreover, HLA-B40-DRB1*1501 and HLA-B40-DRB1*04 haplotypes may be associated with susceptibility to HIV infection and to PTB in HIV patients.
... DQ and DR are two of five isotypes of HLA class ⌱⌱ proteins; heterodimers composed of ␣ and  chains, encoded by the highly polymorphic loci, HLA-DQ and -DR, respectively. The HLA class ⌱⌱ variant, DR2 encoded by alleles DRB1*15 and DRB1*16, is associated with TB in several populations [4,5], but not in others [6,7]. The less common DQB1*0503 HLA class II allele associated with TB in Cambodia [7] was shown to bind a peptide from the central region of the Mycobacterium tuberculosis immunogenic protein, ESAT-6, with low affinity, stimulating weak effector T-cell responses [12]. ...
... DRB1*1302 and DRB1*1301 alleles, encoding identical : chain allotypes, except for a Val or Gly at residue 86, occurred at significantly higher frequencies in cases and controls respectively (Table 3). This study did not support the association of DR2 (DRB1*15 and DRB1*16) with TB susceptibility commonly found in other populations [4,5]. Instead, DRB1*1302 and DRB1*1101-1121, alone or in haplotypes, (Table 5) featured in associations with TB in the Venda. ...
The vitamin D receptor (VDR) and the human leukocyte antigen (HLA) class II complex affect innate and/or adaptive immunity against Mycobacterium tuberculosis. HLA-DRB1, HLA-DQB1, and VDR gene (VDR) polymorphisms were previously associated with tuberculosis (TB) and are here investigated as candidates for TB susceptibility in the Venda population of South Africa. Genomic DNA from 95 patients with pulmonary tuberculosis (PTB) and 117 ethnically matched, healthy controls were typed for HLA-DRB1, DRB3, DRB4, DRB5, DQB1, and VDR polymorphisms FokI, BsmI, ApaI, and TaqI using polymerase chain reaction-sequence specific primers (PCR-SSP). Allele and haplotype frequencies were calculated by the estimator maximum (EM) algorithm. DRB1*1302 phenotype was significantly associated with TB occurring at a significantly higher allele frequency in cases than controls and found in haplotype with DQB1*0602/3. DQB1*0301-0304 phenotype was significantly associated with TB and found in haplotype with DRB1*1101-1121, showing significant linkage disequilibrium (LD) in both cases and controls. Only DRB1*1101-1121-DQB1*05 was significantly associated with TB based on the sequential Bonferroni p value. VDR SNP phenotypes were not associated with TB, but the haplotype F-b-A-T significantly protected from TB. In conclusion, common African HLA-DRB1 and -DQB1 variants, previously associated with protection from malaria and hepatitis B/C virus persistence, predispose the Venda to TB, whereas the proposedly active VDR haplotype F-b-A-T showed significant protection.
... However, a study in Uganda reported a negative correlation between TB susceptibility and the DQB1*3 allele, which contradicted our findings [15]. Additionally, other studies in India [16], Thailand [17], and Iran [18] reported a positive correlation between TB susceptibility and expression of DQB alleles. From the available data, the divergent associations might be due to differences in sample size, study designs, and the genetic heterogeneity of the Mycobacterium tuberculosis complex, which were not controlled during our analyses. ...
Introduction: human leukocyte antigen (HLA) class II alleles play an important role in the early immune response to tuberculosis (TB) by presenting antigenic peptides to CD4+ T cells, hence polymorphisms in those genes can influence the efficiency of the immune response to infection and progression to active disease.
Methods: an analytical cross-sectional study of adult pulmonary tuberculosis (PTB) patients at Mbagathi County Hospital, Nairobi and their HHCs. Sociodemographic data were captured on questionnaires and clinical data extracted from patient files. Intravenous blood samples were drawn for interferon-gamma release assay (IGRA) to determine latent tuberculosis infection (LTBI) among HHCs, and for extraction of DNA used in typing of HLA-DQB1 and HLA-DRB1 alleles by PCR sequence specific primer amplification. Chi-square and Fisher's exact test were used to compare the HLA type II allele frequencies of LTBI negative HHCs, LTBI positive HHCs and active TB patients. Logistic regression was used to adjust for HIV status.
Results: the HLA-DQB1 and HLA-DRB1 alleles were analyzed in 17 PTB and 37 HHCs. Nineteen (19) HHCs were LTBI positive, while 18 were LTBI negative. The frequency of DRB3*1 was 0.17-fold lower [95% CI=0.03-0.83] among PTB patients compared to HHCs before adjustment for HIV status (p=0.048). The frequency of the DRB5*2 allele was significantly higher (p=0.013) among PTB patients (23.5%) compared to HHCS (0.00%). After adjusting for HIV status, the frequency of DRB1*14 was 12-fold higher [95% CI=1.11-138.2] among PTB patients compared to HHCs (p=0.040).
Conclusion: the higher frequencies of HLA-DRB5*2 and HLA-DRB1*14 alleles in PTB patients suggest a likely association with progression to active PTB. The higher frequency of HLA-DRB3*1 allele among LTBI negative HHCs shows its likely protective role against M. tuberculosis infection in this population.
... South Indian populations with a highest frequency of 45.19% in Kani tribes of Western Ghats and a lowest frequency of 1% in Narikuravars, a nomadic group living in various parts of Tamil Nadu [7]. The disease susceptibility studies of DR2 revealed a strong association with pulmonary tuberculosis in South India [8][9][10][11]. ...
The present study was aimed to study HLA-DRB1, -DQB1 alleles and haplotypes of two endogamous groups of South India. PCR-SSP typing of HLA-DRB1, -DQB1 alleles were performed on 63 Mukkuvar, primarily a coastal population and 101 Valayar, a population primarily living on the fringes of forest areas. Genetic distances, neighbor-joining dendrograms and correspondence analysis have been performed. The HLA class II alleles, DRB1*07 (32.5%), DRB1*15 (23.0%), DRB1*13 (11.1%) and DRB1*12 (10.3%) were more frequent among Mukkuvar. Among Valayar, DRB1*12 (18.8%), DRB1*15 (17.3%), DRB1*04 (15.4%), DRB1*07 (13.4%) and DRB1*10 (10.9%) were more frequent. Similarly, DQB1*06 (38.1%), DQB1*02 (26.2%) and DQB1*05 (20.5%) alleles among Mukkuvar and DQB1*06 (40.2%) and DQB1*05 (28.9%) among Valayar were more frequent. We genotyped the two most common South Indian two-locus haplotypes, such as DRB1*15-DQB1*06 and DRB1*07-DQB1*02 for HLA-A, -B and -C alleles to identify the 5-locus extended haplotypes. We identified the presence of a highly unique extended haplotype A*03-B*35-C*12-DRB1*07-DQB1*02 in Valayar (HF: 0.2777) and Mukkuvar (HF: 0.1666) hitherto not reported in any of the world populations. The HLA-DRB1 allele based phylogenetic analysis have demonstrated the unique and distinct phylogenetic relatedness of Mukkuvar and Valayar with other ethnic populations. The coastal population Mukkuvar is more closely related to Hispanic and Guanche populations. However, the Valayar revealed phylogenetic relatedness with Austronesian and Micronesian populations supporting the theory of coastal migrations of Out-of-Africa ancestral founding populations.
... HLA and Response to Mycobacteria: HLA DR2 associated with pulmonary tuberculosis and leprosy was also found to be a high responder to mycobacterial antigens (Bothamley et al. 1989;Khomenko et al. 1990;Brahmajothi et al. 1991;Selvaraj et al. 1998). Correlation between IFN-g, IL-10 cytokine status and HLA status with regard to disease status have also been made: there was more IL-10 production in non-DR2, BCG scar negative patients (Dheenadhayalan et al. 2001). ...
Major advances in genetic epidemiological methodologies have helped in understanding the role of host genetic factors in susceptibility / resistance to infectious diseases. Recent human genome mapping information and the identification of a large number of candidate genes provide the tools for such studies. In the present article we review the implications of host genetic factors in infectious diseases such as leprosy, tuberculosis and HIV. India being known for its genetic diversity, studying the role of host genetic factors in disease susceptibility / resistance in Indian populations would throw light on pathogenesis of disease and for the design of preventive and therapeutic strategies.
... Molecular study has revealed that the allele DRB1*1501 of HLA-DR2 was higher compared with DRB1*1502 in North Indian patients. [117][118][119][120][121]123 Moreover, the TAP2 has been found associated with active tuberculosis along with HLA-DR2 in North Indian pulmonary tuberculosis patients. 112 ...
p>It is well documented that infectious pathogen burden and infected cell mass determine the clinical severity of infectious diseases, however, the ability of the host to recognize and process antigens to produce antibodies or the cellular immune response during infection could be under genetic control. The Major Histocompatibility Complex (MHC) or Human Leukocyte Antigen (HLA) system is the most intensively studied of all genetic systems because of its influence to many important traits, including resistance to infectious diseases, autoimmunity and immunological self or nonself compatibility. This is understandable in the light of the evolutionary pressure so that we are equipped to face the multitude of infectious challenges. Infectious diseases are a major selective pressure;and genes involved in the immune response are the most numerous and diverse in the human genome; reflecting the evolutionary advantages of a diverse immunological response to a wide range of infectious pathogens.
Asian Journal of Medical Sciences Vol.8(2) 2017 1-13 </p
... In India DRB1 15 and DRB1 16, were reported to confer susceptibility to TB in some communities [36] but there was no association in others [17]. Studies conducted on South Indian patients showed no association of HLA-DR and HLA-DQ genes with pulmonary TB. ...
Background:
Mycobacterium tuberculosis (Mtb) is reported to infect about a third of the world's population but only 10 % are thought to develop active tuberculosis (TB) disease. Host immunity regulated by human leukocyte antigens (HLA) is an important determinant of the outcome of the disease. Here we investigate HLA class II gene polymorphisms in susceptibility to TB, and whether particular HLA class II alleles were associated with TB in Uganda.
Methods:
HIV negative patients with pulmonary TB (n = 43) and genetically related healthy household controls (n = 42) were typed for their HLA II class alleles using polymerase chain reaction sequence specific primer amplification.
Results:
The HLA-DQB1*03:03 allele was significantly less frequent in patients compared to healthy controls (10 % in controls versus 0 % in patients, p = 0.003). After correction for multiple comparisons the difference remained significant (p = 0.018).
Conclusions:
Our results suggest that the HLA-DQB1*03:03 allele may be associated with resistance to TB.
... HLA-II binding peptides predicted for Mtb72F were found to cover a wide array of alleles (Additional file 1). For DRB1*15 and DRB1*16, which have been linked to susceptibility to TB in Indian populations [34,35], we predicted an average of 64 binding peptides in Mtb72F per allele for the three defined Indian regions. Across geographical regions, the highest numbers of binding peptides for Mtb72F were predicted for DRB1*01:02, 01:04, 08:10, 08:06, 01:01 and 01:08, i.e., 533-468 peptides/allele, or 0.65-0.75/allele ...
Background:
Requisites for an efficacious tuberculosis (TB) vaccine are a minimal genomic diversity among infectious Mycobacterium tuberculosis strains for the selected antigen, and the capability to induce robust T-cell responses in the majority of human populations. A tool in the identification of putative T-cell epitopes is in silico prediction of major histocompatibility complex (MHC)-peptide binding. Candidate TB vaccine antigen Mtb72F and its successor M72 are recombinant fusion proteins derived from Mtb32A and Mtb39A (encoded by Rv0125 and Rv1196, respectively). Adjuvanted Mtb72F and M72 candidate vaccines were shown to induce CD4(+) T-cell responses in European, US, African and Asian populations.
Methods:
Sequence conservation of Mtb32A, Mtb39A, Mtb72F and M72 among 46 strains (prevalent Mycobacterium strains causing human TB disease, and H37Ra) was assessed by multiple alignments using ClustalX. For Mtb32A, Mtb39A and Mtb72F, 15-mer human leukocyte antigen (HLA)-class II-binding peptides were predicted for 158 DRB1 alleles prevailing in populations with high TB burden, 6 DRB3/4/5, 8 DQ and 6 DP alleles, using NetMHCII-pan-3.0. Results for 3 DRB1 alleles were compared with previously published allele-matched in vitro binding data. Additional analyses were done for M72. Nonameric MHC class I-binding peptides in Mtb72F were predicted for three alleles representative of class I supertypes A02, A03 and B07, using seven prediction algorithms.
Results:
Sequence identity among strains was ≥98 % for each protein. Residue changes in Mtb39A comprised primarily single residue or nucleotide insertions and/or deletions in repeat regions, and were observed in 67 % of strains. For Mtb72F, 156 DRB1, 6 DRB3/4/5, 7 DQ and 5 DP alleles were predicted to contain at least one MHC class II-binding peptide, and class I-binding peptides were predicted for each HLA-A/B allele. Comparison of predicted MHC-II-binding peptides with experimental data indicated that the algorithm's sensitivity and specificity were variable among alleles.
Conclusions:
The sequences from which Mtb72F and M72 are derived are highly conserved among representative Mycobacterium strains. Predicted putative T-cell epitopes in M72 and/or Mtb72F covered a wide array of HLA alleles. In silico binding predictions for class I- and II-binding putative epitopes can be complemented with biochemical verification of HLA binding capacity, processing and immunogenicity of the predicted peptides.
... It may also result from direct invasion of a paravertebral focus by lymphangitic spread from paravertebral lymph nodes or the pleural space 1,2 . Our earlier studies in pulmonary tuberculosis revealed the association of HLA-DR2 antigen with the susceptibility to pulmonary tuberculosis 3 . Our further studies also revealed the influence of HLA-DR2 antigen on antibody titre, spontaneous lymphoproliferative response and antigen induced lymphocyte response including memory response in pulmonary tuberculosis 4,5 . ...
Background: Our earlier studies on Human Leucocyte Antigens (HLA) in pulmonary tuberculosis patients revealed the association of HLA-DR2 antigen with susceptibility to pulmonary TB and DR2 antigen has been shown to influence the immunity to tuberculosis. Objectives: The present study was carried out to find out whether HLA-DR antigens are associated with susceptibility to spinal tuberculosis. Moreover, the role of HLA-DR antigens on lymphoproliferative response to Mycobacterium tuberculosis culture filtrate antigens was studied using Lymphocyte Transformation Test (LTT). Material and Methods: HLA-DR genotyping and lymphoproliferative response was carried out in 63 cured spinal TB patients and 63 control subjects (spouses of pulmonary and spinal TB patients). Results: A trend towards an increased frequency of HLA-DR9 antigen was observed in spinal TB patients compared to controls. A significantly decreased lymphocyte response to M. tuberculosis antigens was observed in HLA-DR9 antigen positive control subjects compared to HLA-DR9 antigen negative subjects (P=0.0009) whereas increased response was observed with DR9 positive cured spinal TB patients compared to HLA-DR9 antigen negative patients. Further, HLA-DR3 antigen positive patients showed a decreased lymphocyte response compared to HLA-DR3 antigen negative patients (P<0.05). Conclusion: The study suggests that HLA-DR9 antigen either alone or in combination with other HLA antigen as lhplotype and non-HLA genes may be associated with susceptibility to spinal TB and play a regulatory role on the immune response to M. tuberculosis in spinal tuberculosis patients.
... A growing body of evidence suggests that host genetics play a role in the predisposition to tuberculosis (TB) disease, in addition to pathogen, environmental, and socioeconomic factors [39,40]. Genetic factors contributing to TB susceptibility include variants of the human leukocyte antigen (HLA) class II complex [41][42][43][44] and the vitamin D receptor gene (VDR) [45][46][47][48]. HLA alleles are found to be associated with susceptibility and resistance to infectious diseases including HIV/AIDS, tuberculosis, and malaria that impose huge public health burdens in sub-Saharan Africa [49,50]. ...
Sub-Saharan Africa has continued leading in prevalence and incidence of major infectious disease killers such as HIV/AIDS, tuberculosis, and malaria. Epidemiological triad of infectious diseases includes susceptible host, pathogen, and environment. It is imperative that all aspects of vertices of the infectious disease triad are analysed to better understand why this is so. Studies done to address this intriguing reality though have mainly addressed pathogen and environmental components of the triad. Africa is the most genetically diverse region of the world as well as being the origin of modern humans. Malaria is relatively an ancient infection in this region as compared to TB and HIV/AIDS; from the evolutionary perspective, we would draw lessons that this ancestrally unique population now under three important infectious diseases both ancient and exotic will be skewed into increased genetic diversity; moreover, other evolutionary forces are also still at play. Host genetic diversity resulting from many years of malaria infection has been well documented in this population; we are yet to account for genetic diversity from the trio of these infections. Effect of host genetics on treatment outcome has been documented. Host genetics of sub-Saharan African population and its implication to infectious diseases are an important aspect that this review seeks to address.
... In different populations, specific alleles and haplotypes have been identified which are associated with TB (16)(17)(18)(19)(20)(21)(22)(23). Our study showed that five alleles (DQA1*03:02 , DQA1*03:03 , DQB1*06:01 , DRB1*08:01 and DRB1*08:03 ) were more frequent among patients with TB than among controls (P < 0.05) (Tables 2-4). ...
The human leukocyte antigen (HLA) system has a major role in the regulation of the immune response as it is involved in the defense against pathogens. Some studies have reported that HLA class II genes play a strong role in severe cases of pulmonary tuberculosis (PTB) in several populations. Thus the aim of the study was to compare the HLA-class II alleles of patients with drug resistant tuberculosis with those of healthy controls from the same ethnic group in Kazakhstan. The aim of the present study was to evaluate the correlation of HLA-class II alleles by patients with drug resistant tuberculosis and the healthy controls of the same ethnic group in Kazakhstan. The HLA-class II alleles of 76 patients with tuberculosis (TB) and 157 healthy volunteers were investigated using sequence-based typing (SBT)-method. HLA-DQA1*03:02 HLA-DRB1*08:01 and DRB1*08:03 occurred more frequently (P = 0.05) in patients with drug resistant tuberculosis than in controls. We observed a possible association between certain HLA alleles and TB that are specific for the Kazakh population. Further studies are needed to confirm our findings using a larger number of patients with drug resistant tuberculosis.
... However, even before the study reported in [15], the involvement of human genes in tuberculosis has been suggested by numerous epidemiological observations [1,[16][17][18][19][20][21]. These studies employed, amongst other methods, large scale control studies of target genes, family-based linkages including twin studies and investigation of rare individuals with exceptional mycobacteria susceptibility. ...
The effect of difference in susceptibility on the dynamics of tuberculosis is an ongoing study. Several genes in TB co-receptors (e.g. HLA and non-HLA) have been correlated with susceptibility and resistance to tuberculosis and rate of progression to active TB. In this paper, we present a novel mathematical model that distinguishes between susceptibility amongst the population. The model classifies the susceptibles as having no, partial or full natural resistance to tuberculosis and the latently infecteds as rapid, normal or very slow (or no) progressors to active TB depending on the genes. The goal of this paper is to investigate the impact of such heterogeneity on the spread of tuberculosis and to identify key parameters that could be used in understanding these heterogeneities more fully. We derived the reproduction number RTRT for the model and examine the relative contributions to RTRT from the three latently infected classes as well as the infectious classes. The effect of treatment under the heterogeneity is also examined.
... An association between HLA and TB has been examined in several populations, but the results have been inconsistent. The HLA class II variant, DR2 encoded by alleles DRB1 * 15 and DRB1 * 16, is associated with TB in several populations [38,39], but not in others [40,41]. In South Africans [42], a significant interaction between HLA-DRB1 * 1302 allele and susceptibility to TB was observed. ...
Background:
To explore the potential role of natural-resistance-associated macrophage protein 1 (NRAMP1) gene, vitamin D receptor (VDR) gene, (human leukocyte antigen, (HLA-DRB1) HLA)-DRB1 gene, and HLA-DQB1 gene polymorphisms in susceptibility to tuberculosis (TB) in the Chinese Kazakh population.
Methods:
A case-control study was performed on the Chinese Kazak population. Genetic polymorphisms of NRAMP1 gene (3'UTR) and VDR gene (TaqI and FokI) were analysed using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and sequencing analysis in TB patients and healthy controls. Genetic polymorphisms of HLA-DRB1 gene and HLA-DQB1 gene in the two groups were detected with polymerase chain reaction-sequence-specific primers (PCR-SSPs) technique and sequencing analysis.
Results:
There was statistically significant difference in the 3'UTR polymorphism between the TB patients and healthy controls in the Chinese Kazak population (P = 0.002; OR = 1.859; 95% CI = 1.182-2.926). Significant difference was observed in the FokI polymorphism between the TB patients and healthy controls (P = 0.001; OR = 1.530; 95% CI = 1.007-2.325). It does not disclose any significant association between the disease and TaqI (P > 0.05). Alleles HLA-DRB1*04 and HLA-DQB1*0201 occurred more frequently in patients than in controls (P = 0.011 and 0.002; OR = 1.889 and 1.802; 95% CI = 1.153-3.095 and 1.230-2.639, resp.).
Conclusions:
Polymorphisms in the NRAMP1 gene, VDR gene, HLA-DRB1 gene, and HLA-DQB1 gene are statistically associated with susceptibility to TB in the Chinese Kazakh population.
... Of the numerous Indian studies on HLA association with pulmonary tuberculosis, an increased frequency of HLA-DR2 and -DQ1 was shown to be associated with the susceptibility to pulmonary tuberculosis [22][23][24] . Molecular study has revealed that the allele DRB1 *1501 of HLA-DR2 was higher compared with DRB1 *1502 in north Indian patients 25 . ...
β), mannose bind- ing lectin (MBL), vitamin D receptor (VDR) (BsmI, ApaI, TaqI and FokI polymorphisms) , Interleukin -1 receptor antagonist (IL-1RA) and natural resistance associated macrophage protein-1 (NRAMP -1) genes revealed the association of TAP2 gene variant along with HLA-DR2 and functional mutant homozygotes (FMHs) of MBL with the susceptibility to pulmonary TB. The polymorphic BsmI, ApaI, TaqI and FokI gene variants of VDR showed differential susceptibility and resistance with male and female subjects. These studies suggest that multicandidate genes are associated with the susceptibility to pulmonary tuberculosis in India.
... 60 Earlier studies have also revealed the association of HLA-DR2 with susceptibility to PTB in the south Indian population. 61 Therefore, individuals positive for HLA-DR2 who have HIV-1 infection latently infected with M. tuberculosis may have a higher propensity to develop active disease. Association of HLA-DRB alleles HLA-DRB1*04:03:01, HLA-DRB1*09:01:02, and HLA-DRB1*14:01:03 with susceptibility to HIV-PTB (HIV-pulmonary TB) coinfection among western Indian population has been recently reported. ...
Tuberculosis (TB) is the frequent major opportunistic infection in HIV-infected patients, and is the leading cause of mortality among HIV-infected patients. Genetic susceptibility to TB in HIV negative subjects is well documented. Since coinfections can influence the way in which immune system respond to different pathogens, genetic susceptibility to TB in HIV patients might also change. Studies from India and other parts of the world have shown that genetic susceptibility to TB is influenced by HIV infection. In the present review, we emphasize the role of genetic factors in determining susceptibility to HIV infection, disease progression and development of TB in HIV-infected patients. Polymorphisms in human leukocyte antigen (HLA), MBL2, CD209, vitamin D receptor, cytokine, chemokine and chemokine receptor genes have been shown to be associated with development of TB in HIV patients. However, the results are inconclusive and larger well-defined studies with precise clinical data are required to validate these associations. Apart from candidate gene approach, genome-wide association studies are also needed to unravel the unknown or to establish the previously reported genetic associations with HIV associated TB. Despite the preliminary status of the reported associations, it is becoming clear that susceptibility to development of TB in HIV patients is influenced by both environmental and genetic components. Understanding the genetic and immunologic factors that influence susceptibility to TB in HIV patients could lead to novel insights for vaccine development as well as diagnostic advances to target treatment to those who are at risk for developing active disease.
... Earlier studies on the serological determination of HLA-DR antigens in TB reported an association between progressive TB and HLA-DR2 in populations from India, Indonesia and Russia. [18][19][20][21][22][23] The association of HLA-DR2 with susceptibility to TB has been consistently observed across ethnic boundaries. Molecular typing of HLA-DR2 at the allelic level showed that the frequency of the allele DRB1*1501 was higher than that of DRB1*1502 in north Indian patients, and it has been suggested that the DR2 association was stronger in patients with drug failure. ...
The importance of host genetic factors in determining susceptibility to tuberculosis (TB) has been studied extensively using various methods, such as case-control, candidate gene and genome-wide linkage studies. Several important candidate genes like human leucocyte antigen/alleles and non-human leucocyte antigen genes, such as cytokines and their receptors, chemokines and their receptors, pattern recognition receptors (including toll-like receptors, mannose binding lectin and the dendritic cell-specific intercellular adhesion molecule-3 grabbing nonintegrin), solute carrier family 11A member 1 (formerly known as natural resistance-associated macrophage protein 1) and purinergic P2X7 receptor gene polymorphisms, have been associated with differential susceptibility to TB in various ethnic populations. This heterogeneity has been explained by host-pathogen and gene-environment interactions and evolutionary selection pressures. Although the achievements of genetics studies might not yet have advanced the prevention and treatment of TB, researchers have begun to widen their scope of investigation to encompass these practical considerations.
... HLA genes have been examined in several tuberculosis susceptibility studies and were some of the first genes to be investigated and associated with the disease. The HLA-DR2 is the most consistently associated with tuberculosis in several populations such as India (Meyer et al., 1998;Ravikumar et al., 1999), Thailand (Vejbaesya et al., 2002), Indonesia (Selvaraj et al., 1998a) and Russia (Khomenko et al., 1990). It was found that the HLA-DQB1 Ã 0503 influence the progression of tuberculosis in the Cambodian population (Goldfeld et al., 1998), whereas the DQB1 Ã 0601 was associated with tuberculosis in the Thai and South Indian population (Ravikumar et al., 1999;Vejbaesya et al., 2002). ...
The historical impression that tuberculosis was an inherited disorder has come full circle and substantial evidence now exists of the human genetic contribution to susceptibility to tuberculosis. This evidence has come from several whole-genome linkage scans, and numerous case-control association studies where the candidate genes were derived from the genome screens, animal models and hypotheses pertaining to the disease pathways. Although many of the associated genes have not been validated in all studies, the list of those that have been is growing, and includes NRAMP1, IFNG, NOS2A, MBL, VDR and some TLR. Certain of these genes have consistently been associated with tuberculosis in diverse populations. The future investigation of susceptibility to tuberculosis is almost certain to include genome-wide association studies, admixture mapping and the search for rare variants and epigenetic mechanisms. The genetic identification of more vulnerable individuals is expected to inform personalized treatment and perhaps vaccination strategies.
... It may also result from direct invasion of a paravertebral focus by lymphangitic spread from paravertebral lymph nodes or the pleural space 1,2 . Our earlier studies in pulmonary tuberculosis revealed the association of HLA-DR2 antigen with the susceptibility to pulmonary tuberculosis 3 . Our further studies also revealed the influence of HLA-DR2 antigen on antibody titre, spontaneous lymphoproliferative response and antigen induced lymphocyte response including memory response in pulmonary tuberculosis 4,5 . ...
Major histocompatibility complex (MHC) genes are known to influence the immune functions. In the present study, the influence of non-MHC genes such as mannose binding protein (MBP), vitamin D receptor (VDR) and interleukin-1 receptor antagonist (IL-1RA) gene polymorphisms on lymphocyte response to Mycobacterium tuberculosis culture filtrate antigen (10 micrograms/ml) was studied in 44 patients with active pulmonary TB and the family contacts (35) and in 32 normal healthy subjects. The influence of these gene polymorphisms on tuberculin (1TU of PPD of M. tuberculosis) reactivity status in 146 pulmonary TB patients was also studied.
The MBP and VDR genes were amplified using polymerase chain reaction (PCR) and genotyping was carried out using sequence specific oligonucleotide probes by dot blot and IL-1RA by agarose gel electrophoresis.
A significantly decreased lymphocyte response to M. tuberculosis antigen was seen in pulmonary TB patients positive for functional mutant homozygotes of MBP (OO) compared to heterozygote carriers (AO; P < 0.02) and wild homozygotes (AA; P < 0.01). The variant mutant genotype (tt) of VDR gene was associated with an increased lymphocyte response in control subjects compared to active TB patients with tt genotype (P < 0.05). Heterozygote carriers of MBP (AO) were associated with a significantly (P < 0.001) decreased tuberculin reactivity compared to wild homozygotes (AA). The VDR genotype Tt (heterozygote carrier) was associated with an increased tuberculin reactivity in female TB patients as compared to male patients (P < 0.001).
The present study suggested that MBP and VDR genes influence the cell mediated immune response in pulmonary TB patients. Non-MHC genes along with HLA-Class II genes/gene products may be playing an immunoregulatory role in the mechanism of susceptibility/resistance to tuberculosis.
Mycobacterium tuberculosis infection is generally asymptomatic as latent tuberculosis, but it is still known as the world’s leading bacterial cause of death. The diagnosis of latent tuberculosis infection relies on the evidence of cellular immunity to mycobacterial antigens. Since the association between HLA class II and tuberculosis infection has been reported in several population groups, a detailed study on the CD4 ⁺ T cell response to major tuberculosis antigens is needed. To elucidate which HLA class II allotypes in an individual are preferentially used in tuberculosis, CD4 ⁺ T cells specific to TB10.4, Ag85b, ESAT-6, and CFP-10 of Mycobacterium tuberculosis antigens were analyzed comprehensively. A total of 33 healthy donors were analyzed by ex vivo and cultured ELISPOT using panels of artificial antigen-presenting cells expressing a single HLA class II allotype. The CD4 ⁺ T cell responses were increased by an average of 39-fold in cultured ELISPOT compared with ex vivo ELISPOT. In ex vivo and cultured ELISPOT, CD4 ⁺ T cell responses showed significantly higher by HLA-DR than those of HLA-DQ and HLA-DP locus. In cultured ELISPOT, 9 HLA-DR allotypes, 4 HLA-DQ allotypes, and 3 HLA-DP allotypes showed positive CD4 ⁺ T cell responses. Among ten donors with positive CD4 ⁺ T cell responses when tested for mixed Mycobacterium tuberculosis antigens, seven donors were positive for only a single allotype, and three were positive for two allotypes in an individual. However, only one allotype was used for a single antigen-specific response when a single tuberculosis antigen was used individually. These results on the distribution of HLA class II allotypes showing high CD4 ⁺ T-cell responses to Mycobacterium tuberculosis antigens and the intra-individual allotype dominance will provide valuable information for understanding the immunobiology and immunogenetics of tuberculosis, which can contribute to the development of more effective vaccines.
Tuberculosis (TB) still remains the major threat for human health worldwide. Several case-control, candidate-gene, family studies and genome-wide association studies (GWAS) suggested the association of host genetic factors to TB susceptibility or resistance in various ethnic populations. Moreover, these factors modulate the host immune responses to tuberculosis. Studies have reported genetic markers to predict TB development in human leucocyte antigen (HLA) and non-HLA genes like killer immunoglobulin-like receptor (KIR), toll-like receptors (TLRs), cytokine/chemokines and their receptors, vitamin D receptor (VDR) and SLC11A1 etc. Highly polymorphic HLA loci may influence antigen presentation specificities by modifying peptide binding motifs. The recent meta-analysis studies revealed the association of several HLA alleles in particular class II HLA-DRB1 with TB susceptibility and valuable marker for disease development especially in Asian population. Case-control studies have found the association of HLA-DR2 in some populations but not in other populations, this could be due to ethnic specific association of gene variants. Recently, GWAS conducted in case-control and family based studies in Russia, Chinese Han, Morocco, Uganda and Tanzania revealed the association of genes such as ASAP1, Alkylglycerol monooxygenase (AGMO), Forkhead BoxP1 (FOXP1), C-terminal domain phosphatase 1 (UBLCP1) and intergenic SNP rs932347C/T with TB. Whereas, SNP rs10956514A/G were not associated with TB in western Chinese Han and Tibetan population. In this review, we summarize the recent findings of genetic variants with susceptibility/resistance to TB.
We determined the high-resolution allele and haplotype frequencies at the human leucocyte antigen (HLA)A, B and DRB1 loci in the Han population of Hubei province, the TB endemic area of Central China, with pulmonary tuberculosis (PTB), and established the relationship between HLA-A, B and DRB1 alleles as well as haplotypes and susceptibility to multidrug-resistant and rifampicin-resistant tuberculosis (MDR/RR-TB). Blood samples were drawn from 174 patients with MDR/RR-TB and 838 patients with drug-susceptible PTB in ethnic Han population from Hubei province (central China). Four-digit allele genotyping of HLA- A, B and DRB1 loci was performed using polymerase chain reaction with sequence-specific oligonucleotide probes (PCR- SSOP). The allele and haplotype frequencies of HLA-A, B and DRB1 were determined and compared between patients with MDR/RR-TB and patients with drug-susceptible PTB. Statistical analysis of the generated data indicated no departure from expectation of Hardy–Weinberg equilibrium (HWE) at all loci of the control group. Multivariate analysis identified allele DRB1*08:01 (p < .0001; OR = 174.5, 95% CI 15.3–1987.2) as independent predictor of MDR/RR-TB, except for old age (p < .0001; OR = 10. 9, 95% CI 7.6–15.8), previous treatment history (p < .0001; OR = 11.0, 95% CI 7.2–16.7) and poor compliance to treatment (p < .0001; OR = 12.9, 95% CI 8.4–20.0). While in the subgroup of new TB cases, DRB1*08:01 (p < .0001; OR = 80.3, 95% CI 7.0–917.1) and older age (p < .0001; OR = 3.9, 95% CI 2.4–6.4) were independent susceptibility factors for primary MDR/RR-TB. Our results suggest that a combination of clinical and host genetic information about tuberculosis patients may contribute to prediction and early detection of MDR/RR-TB.
Immunology is an all important science, addressing, as it does the most pressing medical needs of our time: infectious disease and transplantation medicine. It has given us vaccines on the one hand and therapeutic antibodies on the other. After a century of empirical research, it is now poised to finally reinvent itself as a quantitative, genome-based science. Like most biological disciplines, immunology must capitalize on the potentially overwhelming deluge of new data delivered by post-genomic, high throughput technologies; data which is both bewilderingly complex and delivered on a hitherto unimaginable scale.Theoretical immunology is the application of mathematical modeling to diverse aspects of immunology ranging from T cell selection in the Thymus to the epidemiology of vaccination. Immunoinformatics, the application of computational informatics to the study of immunological macromolecules, addresses important questions in immunobiology and vaccinology. Immunoinformatics, addresses issues of data management, and has the ability to design and implement efficient new experimental strategies. Artificial Immune Systems (AIS) is an area of computer science which uses ideas and concepts from immunology to guide and inspire new algorithms, data structures, and software development. The influence of AIS is now becoming highly synergistic through its interaction with immunoinformatics.These three different disciplines are now poised to engineer a paradigm shift from hypothesis- to data-driven research, with new understanding emerging from the analysis of complex datasets: theoretical immunology, immunoinformatics, and Artificial Immune Systems (AIS). "in silico Immunology" is a book for the future: it will summarize these emergent disciplines and, while focusing on cutting edge developments, will address the issue of synergy as it shows how these three are set to transform immunological science and the future of health care. © 2007 Springer Science-hBusiness Media, LLC. All rights reserved.
Tuberculosis is a major health problem throughout the world causing large number of deaths, more than that from any other single infectious disease. The review attempts to summarize the information available on host immune response to Mycobacterium tuberculosis. Since the main route of entry of the causative agent is the respiratory route, alveolar macrophages are the important cell types, which combat the pathogen. Various aspects of macrophage-mycobacterium interactions and the role of macrophage in host response such as binding of M. tuberculosis to macrophages via surface receptors, phagosome-lysosome fusion, mycobacterial growth inhibition/killing through free radical based mechanisms such as reactive oxygen and nitrogen intermediates; cytokine-mediated mechanisms; recruitment of accessory immune cells for local inflammatory response and presentation of antigens to T cells for development of acquired immunity have been described. The role of macrophage apoptosis in containing the growth of the bacilli is also discussed. The role of other components of innate immune response such as natural resistance associated macrophage protein (Nramp), neutrophils, and natural killer cells has been discussed. The specific acquired immune response through CD4 T cells, mainly responsible for protective Th1 cytokines and through CD8 cells bringing about cytotoxicity, also has been described. The role of CD-1 restricted CD8(+) T cells and non-MHC restricted gamma/deltaT cells has been described although it is incompletely understood at the present time. Humoral immune response is seen though not implicated in protection. The value of cytokine therapy has also been reviewed. Influence of the host human leucocyte antigens (HLA) on the susceptibility to disease is discussed. Mycobacteria are endowed with mechanisms through which they can evade the onslaught of host defense response. These mechanisms are discussed including diminishing the ability of antigen presenting cells to present antigens to CD4(+) T cells; production of suppressive cytokines; escape from fused phagosomes and inducing T cell apoptosis. The review brings out the complexity of the host-pathogen interaction and underlines the importance of identifying the mechanisms involved in protection, in order to design vaccine strategies and find out surrogate markers to be measured as in vitro correlate of protective immunity.
The haemoglobinopathies – thalassaemias and abnormal
haemoglobins – constitute a major burden of genetic
diseases in India. Our study, based on index cases
from 120 families detected between May 1999 and May
2003, highlights the ethnic distribution of haemoglobinopathies
in regions in and around Varanasi comprising
8–10 districts of eastern Uttar Pradesh andadjoining districts of Bihar, Jharkhand, Chhattisgarh
and Madhya Pradesh. Homozygous and heterozygous
b-thalassaemia was the most common (66.9%), with
thalassaemic haemoglobinopathies HbE-b-thalassaemia
(15.9%) and HbS-b-thalasseamia (7.8%) contributing
to almost a quarter of the cases. Along with HbSS disease
(4.3%), the results indicate a confluence of b-thalassaemia,
HbS and HbE in this region. IVS1-5 nt was
the most common mutation in the few carriers analysed
for mutation detection. The significance of the study lies
in the demonstration of wide prevalence of b-thalassaemia
across all castes and communities of this region,
with migrant population groups of Sindhis and
Punjabis comprising only 5.8% of the index cases.
Also, HbE seems to have a much higher presence in
this region than so far believed and HbS has a significant
presence in general castes as well.
Humoral and cell mediated immune responses were studied in cured spinal tuberculosis patients and their spouses to understand immunit to tuberculosis in cured patients. Antibody litre and immune complex levels were measured and lymphocyte response to Mycobaclerinm tuberculosis culture filtrate antigen was observed in cured spinal tuberculosis patients (n=30) and their spouses (n =27). A trend towards increased antibody litre was seen in cured patients as compared to their spouses. Significantly increased circulating immune complex levels, as measured by PEG OD280 (polyethylene glycol optical density 280) were seen in the contacts compared to cured patients. And a trend towards increased lymphocyte response to M tuberculosis culture filtrate antigen was seen with different antigen concentrations (0.1,1 and 10 µg /ml). Moreover, the effect of active-pulmonary-Tuberculosis (AT B) plasma taken from 1ILA-DR2 positive and DR2 negative patients on lymphocyte response of the cured patients showed no dramatic immunomodulatory effect in the lymphocyte response when treated with DR2 positive or DR2 negative plasma. The study suggests that the memory response lo M tuberculosis is well maintained even after 10-15 years of treatment.
The role of HLA-DR genetic make-up on the IgG, IgA and IgM antibody response to Mycobacterium tuberculosis culture filtrate and 30 kDa antigens was studied in pulmonary tuberculosis. The study was carried out in HLA-DR typed active pulmonary tuberculosis (ATB) patients (n = 37), inactive (cured) pulmonary tuberculosis (ITB) patients (n = 79) and normal healthy subjects (NHS; n = 46). In ATB and ITB (cured) patients, IgG antibody (optical density at 490 nm for 1:3200 dilution) as measured by enzyme-linked immunosorbent assay was the predominant one than IgA and IgM antibodies. Increased IgG antibody titre to culture filtrate (P = 0.03) and decreased titre to 30 kDa antigen were observed with HLA-DR1-positive ATB patients than non-DR1 (ATB) patients. Moreover, HLA-DR4- and HLA-DR6-positive ATB patients showed trends toward an increased IgG antibody response to 30 kDa antigen than HLA-DR4- and HLA-DR6-negative (ATB) patients respectively. Significantly increased IgA antibody to 30 kDa antigen was observed with HLA-DR1-positive ATB patients than non-DR1 patients (P = 0.03). The study suggests that multiple HLA-DR molecules may regulate the IgG and IgA antibody responses to various proteins of M. tuberculosis. Moreover, HLA-DR phenotypes and increased IgG and IgA antibody titres may be useful to differentiate M. tuberculosis-infected subjects from normal subjects and cured patients with the same HLA-DR phenotypes or genetic make-up.
Genetic studies of pulmonary tuberculosis (PTB), including those of human leukocyte antigen (HLA) genes, have been reported in several populations. Some studies also have reported these genes to have a stronger role in severe tuberculosis. We investigated HLA class I and II alleles and haplotypes to ascertain their role in susceptibility and resistance to new and recurrent PTB in 257 PTB patients (216 new and 41 recurrent PTB patients) and 236 healthy controls in Western Javanese (Indonesia). HLA-B*4006 was associated with new PTB (p = 0.044, p(adj) = ns), whereas HLA-B*1802, HLA-B*4001 and HLA-DRB1*1101 were associated with recurrent PTB (p = 0.013, p(adj) = 0.016; p = 0.015, p(adj) = 0.028; and p = 0.008, p(adj) = 0.027 for new PTB vs recurrent PTB, respectively). Except for HLA-B*4006, those associations remained significant after adjustment for age and gender by logistic regression analysis, although they disappeared after correction for multiple testing. Haplotype HLA-B*1802-DRB1*1202 was associated with susceptibility to recurrent PTB (p = 0.014, odds ratio = 3.8, 95% confidence interval = 1.18-12.27). In contrast, HLA-DRB1*1202 in the absence of HLA-B*1802 showed a significant association with resistance to recurrent PTB (p = 8.2 x 10(-4), odds ratio = 0.32, 95% confidence interval = 0.16-0.64), suggesting that stronger susceptibility effect of HLA-B*1802 masked the protective effect of HLA-DRB1*1202. Further studies using larger number of patients with recurrent PTB will be needed to confirm our findings.
Tuberculosis (TB) is an infectious disease, caused by Mycobacterium tuberculosis. MTB infection does not necessarily progress to TB. Only 5-10% of exposed individuals develop clinical signs and symptoms of TB. Given the impact of mycobacterial exposure and the immunoregulatory consequences for host immunity, it is important to study the integrity and the regulation of immune responses and their downstream signaling pathways in TB endemic areas. Indonesia is a highly TB-burdened country and ranks third globally in TB cases. This thesis, consisting of six studies, explored variation in host immune responses to TB and their genetic background, and variation in clinical presentation. (1) MTB-specific stimulation of IFN-γ production as well as IFN-γ receptor signaling was significantly down-regulated during active TB, correlated with disease severity and –activity. (2) Concentrations of plasma granulysin of active TB patients were found to be low during acute disease. (3) Several genetic markers have been identified to affect susceptibility to TB (IL12B, IL12RB1, IFNG and IFNGR1) and (4) TLR8, DC-SIGN, complement component and scavenger receptor. (5) NRAMP polymorphisms were, however, not associated with susceptibility to TB. (6) TB with concomitant type2 DM presented more symptoms; screening fasting blood glucose in TB patients is clinically important.
There is substantial evidence from studies on racial variation in susceptibility to tuberculosis (TB) that human genetic variation is an important determinant of the outcome of infection with Mycobacterium tuberculosis (M tb). In only a minority of cases is there an obvious identifiable risk factor such as human immunodeficiency virus (HIV) infection, advanced age, diabetes, corticosteroid usage or alcohol abuse. In the remainder, a complex interaction of genetic and environmental factors causes the development of clinical TB. Assessment of the contribution of genetics of host resistance to human TB is a long-standing challenge of human genetics research. Several studies demonstrated the association of various human leukocyte antigens (HLA) with disease susceptibility in different ethnic populations. There are likely to be many more TB-susceptibility genes to be identified.
Genetic susceptibility to pulmonary tuberculosis (PTb) has been associated with the HLA (Antigens of the Human Leukocytes) system of the MHC (Major Histocompatibility Complex), mainly with HLA-DR and-DQ antigens. Based on this assumption we carried out a case control study to determine the association of PTb with the HLA-DR and-DQ antigens among a sample of patients attending a medical unit belonging to the Mexican Social Security System (IMSS).
HLA system phenotypes from cases (n=50) and controls (n=417), were defined serologically using a complement dependent microlymphocytotoxic assay. B lymphocytes were obtained using immunobeads. The allele and haplotype frequencies were determined using the Arlequin version 3.01 computer software. Relative risk (RR) was calculated with the Epimax Table Calculator.
The alelles HLA-DR11(5), -DR16(2) and -DQ7(3) and haplotypes /DR11(5)-DQ7(3), /DR14(6)-DQS(1) and /DR16(2)-DQ7(3) had a higher frequency in cases than in controls (RR>1, p<0.05). The HLA-DR17(3) and DQ8(3) alelles and /DR17(3)-DQ2 and /DR4-DQ8(3) haplotypes had a higher frequency among controls than among cases (RR<1, p<.05).
These results indicate an association between PTb with the HLA-DR and -DQ antigens in a Mexican sample. Our results are similar to those found in the international literature.
Mannose binding protein gene polymorphism in pulmonary tuberculosis in India.
To find out whether non-HLA genes such as mannose binding protein (MBP) genes are associated in the susceptibility to pulmonary tuberculosis.
Genotyping of MBP 52, 54 and 57 wild and mutant alleles was carried out in HLA-DR typed pulmonary tuberculosis patients (n = 202) and control subjects (n = 109). Since HLA-DR2 is associated with pulmonary-TB, the interaction of MBP genes on -DR2 and non-DR2 genes on the susceptibility was also studied.
A significantly increased genotype frequency of MBP functional mutant homozygotes (including 52, 54 and 57) was seen in pulmonary tuberculosis (PTB) patients (10.9%) than in control subjects (1.8%; P = 0.008; odds ratio: 6.5). Analysis of interaction of MBP genes and HLA-DR2 on the susceptibility to PTB revealed that these genes are associated with PTB independent of each other.
The present study shows that functional mutants of MBP are associated with PTB. Apart from HLA-DR2 association, association of non-HLA genes in the susceptibility to PTB is evident. This suggests that multigenetic factors (candidate genes) may be involved in the susceptibility/resistance to PTB.
Influence of HLA-DR antigens and lymphocyte responses in pulmonary TB patients.
To elucidate the role of HLA-DR genes/gene products on lymphocyte responses to Mycobacterium tuberculosis antigens and mitogens, the present study was carried out in pulmonary tuberculosis during active and cured stage of the disease.
Serological determination of HLA-DR antigens was carried out in 50 active TB patients, 44 cured TB patients and 58 normal healthy control subjects. The influence of HLA-DR antigens on peripheral blood lymphocyte responses to M. tuberculosis culture filtrate antigens and mitogens such as phytohaemagglutinin (PHA) and concanavalin-A (Con-A) was studied in the patients as well as normal healthy control subjects.
Of all the DR antigens studied, patients (active TB and cured TB) with DR2 antigen showed an increased lymphocyte response (stimulation index) to a higher dose of antigenic (10 micrograms/ml) stimulation. A significantly lower lymphocyte response to antigen and mitogens was seen in HLA-DR3 positive normal healthy subjects than non-DR3 (DR3 negative) subjects.
The present study suggests that HLA-DR genes/gene products may be playing an immunoregulatory role in eliciting an immune response against M. tuberculosis antigens and mitogens induced lymphocyte response in pulmonary TB patients and normal healthy subjects.
The resurgence of tuberculosis worldwide has intensified research efforts directed at examining the host defense and pathogenic mechanisms operative in Mycobacterium tuberculosis infection. This review summarizes our current understanding of the host immune response, with emphasis on the roles of macrophages, T cells, and the cytokine/chemokine network in engendering protective immunity. Specifically, we summarize studies addressing the ability of the organism to survive within macrophages by controlling phagolysosome fusion. The recent studies on Toll-like receptors and the impact on the innate response to M. tuberculosis are discussed. We also focus on the induction, specificity, and effector functions of CD4(+) and CD8(+) T cells, and the roles of cytokines and chemokines in the induction and effector functions of the immune response. Presentation of mycobacterial antigens by MHC class I, class II, and CD1 as well as the implications of these molecules sampling various compartments of the cell for presentation to T cells are discussed. Increased attention to this disease and the integration of animal models and human studies have afforded us a greater understanding of tuberculosis and the steps necessary to combat this infection. The pace of this research must be maintained if we are to realize an effective vaccine in the next decades.
A study of tumour necrosis factor alpha and beta (TNFalpha and beta) gene polymorphism and haplotype analysis with HLA in pulmonary tuberculosis.
To determine whether TNFalpha (-238 and -308) and TNFbeta (Nco I polymorphism in intron 2) genes either alone or in combination with human leucocyte antigens (HLA) as haplotypes afford susceptibility or resistance to pulmonary tuberculosis as well as bacteriological relapse of the disease.
Tumour necrosis factor alpha -238, -308 (TNFalpha -238, -308) and TNFbeta (Nco I) gene polymorphisms were carried out in HLA-A,B and DR typed pulmonary tuberculosis patients (n=210) and 120 normal healthy control subjects.
No difference in the genotype frequencies of TNFalpha-238 and -308 and TNFbeta was seen between control subjects and pulmonary tuberculosis patients. Of the HLA-TNF haplotypes analysed, the infrequent allele (A) of TNFalpha238 was in strong linkage disequilibrium with HLA-A1 (P corrected: Pc=0.001), B17 (Pc<0.0001) and DR7 (Pc=0.01) in control subjects and with B17 (Pc<0.0001) in pulmonary tuberculosis. The infrequent allele 2 of TNFalpha-308 and the infrequent allele 2 of TNFbeta were in strong linkage disequilibrium with HLA-B21. An increased haplotype frequency of HLA-B17-TNFalpha-238/A (P=0.05), B17-TNFalpha308/2 (P=0.03) and B17-TNFalpha308/2 (P=0.01) was observed in bacteriological relapse patients than quiescent patients.
The present study suggests that TNFalpha (-238 and -308) and TNFbeta gene variants are not associated independently with the susceptibility to pulmonary tuberculosis. However, in combination with the HLA genes/gene products such as HLA-A1, B17, B21 and DR7, the TNFalpha and beta genes as haplotypes are associated with protection against the disease as well as an increased susceptibility to bacteriological relapse.
There is wide variation in endemic tuberculosis (TB) levels between countries and we seek to identify possible causes of these differences. In this study we present an epidemiological model of Mycobacterium tuberculosis infection to investigate the effects of host genetics and demographic factors on epidemic TB. We discuss the general framework for this approach and present analytical results to identify important parameters affecting steady-state prevalence and incidence rates of TB disease. We then use numerical simulations of our model to observe the effects of a genetically susceptible subpopulation on TB disease dynamics at the population level. Finally, we simulate infection within a genetically heterogeneous population in two demographic settings: India (a typical population with high TB prevalence) and the USA (a typical population with low TB prevalence). Results show that changes in transmission parameters, the fraction of the population genetically susceptible to infection, and demographic factors strongly affect TB prevalence and incidence rates.
Two Dravidian-speaking castes of Tamil Nadu, Piramalai Kallars (PKs, n = 205) and Yadhavas (YDs, n = 239) and a random panel (84) were studied for HLA-DRB1* and -DQB1* polymorphisms by DNA-SSOP typing methods. XI and XII International Histocompatibility primers and non-radioactive-labelled oligo probes were employed to identify the alleles. Results revealed that PKs possessed >0.1 allele frequencies of HLA-DRB1*15011, 0301, -DQB1*0201, 0501 and 0601; YDs, HLA-DRB1*0301, 0401, 07 and -DQB1*0601; and the random panel, DRB1*15021, 0401, 07, -DQB1 0201, 0301, 0302 and 0501. The highest frequency of DRB1*1501 in the world (GF = 0.225) was found in PKs. The most frequent two-locus haplotype (>500/10,000) in all the study samples was DRB1*10-DQB1*0501, while 1501-0601 was frequent in PKs and YDs. Comparison of the HLA-DRB1* data with Eastern European and South-East Asian populations suggested migration as the prime cause of the observed diversity in DRB1* allele frequencies. Nonetheless, the heterozygocity test and Watterson's homozygosity test indicated that balancing selection still operates on HLA-DRB1* locus, in this endemic region of various infectious diseases. This and spatial autocorrelation analysis support the view that selection may be a cause of "generating" new variants and allelic diversity in different ancient settlements. The study suggested that South Indian, inbred, endogamous, sympatrically isolated castes or similar well-defined breeding isolates around the world, living under the same milieu-epidemiology, may be ideal models to test the immunogenetic basis of disease susceptibility.
Only 10% of persons infected with Mycobacterium tuberculosis develop clinical tuberculosis (TB), indicating the existence of host genetic factors regulating disease expression. We investigated the association of human leukocyte antigen (HLA) class II genes with the susceptibility to pulmonary TB in Koreans, with special emphasis on their association with drug resistance, disease severity, and disease recurrence. Human leukocyte antigens (HLA)-DRB1 and -DQB1 gene polymorphisms were analyzed in 160 Korean patients with pulmonary TB and 200 ethnically matched healthy controls. HLA-DRB1*0803 (25.0% vs. 14.5% in controls, OR = 1.97, p = 0.012, corrected p (p(c)) > 0.05) and DQB1*0601 (27.5% vs. 15.5% in controls, OR = 2.07, p = 0.005, p(c) > 0.05) were weakly associated with general susceptibility to TB. DRB1*0803 was significantly associated with drug resistance (30.9% vs. 14.5%, OR = 2.63, p(c) = 0.047) and more advanced lung lesion (29.8% vs. 14.5%, OR = 2.50, p(c) = 0.022). DRB1*0803 showed the strongest association with disease recurrence, especially after curative treatment for the earlier infection (47.4% vs. 14.5%, OR = 5.31, p(c) = 0.00009). DQB1*0601, which is strongly linked to DRB1*0803 in this population showed similar changes in the patients as those of DRB1*0803. It is suggested that DRB1*0803 and DQB1*0601 alleles are associated with disease progression of TB in Koreans, exerting influence on the development of drug resistance, severe disease, and recurrent disease.
Although IgE is implicated in viral immunity, its role in parvovirus B19 immunity and its relationship to other immunological states has not been studied. Total serum immunoglobulin levels, IgG and IgE anti-parvovirus B19, blood lymphocyte numbers, and epsilon and cytokine specific mRNA were determined in pediatric patients with normal serum IgA levels (IgA+) and selective IgA deficiency (IgA-) on days 0 (initial diagnosis) and 14, and 3 years after recovery (nephelometry, Western blot test, flow cytometry, reverse transcriptase-polymerase chain reaction). We found that both patients had serum IgM, IgG, IgE, and IgA levels within normal ranges on day 0 to 3 years, excluding IgG(1) and IgA in the IgA- patient, which were elevated and negative, respectively, and IgE in the IgA+ patient, which was elevated (>100 IU/ml). The serum IgA+ and IgA- patients made IgE (and IgG) anti-parvovirus B19 at all time points. Excluding CD8(+)CD60+ T cells, determinations of T, B, and NK lymphocyte subsets always were within normal ranges. In both patients, CD8(+)CD60+ T-cell numbers were within normal ranges on day 0, but dramatically increased on day 14 (more than fivefold). At 3 years, they had returned to normal in the IgA+ patient, but remained high in the IgA- patient. On day 0 to 3 years, peripheral blood mononuclear cells of both patients expressed epsilon- and interferon (IFN)-alpha-specific mRNA. On day 0, the IgA+ patient expressed interleukin (IL)-4 and IL-10, but not IL-2, IFN-gamma, or IL-6 mRNA; the IgA- patient expressed IL-6 and IL-10 mRNA, but not IL-4, IL-2, or IFN-gamma mRNA. At 3 years, the IgA+ patient expressed mRNA for all cytokines, but the IgA- patient did not express mRNA for any of these cytokines. Our results suggest that IgE is important in parvovirus B19 immunity, and that IFN-alpha and CD8(+)CD60+ T cells may regulate IgE memory responses and isotype switching.
To evaluate the association between human leukocyte antigens (HLA) of the major histocompatibility complex (MHC) and thoracic tuberculosis (TB) in immunocompetent adults.
We searched Medline, Pascal, Pascal Biomed and Francis databases (all years) with the terms 'tuberculosis' and 'HLA'. Case-control studies were included that reported frequencies for the full range of antigens analysed by serological methods in healthy controls and adult patients not treated with glucocorticoids or immunosuppressive drugs, human immunodeficiency virus status negative or not reported, no debilitating chronic disease, and with a diagnosis of thoracic TB based on microbiological or histological criteria. Two authors independently abstracted the data and resolved disagreements by consensus.
We summarised 60 HLA antigens reported in at least four of 22 studies totalling 1988 patients and 2897 controls. A lower risk of thoracic TB was found in carriers of B13 (OR 0.64, 95% CI 0.50-0.81, P < 0.0001), DR3 (OR 0.72, 95% CI 0.59-0.89, P = 0.002), and DR7 antigens (OR 0.65, 95% CI 0.53-0.80, P < 0.0001). Carriers of DR8 were at higher risk for thoracic TB (OR 1.72, 95% CI 1.21-2.46, P = 0.003). For these antigens, we found no significant heterogeneity between samples or evidence of publication bias. The risk of thoracic TB tended to be higher in carriers of DR2 (OR 1.67, 95% CI 1.16-2.41, P = 0.006), but the results were not consistent between studies (P value for heterogeneity < 0.0001).
Susceptibility to TB is modulated by class I and II HLA antigens. However, these results based on the serological determination of antigens require confirmation by DNA-based methods to precisely identify those alleles involved.
The influence of human leukocyte antigens (HLA) on the immune response is well established. We investigated the regulatory role of HLA-DRB1 alleles on cytokine response to live M. tuberculosis and its culture filtrate antigen (CFA) in normal healthy subjects (NHS) and pulmonary tuberculosis (PTB) patients. Th1 (IFN-gamma and IL-12p40), Th2 (IL-4 and IL-5), pro-inflammatory (IL-6 and IL-8) and anti-inflammatory (TGF-beta and IL-10) cytokines were measured by ELISA in 72-h-old peripheral blood mononuclear cell culture supernatants from 58 NHS and 48 PTB patients. HLA-DRB1 genotyping was carried out by polymerase chain reaction and dot-blot hybridization with biotinylated sequence-specific oligonucleotide probes and detection by chemiluminescence. In response to live M. tuberculosis and CFA, significantly increased levels of IL-6, IL-8 and TGF-beta and decreased IFN-gamma, IL-12p40 and IL-10 were seen in PTB patients compared to NHS. We observed a significantly increased IFN-gamma response in HLA-DRB1*03-positive NHS (p=0.03) and decreased IFN-gamma response in HLA-DRB1*15-positive patients (p=0.04) than respective allele-negative individuals. An increased level of IL-12p40 in DRB1*10 (p=0.02) and IL-10 in DRB1*12- (p=0.03) positive NHS and an increased level of IL-6 in DRB1*04- (p=0.02) positive patients were observed. The study suggests that HLA-DRB1 alleles differentially modulate the various cytokine responses to M. tuberculosis antigens, which may influence the cellular and humoral immune responses to M. tuberculosis infection in a susceptible host.
Perforin is one of the key effector molecules of cytotoxic T cells and natural killer cells. The influence of HLA-DRB1 alleles on peripheral blood perforin-positive CD4, CD8, CD16 and CD 56 cells was studied by flow cytometry. HLA-DRB1 typing was done in normal healthy subjects (NHS: n = 156) and patients with pulmonary tuberculosis (PTB: n = 102) by polymerase chain reaction-based sequence-specific oligonucleotide hybridization method. We observed a significantly decreased percentage of total perforin-positive cells (per(+)) (P = 0.0004); CD8(+)/Per(+) (P = 0.0005); CD16(+)/Per(+) (P = 0.05) and CD 56(+)/Per(+) cells (P = 0.001) in HLA-DR2-positive PTB patients compared to non-DR2 patients. Subtyping of HLA-DR2-positive subjects at the allelic level revealed that the percentage of CD8(+)/Per(+) cells did not differ among DRB1*1501 and DRB1*1502 patients while a trend towards a decreased percentage of CD16(+)/Per(+) and CD 56(+)/Per(+) cells was noticed in DRB1*1501 patients compared to DRB1*1502 patients. The present study suggests that HLA-DR2 may be associated with down-regulation of perforin-positive cytotoxic lymphocytes and natural killer cells in pulmonary tuberculosis.
In three adjacent Newfoundland communities comprising some 1500 people, 589 people have been HLA typed. Forty-six of the typed people gave a history of previous clinical tuberculosis which required treatment. Fifty-six percent of the TB patients carried HLA B8 compared with 20% of the remainder of the population. This is a highly significant difference (P < 0.01). In each community the frequency of B8 as an epidemiological marker correlated with the incidence of tuberculosis. B8 is associated with TB in this study with a relative risk of 5.2 which compares with combined relative risks in the literature for coeliac disease and Addison's disease of 9.5 and 6.4, respectively, and which is greater than the risks for all the other B8-related diseases. The factor B allele, Bf S, was found on all the B8 haplotypes, but the overall Bf gene frequencies in tuberculosis patients did not deviate from expected values.
In three adjacent Newfoundland communities comprising some 1500 people, 589 people have been HLA typed. Forty-six of the typed people gave a history of previous clinical tuberculosis which required treatment. Fifty-six percent of the TB patients carried HLA B8 compared with 20% of the remainder of the population. This is a highly significant difference (P less than 0.01). In each community the frequency of B8 as an epidemiological marker correlated with the incidence of tuberculosis. B8 is associated with TB in ths study with a relative risk of 5.2 which compares with combined relative risks in the literature for coeliac disease and Addison's disease of 9.5 and 6.4, respectively, and which is greater than the risks for all the other B8-related diseases. The factor B allele, Bf S, was found on all the B8 haplotypes, but the overall Bf gene frequencies in tuberculosis patients did not deviate from expected values.
In 204 patients with smear-positive pulmonary tuberculosis HLA-A10, B8 and DR2 were more frequently found than in 404 control subjects (p = 0.01); the greatest attributable risk (0.29) was associated with HLA-DR2. The radiographic extent of disease was also associated with HLA-DR2 (p = 0.0001). In 152 patients with smear-negative pulmonary tuberculosis, the frequencies of HLA-A10 and B8, but not DR2, were greater in the control subjects (p = 0.001 and 0.01 respectively). HLA-DR2 may be involved in the pathogenesis of advanced pulmonary tuberculosis. Study of endogamous, genetically disparate populations (caste) revealed other HLA associations (A3, B12 and DR4) unique to them, suggesting that genes linked with the HLA complex might also be significant in the pathogenesis of tuberculosis.
Tuberculosis patients and healthy subjects from six ethnic groups of the Soviet Union were HLA-A, -B, -C, and DR typed. The frequencies of the HLA-A, -B and -C antigens differed amongst the ethnic groups. With all groups, however, patients with tuberculosis showed a significantly increased frequency of HLA-DR2 and a reduced frequency of HLA-DR3 type. Unfavourable dynamics of tuberculosis was significantly associated with an increased incidence of B15 and DR2 and a reduced incidence of B27 and DR3. Family studies revealed that the inheritance of susceptibility to tuberculosis (from parent to offspring) is associated with the inheritance of certain HLA haplotypes. Tuberculosis patients bearing the DR2 antigen had increased levels of IgG antibodies to PPD and the frequency of B7 and, more particularly, DR2 was higher in anergic patients.
The HLA-A, -B, and -DR antigens were studied in black Americans to analyze deviation in phenotype distribution between ATS Class 3 patients with tuberculosis disease and ATS Class 2 healthy persons with significant tuberculin reaction, but no tuberculosis. Statistical analyses with Fisher's exact test revealed a significant difference in frequency distribution of HLA-B5 (p = 0.046), HLA-DR5 (p = 0.0276), and HLA-DR6y (p = 0.0095) between ATS Class 2 and ATS Class 3 patients. There was a significant decrease in HLA-DR6y (p = 0.01) but increase in HLA-B5 and HLA-DR5 phenotypes in ATS Class 3 patients.
Peripheral blood lymphocytes from 42 unrelated Egyptian patients with tuberculosis and 156 healthy persons were HLA phenotyped for the A,B and DR loci using the NIH lymphocytotoxicity tests. Statistical analysis of the results showed that A2 and B5 had significantly increased frequencies among patients with tuberculosis compared with the controls. Patients with A2 had more severe disease than did patients without A2 and the number with B5 antigen was less than those without the antigen. This observation suggests that A2 and B5 may influence susceptibility to tuberculosis, but not the course of the disease. Furthermore, a linkage disequilibrium was found between A2 and B5 antigen among tuberculous patients, but their association bore no relation to the severity of the disease.
HLA-A, -B, and -C phenotype distributions in 100 Mexican Americans with active tuberculosis were compared with HLA phenotypes in 50 healthy, tuberculin-skin-test-positive and 50 healthy, tuberculin-skin-test-negative Mexican Americans. Although there existed differences in the phenotype frequencies of 5 antigens (Aw30, Aw33, B7, B15, and B17) among the 3 study groups, these differences were not significant using p values that were corrected for the number of antigens tested. Thus, susceptibility (or resistance) to tuberculosis in Mexican Americans does not appear to be linked to a specific HLA-A, -B, or -C phenotype.
The identification of large numbers of candidates genes and the introduction of methodologies for whole-genome screening have provided new opportunities for elucidating the molecular basis of variable susceptibility to major infectious diseases. 12 genes have been implicated in variable susceptibility to malaria and susceptibility/resistance genes for several other infectious diseases are beginning to be identified. Recent work suggests that large-scale family linkage and population association studies will be a more successful route to human disease genes than extrapolation from mouse models of infection.
HLA and tuberculin status in pulmonary tuberculosis patients. Tuberculosis Research Centre, Indian Council of Medical Research, Madras, India.
To elucidate the role of HLA-class-II genes/gene products on tuberculin reactivity in pulmonary tuberculosis patients.
Serological determination of HLA-DR and -DQ antigens was carried out in 62 healthy control subjects and 146 pulmonary tuberculosis patients. The tuberculin reaction pattern of pulmonary tuberculosis patients to PPD was studied and the role of HLA-DR and -DQ antigens (class-II gene products) on tuberculin reaction was analysed.
HLA-DR and -DQ antigens did not influence high, medium and low tuberculin reaction dramatically in active pulmonary tuberculosis patients. However, a heterozygous combination of various HLA-DR antigens influenced the tuberculin reaction.
The HLA-genetic make up (heterozygous combination) of the individual may influence the tuberculin reaction pattern in pulmonary tuberculosis.
HLA - A, B, C, DR, DQ antigen profile of South Indian Tamil-speaking Hindus of Dravidian descent was studied. Phenotype, gene and haplotype frequencies were calculated and compared with the literature. There was a complete lack of A23, A25 and A32 antigens in the sample presently monitored. Except for minor differences (higher incidence of Cw6 and DR10 antigens), the Dravidian Hindus show similarity to North Indio-Aryan and other Hindu samples. The haplotypes A1, B17; A2, B5; A2, B51; A1, DR7; B12, DR7; B13, DR2; B17, DR7; DR2, DQ1; DR3, DQ2; DR4, DQ3; DR5, DQ3; DR7, DQ2; DR11, DQ3; show significant positive linkage disequilibrium whereas A1, DR2; DR2, DQ2; DR7, DQ1 were significant for negative linkage disequilibrium in the Dravidian Hindus.
We have studied TAP polymorphism in a panel of 40 healthy individuals, 57 patients with pulmonary tuberculosis (PTB) and 50 with tuberculoid (TT) leprosy from North India. Only TAP2-A/F occurred with a significantly increased frequency in PTB patients as compared to controls (82.5% vs. 52.5%, P < 0.002, Pc < 0.01) giving a high relative risk of 4.3. On the other hand, TAP2-B was significantly increased in TT leprosy as compared to controls (76% vs. 47.5%, Pc < 0.003, RR 3.5) particularly in patients positive for HLA-DR15 than controls carrying DR15 (77.5% vs. 50%, P < 0.03, RR = 3.4). Further, TAP2-B allele was positively associated with DR15 negative PTB patients as compared to the DR15 positive group (43.8% vs. 17.1%, P < 0.04, RR = 0.3). This study along with our earlier studies on HLA association in mycobacterial diseases suggests that in addition to HLA-DR15 alleles in the TAP2 region influence susceptibility to PTB and TT leprosy.
Tuberculosis Research Centre, Indian Council of Medical Research, Madras, India.
To elucidate the role of HLA-Class II genes/gene products on phagocyte enzymes such as lysozyme, beta-glucuronidase and acid phosphatase in the plasma of pulmonary tuberculosis patients.
Serological determination of HLA-DR and -DQ antigens was carried out in 54 active and 84 inactive pulmonary tuberculosis (quiescent) patients and 36 healthy control subjects. The levels of lysozyme, beta-glucuronidase and acid phosphatase were measured in the plasma of tuberculosis patients and control subjects.
Increased lysozyme levels were observed in active pulmonary tuberculosis patients. beta-glucuronidase activity was higher in inactive-TB than in active-TB patients and control subjects. HLA-DR2 positive patients showed a lower lysozyme level than -DR2 negative patients.
Increase in the plasma lysozyme level in active TB reveals the active stage of the disease. Further, increase in the activity of beta-glucuronidase in inactive-TB patients reveals the quiescent stage of the disease. The low level of lysozyme in HLA-DR2 positive patients may also be one of the possible factors involved in susceptibility to tuberculosis.
ATTEMPTS to define leucocyte groups in man serologically have been hampered by the scarcity of immune human antisera and the capriciousness of the leuco-agglutination reaction1. The method recorded here for assaying lymphocyte cytotoxins in a microscale was developed to circumvent these difficulties. Its extreme sensitivity permits performance of 1,000 or more tests with 1 ml. of antiserum. Furthermore, lymphocytes obtained from one finger-prick sample of blood are sufficient for 100 separate tests. The basic innovation in handling these small quantities of serum and cells and in gaining a greater than ten-fold increase in sensitivity over present-day methods is the performance of the reaction in microdroplets submerged under oil. This permits reduction in numbers of target cells to as few as 500 cells in contrast to the 50,000 or so cells required for previously described cytotoxicity tests2-4. Since the sensitivity of cytotoxicity is inversely proportional to the number of cells used2,3, an increase of sensitivity in the range of 10-100 times may be expected. Unlike the usual de Fonbrune oil chamber employed in micromanipulation, use of a `dish' with a cover-glass bottom facilitated rapid addition of reagents and cells with a microsyringe.