help button home button
AJRCCM
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Published ahead of print on January 16, 2003, doi:10.1164/rccm.200205-438BC
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
200205-438BCv1
167/7/970    most recent
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by López-Maderuelo, D.
Right arrow Articles by Montiel, C.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by López-Maderuelo, D.
Right arrow Articles by Montiel, C.
American Journal of Respiratory and Critical Care Medicine Vol 167. pp. 970-975, (2003)
© 2003 American Thoracic Society

Brief Communication

Interferon-{gamma} and Interleukin-10 Gene Polymorphisms in Pulmonary Tuberculosis

Dolores López-Maderuelo, Francisco Arnalich, Rocio Serantes, Alicia González, Rosa Codoceo, Rosario Madero, Juan J. Vázquez and Carmen Montiel

Department of Internal Medicine, Microbiology, and Clinical Biochemistry, Hospital La Paz; and Department of Pharmacology and Therapeutics, Facultad de Medicina, Universidad Autónoma de Madrid, Madrid, Spain

Correspondence and requests for reprints should be addressed to Francisco Arnalich, Internal Medicine Service, Hospital La Paz, Maternidad Planta 8, Paseo de la Castellana 241, 28046 Madrid, Spain. E-mail: francisco.arnalich{at}uam.es


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Several genes coding for different cytokines may affect host susceptibility to tuberculosis. This study investigates the relationship of the single base change polymorphic variants identified in the first intron of interferon-{gamma} (+874 T/A) and in the promoter region of interleukin-10 gene (-1,082 G/A), with cytokine production by peripheral blood mononuclear cells and tuberculosis susceptibility. We studied a Spanish population of 113 patients with culture-proven pulmonary tuberculosis, 207 healthy close contacts (125 tuberculin reactive and 82 tuberculin negative), and 100 healthy tuberculin-negative control subjects. Multiple logistic regression analysis showed that individuals homozygous for the interferon-{gamma} (+874) A allele had a 3.75-fold increased risk of developing tuberculosis (95% confidence interval, 2.26–6.23, p = 0.0017). Stimulated production of interferon-{gamma} by peripheral mononuclear cells from patients with genotype AA was depressed compared with that of non-AA homozygotes at the time of diagnosis and after completion of therapy. Multivariate analysis showed that the presence of an AA genotype and the absolute number of lymphocytes were the only independent predictors of interferon-{gamma} production. In contrast, the different rates of interleukin-10 production associated with the interleukin-10 polymorphism did not affect susceptibility to tuberculosis. Thus, a genetic defect in the production of interferon-{gamma} in individuals homozygous for the (+874) A allele could contribute to their increased risk of developing tuberculosis.

Key Words: gene polymorphisms • tuberculosis susceptibility • cytokine production • interferon-{gamma} • interleukin-10

Family-based genetic linkage studies (1) and population-based case-control analyses (2–4) have been used to identify candidate genes for susceptibility to tuberculosis in West Africans, but there is no study in a European white population. Polymorphisms in the interleukin (IL)-1ß and IL-1 receptor antagonist genes influenced cytokine response by peripheral blood mononuclear cells (PBMCs) in a case-control study of Gujarati Asians in west London, but these polymorphisms had little effect on tuberculosis susceptibility (5). However, other cytokine polymorphisms could be of interest, as their gene products are known to be directly involved in the pathogenesis of tuberculosis (6). Macrophage activation by IFN-{gamma} is essential for protective immunity, as mice (7) or humans (8, 9) that lack components of the IFN-{gamma} signaling pathway are highly susceptible to tuberculosis. It has also been shown that IL-10 converts human dendritic cells into macrophage-like cells with increased antimycobacterial activity (10).

There are two well-known single-nucleotide polymorphisms in the IFN-{gamma} gene. A CA repeat microsatellite sequence in the noncoding region of the first intron is polymorphic; it has been associated with rheumatoid arthritis susceptibility and severity in Canadians (11). In healthy British white individuals (12), allele 2 is associated with production of higher concentrations of IFN-{gamma} in vitro. In addition, a single nucleotide T/A polymorphism at the 5' end of the CA repeat region in the first intron of the IFN-{gamma} gene (+874 A/T polymorphism) has been correlated with the presence or absence of the microsatellite allele 2 (13). The IL-10 gene may also be implicated in genetic susceptibility to tuberculosis. There are three biallelic polymorphisms in the IL-10 gene promoter. At position -1,082 bp from the transcriptional start site, the presence of G is associated with higher and A with lower production of IL-10 by PBMC cultures (14).

The aim of this work was to test the hypothesis that a genetically determined lower production of either IFN-{gamma}, IL-10, or both might influence susceptibility or severity in pulmonary tuberculosis. We performed a study in white patients with active disease, tuberculin-reactive and tuberculin-negative healthy contacts, and nonexposed control subjects to determine the influence of these polymorphisms on susceptibility and disease expression and to assess any functional significance by correlating ex vivo IFN-{gamma} and IL-10 production with IFN-{gamma} and IL-10 genotypes.


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Subjects
In a 2-year study, venous blood samples were collected from 113 patients with newly diagnosed sputum culture-positive tuberculosis (84 of whom were tuberculin reactive and 29 of whom were tuberculin negative), 207 close contacts (125 tuberculin reactive and 82 tuberculin negative), and 100 healthy tuberculin-negative volunteers. Individuals with other apparent infections such as hepatitis or human immunodeficiency virus and those who had received prior immunosuppressive therapy or had serious medical illness were excluded from the study. Chest radiographic findings at diagnosis (15) revealed that 85 patients had moderately advanced and 28 extensive pulmonary disease. Patients were treated daily with isoniazid, rifampin, ethambutol, and pyrazinamide for 2 months, followed by daily isoniazid and rifampin for another 4 months. All patients achieved a complete clinical and microbiologic response after treatment, and none relapsed. The exposed population consisted of 207 close contacts of the active patients. Isoniazid preventive therapy was given for 6 months to the 125 contacts who had a positive tuberculin skin test without evidence of clinical disease. Eighty-two close contacts remained tuberculin-negative after skin testing twice and did not receive primary chemoprophylaxis. A sample of 100 unrelated, tuberculin-negative blood donors was also studied. All participants were of Spanish white origin and were followed for 18 months to confirm their diagnosis or control status. The study was approved by the local ethics committee, and all participants gave written informed consent.

Genotyping of Subjects
Genomic DNA was extracted as previously described (16). The polymorphisms in IFN-{gamma} (+874*T/A) and IL-10 (-1,082*G/A) genes were typed using amplification refractory mutation system-polymerase chain reaction (PCR) methods (17). Briefly, genomic DNA was amplified with the use of Taq Gold DNA polymerase (Applied Biosystems, Foster City, CA) in two different PCRs for each polymorphism; each reaction employed a generic antisense primer and one of the two allele-specific sense primers. To assess the success of PCR amplification in both reactions, one internal control of 426 bp was amplified using a pair of primers designed from the nucleotide sequence of the human growth hormone (accession number M13438). The amplified products were separated by electrophoresis on a 2% agarose gel stained with ethidium bromide (Figure 1) . The PCR reaction was performed using 10 cycles (95°C for 1 minute, 95°C for 15 seconds, 62°C for 50 seconds, and 72°C for 40 seconds), followed by 20 cycles (95°C for 20 seconds, 56°C for 50 seconds, and 72°C for 50 seconds). The characteristics of the primer sequences are shown in Table 1 .



View larger version (39K):
[in this window]
[in a new window]
  		Figure 1. Genotypes of five patients according to their IFN-{gamma} (A) and IL-10 (B) polymorphisms. The two alleles of the polymorphic region of IFN-{gamma} (A/T) or IL-10 (G/A), corresponding to each patient, were analyzed in two different reaction samples using amplification refractory mutation system-PCR technique described in METHODS. Besides, in every reaction sample, a pair of primers based on the nucleotide sequence of the human growth hormone was also added to amplify a product of 426 bp (control) to assess the success of PCR amplification. Products amplified were run on a 2% agarose gel. M = base pair marker.

 

View this table:
[in this window]
[in a new window]
  		TABLE 1. Characteristics of INTERLEUKIN-10 and ifn-{gamma} polymorphisms and primer sequences used for amplification refractory mutation system-polymerase chain reaction method

 
Ex Vivo Cytokine Production From Stimulated PBMCs
PBMCs were obtained from venous whole blood (20 ml) from all patients before and after completion of therapy and from 174 close contacts (125 tuberculin reactors and 49 tuberculin negative). Cells were cultured at a concentration of 2.0 x 106 cells/ml according to our own protocol (18, 19) and were stimulated with a purified protein derivative (PPD) antigen (10 µg/ml; Statens Seruminstitut, Copenhagen, Denmark) for 96 hours at 37°C with 5% CO2. Culture supernatants were harvested and assayed with ELISA kits for IFN-{gamma} and IL-10 (Biosource International, Camarillo, CA). Both assays presented a detection limit of 4 pg/ml, and their interassay and intra-assay coefficients of variation were less than 10% and less than 6%, respectively. The data are presented as the concentration in supernatants of PPD-stimulated cells minus the concentration in supernatants of cells cultured in media alone.

Statistical Analysis
All calculations were done using the SPSS program (version 9.0 for Windows 98; SPSS, Chicago, IL). Genotype frequencies were compared by the chi-squared test, and the relative risk (odds ratio) for disease susceptibility or clinical course was calculated. Genotype frequencies in patients and control subjects were not significantly different from those predicted under the Hardy-Weinberg equilibrium (Linkage Utility Programs, by Dr. Jurg Ott, Rockefeller University, NY). Results were analyzed by the Mann-Whitney rank-sum test, Fisher's exact test, and two-way analysis of variance with repeated measures (where indicated) (20). A multiple logistic regression model employing the likelihood ratio was used to examine the influence of different genotypes and ex vivo IFN-{gamma} production on susceptibility to tuberculosis. A p of less than 0.05 was considered significant.


   RESULTS
TOP
 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Relationship Between Clinical Findings and Cytokine Polymorphism
The results of genotyping for the patients with tuberculosis, tuberculin reactive and nonreactive contacts, and normal control subjects are presented in Table 2 . All four groups were in Hardy-Weinberg equilibrium with nonsignificant chi-squared values for the observed and expected genotype frequencies of each of the tested polymorphisms. The IL-10 genotype did not differ significantly among healthy subjects and the tuberculosis cases or contacts. In contrast, the IFN-{gamma} +874 A allele was significantly associated with increased susceptibility to tuberculosis. Individuals with two A alleles were markedly overrepresented among the patients with tuberculosis as compared with healthy control subjects (odds ratio, 2.71; 95% confidence interval, 1.54–4.75), as well as to the tuberculin-positive and -negative contacts. We found that carriage of an AA genotype was significantly associated with radiologically far advanced disease at diagnosis (Table 3) . To determine whether carriage of an AA genotype at the IFN-{gamma} +874 locus might be independently associated with susceptibility to pulmonary tuberculosis, a multiple logistic regression analysis was done. After adjusting for age and sex, AA homozygous subjects had a 3.75-fold increased risk of developing tuberculosis (odds ratio 3.75, 95% confidence interval, 2.26–6.23, p = 0.0017).


View this table:
[in this window]
[in a new window]
  		TABLE 2. Demographic data, genotype distribution, and allele ratio in the study population

 

View this table:
[in this window]
[in a new window]
  		TABLE 3. Association of ifn-{gamma} (+874 t/a) genotypes with clinical markers of disease severity in patients with pulmonary tuberculosis

 
Ex Vivo Cytokine Production
Patients with tuberculosis had significantly lower PPD-induced IFN-{gamma} production (877 ± 279 pg/ml) than their tuberculin-positive (1,489 ± 401 pg/ml, p < 0.001) or tuberculin-negative contacts (1,091 ± 254 pg/ml, p < 0.01). The mean absolute number of lymphocytes in patients was similar to that in tuberculin-reactive and -nonreactive contacts (2,847 ± 484 versus 2,868 ± 592 and 2,770 ± 462 cells/mm3, respectively, p = NS). IFN-{gamma} production was correlated with the absolute number of lymphocytes (r = 0.390, p < 0.01) but not with the radiographic extent of disease at diagnosis (r = 0.162, p = 0.29) nor with age or sex. In addition, we noted that IFN-{gamma} production was closely linked to the +874 T/A alleles. Thus, allele A homozygous patients with tuberculosis and contact cases produced significantly lower levels of IFN-{gamma} compared with individuals carrying one or two copies of allele T (p < 0.01 for all comparisons) (Figure 2A) . To determine whether the depressed IFN-{gamma} production in the patients homozygous for allele A was permanent or transitory, we retested all patients 6 months later after completing treatment. Mean IFN-{gamma} concentrations had increased by 21% after therapy (p = NS; Figure 2B) but remained significantly lower in the AA homozygotes than in patients carrying at least one T allele. Multivariate stepwise linear regression, performed taking into account the radiographic extent of disease, age, and sex, absolute number of lymphocytes, and IFN genotypes, showed that the only independent predictors of IFN-{gamma} production were the presence of an AA genotype (r2 = 0.657, p < 0.001) and the absolute number of lymphocytes (r2 = 0.668, p < 0.05).



View larger version (29K):
[in this window]
[in a new window]
  		Figure 2. PPD-induced IFN-{gamma} production by PBMCs related to IFN-{gamma} (+874 T/A) genotypes. (A) IFN-{gamma} production in normal control subjects (white bars), healthy PPD-positive (light gray bars)and -negative (medium gray bars) contacts, and patients with pulmonary tuberculosis (dark gray bars). A comparison of IFN-{gamma} production in subjects homozygous for allele A and in those carrying other allele combinations (genotypes TA and TT). Results (mean values and SEs) are reported as the concentrations in supernatants of PPD-stimulated cells minus those in supernatants of cells cultured in media alone. (B) PPD-induced IFN-{gamma} production by PBMCs in patients with tuberculosis before (dark gray bars) and after 6 months of therapy (light gray bars) according to IFN-{gamma} genotypes.

 
PPD-stimulated production of IL-10 in tuberculosis patients was approximately 35% higher than in either contacts or control subjects (Table 4) . The presence of AA homozygosity was associated with lower IL-10 production in all groups.


View this table:
[in this window]
[in a new window]
  		TABLE 4. Stimulated INTERLEUKIN-10 production (pg/ml) by peripheral blood mononuclear cells from normal control subjects, healthy contacts, and patients with pulmonary tuberculosis related to INTERLEUKIN-10 (-1082 g/a) polymorphism

 

   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
The genetic component that contributes to susceptibility and progression of pulmonary tuberculosis probably involves an interaction between multiple alleles located on different genes and chromosomes (6). Consequently, rather than merely performing a polymorphism-association study, we chose to investigate the functional significance of the relationship between two single nucleotide polymorphisms located in the IFN-{gamma} and IL-10 genes and susceptibility to tuberculosis. In addition, we have been very careful to exclude the possibility of ethnic mismatching or the effects of confounders such as the concomitant presence of other diseases. Our control group has a genotype distribution that is similar to the one reported in healthy British individuals (12, 14).

This study reports three novel major findings. First, it reveals that the IFN-{gamma} (+874 A/T) polymorphism is significantly associated with pulmonary tuberculosis. Multiple logistic regression analysis showed that individuals who were homozygous for the +874 A allele had a 3.75-fold increased risk of developing tuberculosis. Second, the study provides evidence that this polymorphism influences PPD-induced IFN-{gamma} production in patients, healthy contacts, and nonexposed normal subjects. The lowest IFN-{gamma} production was measured in homozygous patients with genotype AA both at the time of diagnosis and after completion of therapy. Multivariate analysis showed that the presence of an AA genotype and the lymphocyte number were the only independent predictors of IFN-{gamma} production. The third noteworthy observation of this study is negative: the different rates of IL-10 production related with a polymorphism at position -1,082 in the promoter region of the IL-10 gene were not associated with tuberculosis susceptibility.

An association between the IFN-{gamma} (+874) T/A polymorphism and tuberculosis has been recently reported in a sample of 45 Sicilian patients affected by tuberculosis (21), although the functional significance of the association was not explored. Our study evaluated the relationship between IFN-{gamma} production and IFN-{gamma} (+874) T/A alleles in healthy control subjects and in three groups of individuals exposed to tuberculosis who developed different immune responses: noninfected contacts, tuberculin-sensitized contacts, and patients with active tuberculosis. Tuberculin-positive and -negative contacts that were homozygous for allele A produced significantly lower levels of IFN-{gamma} than those carrying one or two copies of allele T. Similarly, stimulated production of IFN-{gamma} from tuberculosis patients with the AA genotype was about two-thirds lower than in patients with other genotypes (AT and TT) and remained depressed 6 months later when compared with control values. The persistence of low IFN-{gamma} production by PBMCs for more than 6 months suggests the presence of a genetic defect in IFN-{gamma} production in patients with allele A homozygosity that may also underlie their increased risk for reactivation of a latent pulmonary tuberculosis focus.

Several studies have reported that the clinical manifestations of patients with tuberculosis correlate with Mycobacterium tuberculosis–stimulated IFN-{gamma} production by PBMCs, which was lower in patients with tuberculosis than in healthy tuberculin reactors (22, 23) and even lower in patients with extensive disease (24). Our findings confirm these results and indicate that differences in the distribution of the IFN-{gamma} genotype could explain the lower production of this cytokine in tuberculosis patients; they have a higher frequency of the homozygous A genotype that was associated with lower PPD-stimulated IFN-{gamma} production. As expected, there were no significant differences in the levels of IFN-{gamma} in supernatants of PBMC cultures from tuberculin-negative healthy contacts or the control subjects. It is surprising that despite frequent contact with infectious tuberculosis patients, just a small subgroup (6 out of 82, 7.3%) of the nonsensitized healthy contacts showed PPD skin conversion, indicating that the rest of the exposed contacts were probably resistant to infection, at least during the time of the study, and that they may possess innate mechanisms of resistance that do not involve the secretion of IFN-{gamma}.

The mechanisms of altered gene expression associated with polymorphisms are still poorly understood. There is evidence that sequence changes in the noncoding regions of cytokine genes may influence production of the corresponding peptide due to linkage with another marker directly affecting gene expression. We have recently described an association between ex vivo production of IL-1 receptor antagonist by peripheral blood cells and the presence of IL-1 receptor antagonist gene allele 2, which lies in the noncoding nucleotide sequence of the gene, in a group of 78 patients with severe sepsis and a group of 30 blood donors (19). The association between IFN-{gamma} (+874 T/A) polymorphism and ex vivo production of IFN-{gamma} by PBMCs observed in this study may indicate some linkage with functional variants in other loci in the regulatory region of the gene. Specific binding of the nuclear transcription factor-{kappa}B to the DNA sequence containing the +874 T allele has been reported (25); it could have functional consequences for the transcription of the IFN-{gamma} gene and could then influence the rate of IFN-{gamma} production (12, 25). Because the influence of gene polymorphisms on protein production may differ with tissue and cell type (26–28), further studies are needed to assess the relative influence of the IFN-{gamma} +874 T/A alleles in the local production of IFN-{gamma} in the lung.

Published data suggest that IL-10 inhibits synthesis of IFN-{gamma} by T cells (22) and that production of IL-10 has been associated with anergy in tuberculosis (29). In view of the important role played by IL-10 in the modulation of proinflammatory CD4+ T-helper cell responses, particularly IFN-{gamma} secretion (10), we were attracted by the proposal that differences in IL-10 production could influence either disease susceptibility or disease progression or both. Heterozygosity for the -1,082 polymorphism of the IL-10 promoter was associated with tuberculosis susceptibility in the Cambodian population (30) but not in patients from the Gambia (2). In contrast to the findings in Cambodia, we observed no differences in IL-10 genotype frequencies among patients, tuberculin-reactive and tuberculin-negative contacts, and normal subjects. Interestingly, the distribution of tuberculosis cases among the different genotypes is similar irrespective of their level of IL-10 production by PBMCs. Our data suggest that genetically determined high or low IL-10 production by PBMCs is unlikely to predispose white individuals to tuberculosis or to protect them from it. An explanation for the apparent inconsistency between these studies is that ethnic-specific genetic variations could greatly influence host immunity to tuberculosis, causing different tuberculosis susceptibility on the ethnic populations studied.

In summary, we have observed a significant association between the IFN-{gamma} (+874 A/T) polymorphism and the development of pulmonary tuberculosis and found that this association is functional. Patients with tuberculosis- and tuberculin-reactive contacts that were homozygous for the IFN-{gamma} +874 A allele were shown to produce significantly less IFN-{gamma} than those with other allele combinations. In contrast, a polymorphism at position -1,082 in the promoter region of the IL-10 gene was not associated with disease susceptibility. We believe there are many more potentially influential and polymorphic immunoregulatory genes still to be investigated in patients with tuberculosis, and further studies are warranted.


   FOOTNOTES
 
Supported by grants from the Universidad Autónoma de Madrid (PI 103/2001) and the Fondo de Investigaciones Sanitarias (PI:021056/2002) (to F.A.) and from Ministerio de Ciencia y Tecnologia, Spain (PI:SAF2002–0151) (to C.M.)

Received in original form May 16, 2002; accepted in final form January 8, 2003


   REFERENCES
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

  1. Bellamy R, Beyers N, McAdam KPWJ, Ruwende C, Gie R, Samaai P, Bester D, Meyer M, Corrah T, Collin M, et al. Genetic susceptibility to tuberculosis in Africans: a genome-wide scan. Proc Natl Acad Sci USA 2000;97:8005–8009.[Abstract/Free Full Text]
  2. Bellamy R, Ruwende C, Corrah T, McAdam KPWJ, Whittle HC, Hill AVS. Assessment of the interleukin 1 gene cluster and other candidate gene polymorphisms in host susceptibility to tuberculosis. Tuber Lung Dis 1998;79:83–89.[CrossRef][Medline]
  3. Bellamy R, Ruwende C, Corrah T, McAdam KPWJ, Whittle HC, Hill AVS. Variation in the NRAMPI gene and susceptibility to tuberculosis in West Africans. N Engl J Med 1998;338:640–644.[Abstract/Free Full Text]
  4. Bellamy R, Ruwende C, Corrah T, McAdam KPWJ, Thursz M, Whittle HC, Hill AVS. Resistance to tuberculosis and chronic hepatitis B virus infection in Africans and variation in the vitamin D receptor gene. J Infect Dis 1999;179:721–724.[CrossRef][Medline]
  5. Wilkinson RJ, Patel P, Llewelyn M, Hirsch CS, Pasvol G, Snounou G, Davidson RN, Toossi Z. Influence of polymorphism in the genes for the interleukin (IL)-1 receptor antagonist and IL-1ß on tuberculosis. J Exp Med 1999;189:1863–1873.[Abstract/Free Full Text]
  6. Hill AV. The immunogenetics of human infectious diseases. Annu Rev Immunol 1998;16:593–617.[CrossRef][Medline]
  7. Flynn J, Chan J, Triebold KJ, Dalton DK, Stewart TA, Bloom BR. An essential role for interferon-{gamma} in resistance to Mycobacterium tuberculosis infection. J Exp Med 1993;178:2249–2254.[Abstract/Free Full Text]
  8. Newport MJ, Huxley CM, Huston S, Hawrylowicz CM, Oostra BA, Williamson R, Levin M. A mutation in the IFN-{gamma} receptor gene and susceptibility to mycobacterial infection. N Engl J Med 1996;335:1941–1949.[Abstract/Free Full Text]
  9. Jouanguy E, Altare F, Lamhamendi S, Revy P, Emile JF, Newport M, Levin M, Blanche S, Sebouin E, Fischer A, et al. IFN-{gamma} receptor deficiency in an infant with fatal bacille Calmette-Guerin infection. N Engl J Med 1996;335:1956–1961.[Free Full Text]
  10. Förtsch D, Röllinghoff M, Stenger S. IL-10 converts human dendritic cells into macrophage-like cells with increased antibacterial activity against virulent Mycobacterium tuberculosis. J Immunol 2000;165:978–987.[Abstract/Free Full Text]
  11. Khani-Hanjani A, Lacalle D, Hoar D, Chalmers A, Horsman D, Anderson M, Balshaw R, Keown PA. Association between dinucleotide repeat in non-coding region of interferon-gamma gene and susceptibility to, and severity of, rheumatoid arthritis. Lancet 2000;356:820–825.[CrossRef][Medline]
  12. Pravica V, Asderakis A, Perrey C, Hajeer A, Sinnott PJ, Hutchinson IV. In vitro production of IFN-{gamma} correlates with CA repeat polymorphism in the human IFN-{gamma} gene. Eur J Immunogenet 1999;25:1–3.
  13. Pravica V, Perrey C, Stevens A, Lee JH, Hutchinson IV. A single nucleotide polymorphism in the first intron of the human IFN-{gamma} gene: absolute correlation with a polymorphic CA microsatellite marker of high IFN-{gamma} production. Hum Immunol 2000;61:863–866.[CrossRef][Medline]
  14. Turner DM, Williams DM, Sankaran D, Lazarus M, Sinnott PJ, Hutchinson IV. An investigation of polymorphism in the interleukin-10 gene promoter. Eur J Immunogenet 1997;24:1–8.[Medline]
  15. National Tuberculosis and Respiratory Disease Association. Diagnostic standards and classification of tuberculosis. New York: National Tuberculosis and Respiratory Disease Association; 1969.
  16. Garcia-Palomero E, Cuchillo-Ibañez I, Garcia AG, Renart J, Albillos A, Montiel C. Greater diversity than previously thought of chromaffin cell Ca2+ channels, derived from mRNA identification studies. FEBS Lett 2000;481:235–239.[CrossRef][Medline]
  17. Perrey C, Turner SJ, Pravica V, Howell WM, Hutchinson IV. ARMS-PCR methodologies to determine IL-10, TNF-{alpha}, TNF-ß and TGF-ß1 gene polymorphisms. Transpl Immunol 1999;7:127–128.[CrossRef][Medline]
  18. Arnalich F, Hernanz A, Vázquez JJ, Amores A. Cell-mediated immune response and cytokine production in idiopathic senile anorexia. Mech Ageing Dev 1994;77:67–74.[CrossRef][Medline]
  19. Arnalich F, Lopez-Maderuelo D, Codoceo R, Lopez J, Solis-Garrido LM, Capiscol C, Fernandez-Capitan C, Madero R, Montiel C. Interleukin-1 receptor antagonist gene polymorphism and mortality in patients with severe sepsis. Clin Exp Immunol 2002;127:331–336.[CrossRef][Medline]
  20. Lang TA, Secic M. How to report statistics in medicine. Philadelphia: American College of Physicians; 1997.
  21. Lio D, Marino V, Serauto A, Gioia V, Scola L, Crivello A, Forte GI, Colonna-Romano G, Candore G, Caruso C. Genotype frequencies of the +874T->A single nucleotide polymorphism in the first intron of the interferon-gamma gene in a sample of Sicilian patients affected by tuberculosis. Eur J Immunogenet 2002;29:371–374.[CrossRef][Medline]
  22. Sánchez FO, Rodriguez JI, Agudelo G, Garcia LF. Immune responsiveness and lymphokine production in patients with tuberculosis and healthy controls. Infect Immun 1994;62:5673–5678.[Abstract/Free Full Text]
  23. Zhang M, Lin Y, Iyer DV, Gong J, Abrams JS, Barnes PF. T cell cytokine responses in human infection with Mycobacterium tuberculosis. Infect Immun 1995;63:3231–3234.[Abstract]
  24. Sodhi A, Gong J-H, Silva C, Qian D, Barnes PF. Clinical correlates of interferon {gamma} production in patients with tuberculosis. Clin Infect Dis 1997;25:617–620.[Medline]
  25. Heinemeyer T, Wingender E, Reuter I, Hermjakob H, Kel AE, Kel OV, Ignatieva EV, Ananko EA, Podkolodnaya OA, Kolpakov FA, et al. Databases on transcriptional regulation: TRANSFAC, TRRD and COMPEL. Nucleic Acids Res 1998;26:362–367.[Abstract/Free Full Text]
  26. Barnes PF, Shuzhuang LU, Abrams JS, Wang E, Yamamura M, Modlin RL. Cytokine production at the site of disease in human tuberculosis. Infect Immun 1993;61:3482–3489.[Abstract/Free Full Text]
  27. Lin Y, Zhang M, Hofman FM, Gong J, Barnes PF. Absence of a prominent Th2 response in human tuberculosis. Infect Immun 1996;64:1351–1356.[Abstract]
  28. Hirsch CS, Toossi Z, Johnson JL, Luzze H, Nitambi L, Peters P, Mchugh M, Okwera A, Jobba M, Mugvenvi P, et al. Augmentation of apoptosis and interferon-y production at sites of active mycobacterium tuberculosis infection in human tuberculosis. J Infect Dis 2001;183:779–788.[CrossRef][Medline]
  29. Boussiotis VA, Tsai EY, Yunis E, Thim S, Delgado JC, Dascher CC, Berezovskaya A, Rousset D, Reynes JM, Goldfeld AE. IL-10 producing T cells suppress immune responses in anergic tuberculosis patients. J Clin Invest 2000;105:1317–1325.[Medline]
  30. Delgado JC, Baena A, Thim S, Goldfeld AE. Ethnic-specific genetic associations with pulmonary tuberculosis. J Infect Dis 2002;186:1463–1468.[CrossRef][Medline]



This article has been cited by other articles:


Home page
 Am. J. Respir. Crit. Care Med.Home page
G. S. Cooke, S. J. Campbell, S. Bennett, C. Lienhardt, K. P. W. J. McAdam, G. Sirugo, O. Sow, P. Gustafson, F. Mwangulu, P. van Helden, et al.
Mapping of a Novel Susceptibility Locus Suggests a Role for MC3R and CTSZ in Human Tuberculosis
Am. J. Respir. Crit. Care Med., July 15, 2008; 178(2): 203 - 207.
[Abstract] [Full Text] [PDF]

Home page
 Infect. Immun.Home page
S. T. Chang, J. J. Linderman, and D. E. Kirschner
Effect of Multiple Genetic Polymorphisms on Antigen Presentation and Susceptibility to Mycobacterium tuberculosis Infection
Infect. Immun., July 1, 2008; 76(7): 3221 - 3232.
[Abstract] [Full Text] [PDF]

Home page
 Arch NeurolHome page
O. H. Kantarci, D. D. Hebrink, J. Schaefer-Klein, Y. Sun, S. Achenbach, E. J. Atkinson, S. Heggarty, A. C. Cotleur, M. de Andrade, K. Vandenbroeck, et al.
Interferon Gamma Allelic Variants: Sex-Biased Multiple Sclerosis Susceptibility and Gene Expression
Arch Neurol, March 1, 2008; 65(3): 349 - 357.
[Abstract] [Full Text] [PDF]

Home page
 PediatricsHome page
T. R. Sterling, T. Martire, A. S. de Almeida, L. Ding, D. E. Greenberg, L. A. Moreira, H. Elloumi, A. P.V. Torres, C. C. Sant'Anna, E. Calazans, et al.
Immune Function in Young Children With Previous Pulmonary or Miliary/Meningeal Tuberculosis and Impact of BCG Vaccination
Pediatrics, October 1, 2007; 120(4): e912 - e921.
[Abstract] [Full Text] [PDF]

Home page
 J. Virol.Home page
J. R. Abend, J. A. Low, and M. J. Imperiale
Inhibitory Effect of Gamma Interferon on BK Virus Gene Expression and Replication
J. Virol., January 1, 2007; 81(1): 272 - 279.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Respir. Crit. Care Med.Home page
G. S. Cooke, S. J. Campbell, J. Sillah, P. Gustafson, B. Bah, G. Sirugo, S. Bennett, K. P. W. J. McAdam, O. Sow, C. Lienhardt, et al.
Polymorphism within the Interferon-{gamma}/Receptor Complex Is Associated with Pulmonary Tuberculosis
Am. J. Respir. Crit. Care Med., August 1, 2006; 174(3): 339 - 343.
[Abstract] [Full Text] [PDF]

Home page
 Proc. Natl. Acad. Sci. USAHome page
K. Tosh, S. J. Campbell, K. Fielding, J. Sillah, B. Bah, P. Gustafson, K. Manneh, I. Lisse, G. Sirugo, S. Bennett, et al.
Variants in the SP110 gene are associated with genetic susceptibility to tuberculosis in West Africa
PNAS, July 5, 2006; 103(27): 10364 - 10368.
[Abstract] [Full Text] [PDF]

Home page
 J. Exp. Med.Home page
P. O. Flores-Villanueva, J. A. Ruiz-Morales, C.-H. Song, L. M. Flores, E.-K. Jo, M. Montano, P. F. Barnes, M. Selman, and J. Granados
A functional promoter polymorphism in monocyte chemoattractant protein-1 is associated with increased susceptibility to pulmonary tuberculosis
J. Exp. Med., December 19, 2005; 202(12): 1649 - 1658.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Respir. Crit. Care Med.Home page
P. T. G. Elkington, R. K. Nuttall, J. J. Boyle, C. M. O'Kane, D. E. Horncastle, D. R. Edwards, and J. S. Friedland
Mycobacterium tuberculosis, but Not Vaccine BCG, Specifically Upregulates Matrix Metalloproteinase-1
Am. J. Respir. Crit. Care Med., December 15, 2005; 172(12): 1596 - 1604.
[Abstract] [Full Text] [PDF]

Home page
 Physiol. GenomicsHome page
R. Pawliczak, C. Logun, P. Madara, J. Barb, A. F. Suffredini, P. J. Munson, R. L. Danner, and J. H. Shelhamer
Influence of IFN-{gamma} on gene expression in normal human bronchial epithelial cells: modulation of IFN-{gamma} effects by dexamethasone
Physiol Genomics, September 21, 2005; 23(1): 28 - 45.
[Abstract] [Full Text] [PDF]

Home page
 BloodHome page
J. E. Dierksheide, R. A. Baiocchi, A. K. Ferketich, S. Roychowdhury, R. P. Pelletier, C. F. Eisenbeis, M. A. Caligiuri, and A. M. VanBuskirk
IFN-{gamma} gene polymorphisms associate with development of EBV+ lymphoproliferative disease in hu PBL-SCID mice
Blood, February 15, 2005; 105(4): 1558 - 1565.
[Abstract] [Full Text] [PDF]

Home page
 ThoraxHome page
A A Awomoyi, S Nejentsev, A Richardson, J Hull, O Koch, M Podinovskaia, J A Todd, K P W J McAdam, J M Blackwell, D Kwiatkowski, et al.
No association between interferon-{gamma} receptor-1 gene polymorphism and pulmonary tuberculosis in a Gambian population sample
Thorax, April 1, 2004; 59(4): 291 - 294.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Respir. Crit. Care Med.Home page
M. J. Tobin
Tuberculosis, Lung Infections, Interstitial Lung Disease, Social Issues and Journalology in AJRCCM 2003
Am. J. Respir. Crit. Care Med., January 15, 2004; 169(2): 288 - 300.
[Full Text] [PDF]

Home page
 Am. J. Respir. Crit. Care Med.Home page
B. M. Schaaf, F. Boehmke, H. Esnaashari, U. Seitzer, H. Kothe, M. Maass, P. Zabel, and K. Dalhoff
Pneumococcal Septic Shock Is Associated with the Interleukin-10-1082 Gene Promoter Polymorphism
Am. J. Respir. Crit. Care Med., August 15, 2003; 168(4): 476 - 480.
[Abstract] [Full Text] [PDF]

Home page
 JWatch Infect. DiseasesHome page
Interferon-{gamma} Polymorphism Increases Risk of Active TB
Journal Watch Infectious Diseases, May 9, 2003; 2003(509): 10 - 10.
[Full Text]

Home page
 Am. J. Respir. Crit. Care Med.Home page
R. Bellamy
Interferon-{gamma} and Host Susceptibility to Tuberculosis
Am. J. Respir. Crit. Care Med., April 1, 2003; 167(7): 946 - 947.
[Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
200205-438BCv1
167/7/970    most recent
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by López-Maderuelo, D.
Right arrow Articles by Montiel, C.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by López-Maderuelo, D.
Right arrow Articles by Montiel, C.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Proc. Am. Thorac. Soc. Am. J. Respir. Cell Mol. Biol.
Copyright © 2003 American Thoracic Society