Evidencia, actualizacion en la práctica ambulatoria, 2000
VoLUMEN 3 runo 3 Nóduto pulmonar solitario Un nódu[o pu[monar sotitario (NPS) puede ser eI modo d... more VoLUMEN 3 runo 3 Nóduto pulmonar solitario Un nódu[o pu[monar sotitario (NPS) puede ser eI modo de presentacjón de procesos benignos o ma[ignos, constituyendo un desafio
The monocyte chemotactic protein-1 (MCP-1) is a chemokine that plays an important role in the rec... more The monocyte chemotactic protein-1 (MCP-1) is a chemokine that plays an important role in the recruitment of monocytes to M. tuberculosis infection sites, and previous studies have reported that genetic variants in MCP1 are associated with differential susceptibility to pulmonary tuberculosis (PTB). We examined eight MCP1 single nucleotide polymorphisms (SNPs) in a multi-ethnic, case-control design that included: 321 cases and 346 controls from Guinea-Bissau, 258 cases and 271 controls from The Gambia, 295 cases and 179 controls from the U.S. (African-Americans), and an additional set of 237 cases and 144 controls of European ancestry from the U.S. and Argentina. Two locus interactions were also examined for polymorphisms in MCP1 and interleukin 12B (IL12B), another gene implicated in PTB risk. Examination of previously associated MCP1 SNPs rs1024611 (22581A/G), rs2857656 (2362G/C) and rs4586 (+900C/T) did not show evidence for association. One interaction between rs2857656 and IL12B SNP rs2288831 was observed among Africans but the effect was in the opposite direction in Guineans (OR = 1.90, p = 0.001) and Gambians (OR = 0.64, p = 0.024). Our data indicate that the effect of genetic variation within MCP1 is not clear cut and additional studies will be needed to elucidate its role in TB susceptibility.
We examined whether polymorphisms in interleukin-12B (IL12B) associate with susceptibility to pul... more We examined whether polymorphisms in interleukin-12B (IL12B) associate with susceptibility to pulmonary tuberculosis (PTB) in two West African populations (from The Gambia and Guinea-Bissau) and in two independent populations from North and South America. Nine polymorphisms (seven SNPs, one insertion/deletion, one microsatellite) were analyzed in 321 PTB cases and 346 controls from Guinea-Bissau and 280 PTB cases and 286 controls from The Gambia. For replication we studied 281 case and 179 control African-American samples and 221 cases and 144 controls of European ancestry from the US and Argentina. First-stage single locus analyses revealed signals of association at IL12B 39 UTR SNP rs3212227 (unadjusted allelic p = 0.04; additive genotypic p = 0.05, OR = 0.78, 95% CI [0.61-0.99]) in Guinea-Bissau and rs11574790 (unadjusted allelic p = 0.05; additive genotypic p = 0.05, OR = 0.76, 95% CI [0.58-1.00]) in The Gambia. Association of rs3212227 was then replicated in African-Americans (rs3212227 allelic p = 0.002; additive genotypic p = 0.05, OR = 0.78, 95% CI [0.61-1.00]); most importantly, in the African-American cohort, multiple significant signals of association (seven of the nine polymorphisms tested) were detected throughout the gene. These data suggest that genetic variation in IL12B, a highly relevant candidate gene, is a risk factor for PTB in populations of African ancestry, although further studies will be required to confirm this association and identify the precise mechanism underlying it.
Background. The proinflammatory cytokine interleukin 17 (IL-17) plays an important role in immune... more Background. The proinflammatory cytokine interleukin 17 (IL-17) plays an important role in immune responses but it is also associated with tissue-damaging inflammation. So, we evaluated the ability of Mycobacterium tuberculosis clinical isolates to induce IL-17 in tuberculosis (TB) patients and in healthy human tuberculin reactors (PPD 1 HD). Methods. IL-17, interferon c (IFN-c), and interleukin 23 (IL-23) receptor expression were evaluated ex vivo and cultured peripheral blood mononuclear cells from TB and PPD 1 HD stimulated with irradiated clinical isolates from multidrug resistant (MDR) outbreaks M (Haarlem family) and Ra (Latin American-Mediterranean family), as well as drug-susceptible isolates belonging to the same families and laboratory strain H37Rv for 48 hours in T-cell subsets by flow cytometry. Results. We observed that: (1) MDR strains M and Ra are stronger IL-17 inducers than drug-susceptible Mtb strains of the Haarlem and Latin American-Mediterranean families, (2) MDR-TB patients show the highest IL-17 expression that is independent on the strain, (3) IL-17 expression is dependent on CD4 1 and CD8 1 T cells associates with persistently high antigen load. Conclusions. IL-17-producing T cells could play an immunopathological role in MDR-TB promoting severe tissue damage, which may be associated with the low effectiveness of the second-line drugs employed in the treatment.
Tuberculosis (TB) is a global public health problem and a source of preventable deaths each year,... more Tuberculosis (TB) is a global public health problem and a source of preventable deaths each year, with 8.8 million new cases of TB and 1.6 million deaths worldwide in 2005. Approximately, 10% of infected individuals develop pulmonary or extrapulmonary TB, suggesting that host defense factors influence development of active disease. Toll-like receptor' (TLR) polymorphisms have been associated with regulation of TLR expression and development of active TB. In the present study, 71 polymorphisms in TLR1, TLR2, TLR4, TLR6, and TLR9 were examined from 474 (295 cases and 179 controls) African-Americans, 381 (237 cases and 144 controls) Caucasians, and from 667 (321 cases and 346 controls) Africans from Guinea-Bissau for association with pulmonary TB using generalized estimating equations and logistic regression. Statistically significant associations were observed across populations at TLR9 and TLR2. The strongest evidence for association came at an insertion (I)/deletion (D) polymorphism (−196 to −174) in TLR2 that associated with TB in both Caucasians (II vs. ID&DD, OR=0.41 [95% CI 0.24-0.68], p=0.0007) and Africans (II vs. ID&DD, OR=0.70 [95% CI 0.51-0.95], p=0.023). Our findings in three independent population samples indicate that variations in TLR2 and TLR9 might play important roles in determining susceptibility to TB.
SUMMARY Tuberculosis is a chronic infectious disease caused by Mycobacterium tuberculosis where f... more SUMMARY Tuberculosis is a chronic infectious disease caused by Mycobacterium tuberculosis where formyl peptides, which are cleavage products of bacterial and mitochondrial proteins, are present. In this study, we demonstrated that interferon gamma (IFN)-γ and interleukin (IL)-10 induced the overexpression of the receptor for the Fc portion of IgG I (FcγRI) in monocytes from tuberculosis (TB) patients, showing that these cells respond to IFN-γ and IL-10 signals. We also demonstrated that lower doses of IL-10 render monocytes from TB patients less responsive to higher doses of the cytokine. Although the prototypic formyl peptide N-formyl-methionyl-leucyl-phenylalanine (FMLP) is a well-known proinflammatory agonist, we have demonstrated previously that preincubation of monocytes with FMLP inhibited the up-regulation of FcγRI induced by IFN-γ or IL-10. This effect was not observed in monocytes from TB patientes. FMLP also induced the down-regulation of the expression of FcγRI in monocyt...
Objectives: Current drug choices to treat extensively drug-resistant (XDR) tuberculosis (TB) are ... more Objectives: Current drug choices to treat extensively drug-resistant (XDR) tuberculosis (TB) are scarce; therefore, information on the safety, tolerability and efficacy of alternative regimens is of utmost importance. The aim of this study was to describe the management, drug adverse effects and outcome of alternative combined treatment in a series of XDR-TB patients. Patients and methods: A retrospective study was performed on 17 non-AIDS, pulmonary adult patients with XDR-TB admitted to a referral treatment centre for infectious diseases in Buenos Aires from 2002 through 2008. Drug susceptibility testing was performed under regular proficiency testing and confirmed at the national TB reference laboratory. Results: Linezolid was included in the drug regimens of all patients; moxifloxacin and/or thioridazine were included in the regimens of 14 patients. Clinically tractable drug adverse effects were observed in nine patients, the most frequent being haematological disorders and neurotoxicity. In two patients, thioridazine was discontinued. Negative culture conversion was achieved in 15 patients, 11 completed treatment meeting cure criteria, 4 are still on follow-up with good evolution, 1 defaulted treatment and 1 was lost to follow-up. Conclusions: The combination of linezolid, moxifloxacin and thioridazine is recommended for compassionate use in specialized centres with expertise in the management of XDR-TB.
Effective host defense against Mycobacterium tuberculosis requires the induction of Th1 cytokine ... more Effective host defense against Mycobacterium tuberculosis requires the induction of Th1 cytokine responses. We investigated the regulated expression and functional role of the inducible costimulator (ICOS), a receptor known to regulate Th cytokine production, in the context of human tuberculosis. Patients with active disease, classified as high responder (HR) or low responder (LR) patients according to their in vitro T cell responses against the Ag, were evaluated for T cell expression of ICOS after M. tuberculosis-stimulation. We found that ICOS expression significantly correlated with IFN-gamma production by tuberculosis patients. ICOS expression levels were regulated in HR patients by Th cytokines: Th1 cytokines increased ICOS levels, whereas Th2-polarizing conditions down-regulated ICOS in these individuals. Besides, in human polarized Th cells, engagement of ICOS increased M. tuberculosis IFN-gamma production with a magnitude proportional to ICOS levels on those cells. Moreover...
International Journal of Tuberculosis and Lung Disease, 1999
CADRE : Tuberculose a germes multiresistants chez des patients seronegatifs pour le virus de l... more CADRE : Tuberculose a germes multiresistants chez des patients seronegatifs pour le virus de l'immunodeficience humaine (VIH) et porteurs de Mycobacterium tuberculosis resistant a presque tous les medicaments disponibles. OBJECTIF : Essai limite de phase Il au moyen d'interferon-α2b recombinant chez 5 patients atteints d'une tuberculose incurable, chronique, a germes multiresistants. METHODES: Administration sous-cutanee hebdomadaire pendant 12 semaines de 3 000 000 unites de r-IFN-α2b. Examen clinique et radiologique avant et apres traitement, ainsi que pendant un suivi de 30 mois en association avec des tests de laboratoire en matiere bacteriologique, immunologique et de routine. RESULTATS: Chez deux des cinq patients, la bacilloscopie et la culture sont devenues negatives a long terme, apres le traitement a base de r-IFN-α2b. Chez un des patients, on a note une amelioration clinique et une bacilloscopie negative apres traitement, mais la culture est restee positive. C...
Tuberculosis is a worldwide prevalent disease. The emergence of multidrug-resistant strains spurr... more Tuberculosis is a worldwide prevalent disease. The emergence of multidrug-resistant strains spurred the search for new drugs. There are several tuberculosis treatment guidelines, international and local in a programmatic approach. An Argentinean specialists panel draw practical guidelines based in clinical criteria and the local and international bibliography through consensus meetings, including issues as: antituberculosis drugs available in Argentina, initial and re-treatement modalities, special situations treatment, adverse reactions to antituberculosis drugs, current indications of surgical treatment and new drugs under study for the treatment of the disease.
Updated Argentine Consensus on chronic obstructive pulmonary disease. Due to the increase in morb... more Updated Argentine Consensus on chronic obstructive pulmonary disease. Due to the increase in morbidity and mortality from Chronic Obstructive Pulmonary Disease (COPD), a group of chest physicians updates the basic knowledge on COPD since the last Consensus in 1994 in order to prepare guidelines for its diagnosis, prevention and treatment. The authors review the definition of COPD together with the most recent information on its pathophysiology. The clinical presentation is summarized together with functional evaluation and imaging. Early diagnosis by means of functional testing (i.e., spirometry) is stressed, emphasizing smoking cessation as the only measure that has been shown to alter the outcome of the disease. Smoking cessation strategies are described as well as pharmacological and non-pharmacological treatment. In the pharmacological section, the use of inhaled bronchodilators (anticholinergic, beta 2 adrenergic agonists or both) is considered the first option for treatment. L...
Material and Methods: The INLASA-BOLIVA begun in 1988 a study of HIV infection associated with Tu... more Material and Methods: The INLASA-BOLIVA begun in 1988 a study of HIV infection associated with Tuberculosis and the implementation a serologic level, habits, Sexual Transmited Diseases, adiction of alcohol and drugs, Mantoux test, X-rays, smear and culture in Lowestein Jennsen medium. This protocol were distributed by seminars in Bolivia and now is a special survey of the AIDS program. Results: In regards that in Bolivia have a real register of AIDS cases, at present 102 (AIDS = 62 and HIV = 40), that 62 AIDS cases were death 53 (88%), 16 patients (30 %) had a clinical and radiologic diagnostic of tuberculosis, in only 8 patients had the bacteriologic studies by smears 5 (62,.5 %) and 3 (37.5 %) by culture, the seropositive patients (21) are with HIV chemoprophylaxis for 6 months (PAHDW.H.0. recomendations) Conclusion: For the prevention measure of the serious problems for the health of the community, it's necessary to continue this activites for the search the tuberculosis and HIV infection.
Due to the increase in morbidity and mortality from Chronic Obstructive Pulmonary Disease (COPD),... more Due to the increase in morbidity and mortality from Chronic Obstructive Pulmonary Disease (COPD), a group of chest physicians updates the basic knowledge on COPD since the last Consensus in 1994 in order to prepare guidelines for its diagnosis, prevention and treatment. The authors review the definition of COPD together with the most recent information on its pathophysiology. The clinical presentation is summarized together with functional evaluation and imaging. Early diagnosis by means of functional testing (i.e., spirometry) is stressed, emphasizing smoking cessation as the only measure that has been shown to alter the outcome of the disease. Smoking cessation strategies are described as well as pharmacological and non-pharmacological treatment. In the pharmacological section, the use of inhaled bronchodilators (anticholinergic, beta 2 adrenergic agonists or both) is considered the first option for treatment. Long acting bronchodilators improve patient compliance and treatment effectiveness. Inhaled corticosteroids are indicated for patients with severe airways obstruction and known response to corticosteroids. These agents can diminish the number of exacerbations. Annual influenza vaccination is recommended in all patients. In the non-pharmacological section, surgery for emphysema is suggested in particular cases. Rehabilitation, including exercise training, kinesitherapy and nutrition, is a useful tool for patients who are physically disabled. Long-term oxygen therapy at home improves survival in patients with severe chronic hypoxemia. Other therapeutic interventions such as non-invasive home ventilation have specific indications. Acute exacerbations must be aggressively treated with oxygen, corticosteroids, antibiotics, combination of bronchodilators, and eventually respiratory support. The role of public education of the patients and their families is essential in the prevention and treatment of the disease.
The International Journal of Tuberculosis and Lung Disease the Official Journal of the International Union Against Tuberculosis and Lung Disease, Sep 1, 2009
SETTINGHost defense factors may influence the development of active tuberculosis (TB).OBJECTIVETo... more SETTINGHost defense factors may influence the development of active tuberculosis (TB).OBJECTIVETo test variants in solute carrier family 11A, member 1 (SLC11A1), for an association with TB.METHODSA mixed case-control study of TB cases, relatives or close contact controls, consisting of 474 African-Americans (243 families) and 381 Caucasians (192 families), examined 13 SLC11A1 polymorphisms for association with pulmonary TB using generalized estimating equations adjusting for age and gender.RESULTSTwo associations were observed in Caucasians (rs3731863, P = 0.03, and rs17221959, P = 0.04) and one in African-Americans (rs3731865, P = 0.05). Multilocus analyses between polymorphisms in SLC11A1 and 11 TB candidate genes detected interactions between SLC11A1 and inducible nitric oxide synthase (NOS2A) in Caucasians (rs3731863 [SLC11A1] × rs8073782 [NOS2A], P = 0.009; rs3731863 [SLC11A1] × rs17722851 [NOS2A], P = 0.007) and toll-like receptor 2 (TLR2) in African-Americans (rs3731865 [SLC11A1] x rs1816702, P = 0.005).CONCLUSIONSNo association was detected with 5′(GT)n promoter polymorphism previously associated with lower SLC11A1 expression, rs17235409 (D543N), or rs17235416 (3′ TGTG insertion/deletion polymorphism). SLC11A1 polymorphism rs3731865 was associated with TB in African-Americans, consistent with previous findings in West Africans. These results suggest that variants in SLC11A1 increase susceptibility to pulmonary TB and interact with other variants that differ by race.
The International Journal of Tuberculosis and Lung Disease
Multidrug-resistant tuberculosis patients without human immunodeficiency virus (HIV) infection, w... more Multidrug-resistant tuberculosis patients without human immunodeficiency virus (HIV) infection, with Mycobacterium tuberculosis resistant to almost all of the available drugs. Limited phase II trial with recombinant interferon-alpha2b in five chronic multidrug-resistant tuberculosis patients. Three million units of r-IFN-alpha2b were administered subcutaneously every week for 12 weeks. Before and after treatment, and during a 30-month follow-up period, the patients underwent clinical and radiological examination, together with bacteriological, immunological and routine laboratory testing. Two of the five patients became long-term sputum smear and culture negative after r-IFN-alpha2b therapy; one of the patients showed clinical improvement and negative smear after therapy, but remained culture positive. The other two patients showed no response. The results of this trial suggest that r-IFN-alpha2b should be evaluated further in multidrug-resistant tuberculosis in prospective controll...
The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease, 2009
Host defense factors may influence the development of active tuberculosis (TB). To test variants ... more Host defense factors may influence the development of active tuberculosis (TB). To test variants in solute carrier family 11A, member 1 (SLC11A1), for an association with TB. A mixed case-control study of TB cases, relatives or close contact controls, consisting of 474 African-Americans (243 families) and 381 Caucasians (192 families), examined 13 SLC11A1 polymorphisms for association with pulmonary TB using generalized estimating equations adjusting for age and sex. Two associations were observed in Caucasians (rs3731863, P = 0.03, and rs17221959, P = 0.04) and one in African-Americans (rs3731865, P = 0.05). Multilocus analyses between polymorphisms in SLC11A1 and 11 TB candidate genes detected interactions between SLC11A1 and inducible nitric oxide synthase (NOS2A) in Caucasians (rs3731863 [SLC11A1] x rs8073782 [NOS2A], P = 0.009; rs3731863 [SLC11A1] x rs17722851 [NOS2A], P = 0.007) and toll-like receptor 2 (TLR2) in African-Americans (rs3731865 [SLC11A1] x rs1816702, P = 0.005). ...
Your browser version may not work well with NCBI's web applications. More information here..... more Your browser version may not work well with NCBI's web applications. More information here... ...
Protective immunity against Mycobacterium tuberculosis requires the generation of cell-mediated i... more Protective immunity against Mycobacterium tuberculosis requires the generation of cell-mediated immunity. We investigated the expression and role of programmed death 1 (PD-1) and its ligands, molecules known to modulate T cell activation, in the regulation of IFN-␥ production and lytic degranulation during human tuberculosis. We demonstrated that specific Agstimulation increased CD3 ؉ PD-1 ؉ lymphocytes in peripheral blood and pleural fluid from tuberculosis patients in direct correlation with IFN-␥ production from these individuals. Moreover, M. tuberculosis-induced IFN-␥ participated in the up-regulation of PD-1 expression. Blockage of PD-1 or PD-1 and its ligands (PD-Ls: PD-L1, PD-L2) enhanced the specific degranulation of CD8 ؉ T cells and the percentage of specific IFN-␥-producing lymphocytes against the pathogen, demonstrating that the PD-1:PD-Ls pathway inhibits T cell effector functions during active M. tuberculosis infection. Furthermore, the simultaneous blockage of the inhibitory receptor PD-1 together with the activation of the costimulatory protein signaling lymphocytic activation molecule led to the promotion of protective IFN-␥ responses to M. tuberculosis, even in patients with weak cell-mediated immunity against the bacteria. Together, we demonstrated that PD-1 interferes with T cell effector functions against M. tuberculosis, suggesting that PD-1 has a key regulatory role during the immune response of the host to the pathogen.
We examined whether polymorphisms in interleukin-12B (IL12B) associate with susceptibility to pul... more We examined whether polymorphisms in interleukin-12B (IL12B) associate with susceptibility to pulmonary tuberculosis (PTB) in two West African populations (from The Gambia and Guinea-Bissau) and in two independent populations from North and South America. Nine polymorphisms (seven SNPs, one insertion/deletion, one microsatellite) were analyzed in 321 PTB cases and 346 controls from Guinea-Bissau and 280 PTB cases and 286 controls from The Gambia. For replication we studied 281 case and 179 control African-American samples and 221 cases and 144 controls of European ancestry from the US and Argentina. First-stage single locus analyses revealed signals of association at IL12B 39 UTR SNP rs3212227 (unadjusted allelic p = 0.04; additive genotypic p = 0.05, OR = 0.78, 95% CI [0.61-0.99]) in Guinea-Bissau and rs11574790 (unadjusted allelic p = 0.05; additive genotypic p = 0.05, OR = 0.76, 95% CI [0.58-1.00]) in The Gambia. Association of rs3212227 was then replicated in African-Americans (rs3212227 allelic p = 0.002; additive genotypic p = 0.05, OR = 0.78, 95% CI [0.61-1.00]); most importantly, in the African-American cohort, multiple significant signals of association (seven of the nine polymorphisms tested) were detected throughout the gene. These data suggest that genetic variation in IL12B, a highly relevant candidate gene, is a risk factor for PTB in populations of African ancestry, although further studies will be required to confirm this association and identify the precise mechanism underlying it. Citation: Morris GAJ, Edwards DRV, Hill PC, Wejse C, Bisseye C, et al. (2011) Interleukin 12B (IL12B) Genetic Variation and Pulmonary Tuberculosis: A Study of
Evidencia, actualizacion en la práctica ambulatoria, 2000
VoLUMEN 3 runo 3 Nóduto pulmonar solitario Un nódu[o pu[monar sotitario (NPS) puede ser eI modo d... more VoLUMEN 3 runo 3 Nóduto pulmonar solitario Un nódu[o pu[monar sotitario (NPS) puede ser eI modo de presentacjón de procesos benignos o ma[ignos, constituyendo un desafio
The monocyte chemotactic protein-1 (MCP-1) is a chemokine that plays an important role in the rec... more The monocyte chemotactic protein-1 (MCP-1) is a chemokine that plays an important role in the recruitment of monocytes to M. tuberculosis infection sites, and previous studies have reported that genetic variants in MCP1 are associated with differential susceptibility to pulmonary tuberculosis (PTB). We examined eight MCP1 single nucleotide polymorphisms (SNPs) in a multi-ethnic, case-control design that included: 321 cases and 346 controls from Guinea-Bissau, 258 cases and 271 controls from The Gambia, 295 cases and 179 controls from the U.S. (African-Americans), and an additional set of 237 cases and 144 controls of European ancestry from the U.S. and Argentina. Two locus interactions were also examined for polymorphisms in MCP1 and interleukin 12B (IL12B), another gene implicated in PTB risk. Examination of previously associated MCP1 SNPs rs1024611 (22581A/G), rs2857656 (2362G/C) and rs4586 (+900C/T) did not show evidence for association. One interaction between rs2857656 and IL12B SNP rs2288831 was observed among Africans but the effect was in the opposite direction in Guineans (OR = 1.90, p = 0.001) and Gambians (OR = 0.64, p = 0.024). Our data indicate that the effect of genetic variation within MCP1 is not clear cut and additional studies will be needed to elucidate its role in TB susceptibility.
We examined whether polymorphisms in interleukin-12B (IL12B) associate with susceptibility to pul... more We examined whether polymorphisms in interleukin-12B (IL12B) associate with susceptibility to pulmonary tuberculosis (PTB) in two West African populations (from The Gambia and Guinea-Bissau) and in two independent populations from North and South America. Nine polymorphisms (seven SNPs, one insertion/deletion, one microsatellite) were analyzed in 321 PTB cases and 346 controls from Guinea-Bissau and 280 PTB cases and 286 controls from The Gambia. For replication we studied 281 case and 179 control African-American samples and 221 cases and 144 controls of European ancestry from the US and Argentina. First-stage single locus analyses revealed signals of association at IL12B 39 UTR SNP rs3212227 (unadjusted allelic p = 0.04; additive genotypic p = 0.05, OR = 0.78, 95% CI [0.61-0.99]) in Guinea-Bissau and rs11574790 (unadjusted allelic p = 0.05; additive genotypic p = 0.05, OR = 0.76, 95% CI [0.58-1.00]) in The Gambia. Association of rs3212227 was then replicated in African-Americans (rs3212227 allelic p = 0.002; additive genotypic p = 0.05, OR = 0.78, 95% CI [0.61-1.00]); most importantly, in the African-American cohort, multiple significant signals of association (seven of the nine polymorphisms tested) were detected throughout the gene. These data suggest that genetic variation in IL12B, a highly relevant candidate gene, is a risk factor for PTB in populations of African ancestry, although further studies will be required to confirm this association and identify the precise mechanism underlying it.
Background. The proinflammatory cytokine interleukin 17 (IL-17) plays an important role in immune... more Background. The proinflammatory cytokine interleukin 17 (IL-17) plays an important role in immune responses but it is also associated with tissue-damaging inflammation. So, we evaluated the ability of Mycobacterium tuberculosis clinical isolates to induce IL-17 in tuberculosis (TB) patients and in healthy human tuberculin reactors (PPD 1 HD). Methods. IL-17, interferon c (IFN-c), and interleukin 23 (IL-23) receptor expression were evaluated ex vivo and cultured peripheral blood mononuclear cells from TB and PPD 1 HD stimulated with irradiated clinical isolates from multidrug resistant (MDR) outbreaks M (Haarlem family) and Ra (Latin American-Mediterranean family), as well as drug-susceptible isolates belonging to the same families and laboratory strain H37Rv for 48 hours in T-cell subsets by flow cytometry. Results. We observed that: (1) MDR strains M and Ra are stronger IL-17 inducers than drug-susceptible Mtb strains of the Haarlem and Latin American-Mediterranean families, (2) MDR-TB patients show the highest IL-17 expression that is independent on the strain, (3) IL-17 expression is dependent on CD4 1 and CD8 1 T cells associates with persistently high antigen load. Conclusions. IL-17-producing T cells could play an immunopathological role in MDR-TB promoting severe tissue damage, which may be associated with the low effectiveness of the second-line drugs employed in the treatment.
Tuberculosis (TB) is a global public health problem and a source of preventable deaths each year,... more Tuberculosis (TB) is a global public health problem and a source of preventable deaths each year, with 8.8 million new cases of TB and 1.6 million deaths worldwide in 2005. Approximately, 10% of infected individuals develop pulmonary or extrapulmonary TB, suggesting that host defense factors influence development of active disease. Toll-like receptor' (TLR) polymorphisms have been associated with regulation of TLR expression and development of active TB. In the present study, 71 polymorphisms in TLR1, TLR2, TLR4, TLR6, and TLR9 were examined from 474 (295 cases and 179 controls) African-Americans, 381 (237 cases and 144 controls) Caucasians, and from 667 (321 cases and 346 controls) Africans from Guinea-Bissau for association with pulmonary TB using generalized estimating equations and logistic regression. Statistically significant associations were observed across populations at TLR9 and TLR2. The strongest evidence for association came at an insertion (I)/deletion (D) polymorphism (−196 to −174) in TLR2 that associated with TB in both Caucasians (II vs. ID&DD, OR=0.41 [95% CI 0.24-0.68], p=0.0007) and Africans (II vs. ID&DD, OR=0.70 [95% CI 0.51-0.95], p=0.023). Our findings in three independent population samples indicate that variations in TLR2 and TLR9 might play important roles in determining susceptibility to TB.
SUMMARY Tuberculosis is a chronic infectious disease caused by Mycobacterium tuberculosis where f... more SUMMARY Tuberculosis is a chronic infectious disease caused by Mycobacterium tuberculosis where formyl peptides, which are cleavage products of bacterial and mitochondrial proteins, are present. In this study, we demonstrated that interferon gamma (IFN)-γ and interleukin (IL)-10 induced the overexpression of the receptor for the Fc portion of IgG I (FcγRI) in monocytes from tuberculosis (TB) patients, showing that these cells respond to IFN-γ and IL-10 signals. We also demonstrated that lower doses of IL-10 render monocytes from TB patients less responsive to higher doses of the cytokine. Although the prototypic formyl peptide N-formyl-methionyl-leucyl-phenylalanine (FMLP) is a well-known proinflammatory agonist, we have demonstrated previously that preincubation of monocytes with FMLP inhibited the up-regulation of FcγRI induced by IFN-γ or IL-10. This effect was not observed in monocytes from TB patientes. FMLP also induced the down-regulation of the expression of FcγRI in monocyt...
Objectives: Current drug choices to treat extensively drug-resistant (XDR) tuberculosis (TB) are ... more Objectives: Current drug choices to treat extensively drug-resistant (XDR) tuberculosis (TB) are scarce; therefore, information on the safety, tolerability and efficacy of alternative regimens is of utmost importance. The aim of this study was to describe the management, drug adverse effects and outcome of alternative combined treatment in a series of XDR-TB patients. Patients and methods: A retrospective study was performed on 17 non-AIDS, pulmonary adult patients with XDR-TB admitted to a referral treatment centre for infectious diseases in Buenos Aires from 2002 through 2008. Drug susceptibility testing was performed under regular proficiency testing and confirmed at the national TB reference laboratory. Results: Linezolid was included in the drug regimens of all patients; moxifloxacin and/or thioridazine were included in the regimens of 14 patients. Clinically tractable drug adverse effects were observed in nine patients, the most frequent being haematological disorders and neurotoxicity. In two patients, thioridazine was discontinued. Negative culture conversion was achieved in 15 patients, 11 completed treatment meeting cure criteria, 4 are still on follow-up with good evolution, 1 defaulted treatment and 1 was lost to follow-up. Conclusions: The combination of linezolid, moxifloxacin and thioridazine is recommended for compassionate use in specialized centres with expertise in the management of XDR-TB.
Effective host defense against Mycobacterium tuberculosis requires the induction of Th1 cytokine ... more Effective host defense against Mycobacterium tuberculosis requires the induction of Th1 cytokine responses. We investigated the regulated expression and functional role of the inducible costimulator (ICOS), a receptor known to regulate Th cytokine production, in the context of human tuberculosis. Patients with active disease, classified as high responder (HR) or low responder (LR) patients according to their in vitro T cell responses against the Ag, were evaluated for T cell expression of ICOS after M. tuberculosis-stimulation. We found that ICOS expression significantly correlated with IFN-gamma production by tuberculosis patients. ICOS expression levels were regulated in HR patients by Th cytokines: Th1 cytokines increased ICOS levels, whereas Th2-polarizing conditions down-regulated ICOS in these individuals. Besides, in human polarized Th cells, engagement of ICOS increased M. tuberculosis IFN-gamma production with a magnitude proportional to ICOS levels on those cells. Moreover...
International Journal of Tuberculosis and Lung Disease, 1999
CADRE : Tuberculose a germes multiresistants chez des patients seronegatifs pour le virus de l... more CADRE : Tuberculose a germes multiresistants chez des patients seronegatifs pour le virus de l'immunodeficience humaine (VIH) et porteurs de Mycobacterium tuberculosis resistant a presque tous les medicaments disponibles. OBJECTIF : Essai limite de phase Il au moyen d'interferon-α2b recombinant chez 5 patients atteints d'une tuberculose incurable, chronique, a germes multiresistants. METHODES: Administration sous-cutanee hebdomadaire pendant 12 semaines de 3 000 000 unites de r-IFN-α2b. Examen clinique et radiologique avant et apres traitement, ainsi que pendant un suivi de 30 mois en association avec des tests de laboratoire en matiere bacteriologique, immunologique et de routine. RESULTATS: Chez deux des cinq patients, la bacilloscopie et la culture sont devenues negatives a long terme, apres le traitement a base de r-IFN-α2b. Chez un des patients, on a note une amelioration clinique et une bacilloscopie negative apres traitement, mais la culture est restee positive. C...
Tuberculosis is a worldwide prevalent disease. The emergence of multidrug-resistant strains spurr... more Tuberculosis is a worldwide prevalent disease. The emergence of multidrug-resistant strains spurred the search for new drugs. There are several tuberculosis treatment guidelines, international and local in a programmatic approach. An Argentinean specialists panel draw practical guidelines based in clinical criteria and the local and international bibliography through consensus meetings, including issues as: antituberculosis drugs available in Argentina, initial and re-treatement modalities, special situations treatment, adverse reactions to antituberculosis drugs, current indications of surgical treatment and new drugs under study for the treatment of the disease.
Updated Argentine Consensus on chronic obstructive pulmonary disease. Due to the increase in morb... more Updated Argentine Consensus on chronic obstructive pulmonary disease. Due to the increase in morbidity and mortality from Chronic Obstructive Pulmonary Disease (COPD), a group of chest physicians updates the basic knowledge on COPD since the last Consensus in 1994 in order to prepare guidelines for its diagnosis, prevention and treatment. The authors review the definition of COPD together with the most recent information on its pathophysiology. The clinical presentation is summarized together with functional evaluation and imaging. Early diagnosis by means of functional testing (i.e., spirometry) is stressed, emphasizing smoking cessation as the only measure that has been shown to alter the outcome of the disease. Smoking cessation strategies are described as well as pharmacological and non-pharmacological treatment. In the pharmacological section, the use of inhaled bronchodilators (anticholinergic, beta 2 adrenergic agonists or both) is considered the first option for treatment. L...
Material and Methods: The INLASA-BOLIVA begun in 1988 a study of HIV infection associated with Tu... more Material and Methods: The INLASA-BOLIVA begun in 1988 a study of HIV infection associated with Tuberculosis and the implementation a serologic level, habits, Sexual Transmited Diseases, adiction of alcohol and drugs, Mantoux test, X-rays, smear and culture in Lowestein Jennsen medium. This protocol were distributed by seminars in Bolivia and now is a special survey of the AIDS program. Results: In regards that in Bolivia have a real register of AIDS cases, at present 102 (AIDS = 62 and HIV = 40), that 62 AIDS cases were death 53 (88%), 16 patients (30 %) had a clinical and radiologic diagnostic of tuberculosis, in only 8 patients had the bacteriologic studies by smears 5 (62,.5 %) and 3 (37.5 %) by culture, the seropositive patients (21) are with HIV chemoprophylaxis for 6 months (PAHDW.H.0. recomendations) Conclusion: For the prevention measure of the serious problems for the health of the community, it's necessary to continue this activites for the search the tuberculosis and HIV infection.
Due to the increase in morbidity and mortality from Chronic Obstructive Pulmonary Disease (COPD),... more Due to the increase in morbidity and mortality from Chronic Obstructive Pulmonary Disease (COPD), a group of chest physicians updates the basic knowledge on COPD since the last Consensus in 1994 in order to prepare guidelines for its diagnosis, prevention and treatment. The authors review the definition of COPD together with the most recent information on its pathophysiology. The clinical presentation is summarized together with functional evaluation and imaging. Early diagnosis by means of functional testing (i.e., spirometry) is stressed, emphasizing smoking cessation as the only measure that has been shown to alter the outcome of the disease. Smoking cessation strategies are described as well as pharmacological and non-pharmacological treatment. In the pharmacological section, the use of inhaled bronchodilators (anticholinergic, beta 2 adrenergic agonists or both) is considered the first option for treatment. Long acting bronchodilators improve patient compliance and treatment effectiveness. Inhaled corticosteroids are indicated for patients with severe airways obstruction and known response to corticosteroids. These agents can diminish the number of exacerbations. Annual influenza vaccination is recommended in all patients. In the non-pharmacological section, surgery for emphysema is suggested in particular cases. Rehabilitation, including exercise training, kinesitherapy and nutrition, is a useful tool for patients who are physically disabled. Long-term oxygen therapy at home improves survival in patients with severe chronic hypoxemia. Other therapeutic interventions such as non-invasive home ventilation have specific indications. Acute exacerbations must be aggressively treated with oxygen, corticosteroids, antibiotics, combination of bronchodilators, and eventually respiratory support. The role of public education of the patients and their families is essential in the prevention and treatment of the disease.
The International Journal of Tuberculosis and Lung Disease the Official Journal of the International Union Against Tuberculosis and Lung Disease, Sep 1, 2009
SETTINGHost defense factors may influence the development of active tuberculosis (TB).OBJECTIVETo... more SETTINGHost defense factors may influence the development of active tuberculosis (TB).OBJECTIVETo test variants in solute carrier family 11A, member 1 (SLC11A1), for an association with TB.METHODSA mixed case-control study of TB cases, relatives or close contact controls, consisting of 474 African-Americans (243 families) and 381 Caucasians (192 families), examined 13 SLC11A1 polymorphisms for association with pulmonary TB using generalized estimating equations adjusting for age and gender.RESULTSTwo associations were observed in Caucasians (rs3731863, P = 0.03, and rs17221959, P = 0.04) and one in African-Americans (rs3731865, P = 0.05). Multilocus analyses between polymorphisms in SLC11A1 and 11 TB candidate genes detected interactions between SLC11A1 and inducible nitric oxide synthase (NOS2A) in Caucasians (rs3731863 [SLC11A1] × rs8073782 [NOS2A], P = 0.009; rs3731863 [SLC11A1] × rs17722851 [NOS2A], P = 0.007) and toll-like receptor 2 (TLR2) in African-Americans (rs3731865 [SLC11A1] x rs1816702, P = 0.005).CONCLUSIONSNo association was detected with 5′(GT)n promoter polymorphism previously associated with lower SLC11A1 expression, rs17235409 (D543N), or rs17235416 (3′ TGTG insertion/deletion polymorphism). SLC11A1 polymorphism rs3731865 was associated with TB in African-Americans, consistent with previous findings in West Africans. These results suggest that variants in SLC11A1 increase susceptibility to pulmonary TB and interact with other variants that differ by race.
The International Journal of Tuberculosis and Lung Disease
Multidrug-resistant tuberculosis patients without human immunodeficiency virus (HIV) infection, w... more Multidrug-resistant tuberculosis patients without human immunodeficiency virus (HIV) infection, with Mycobacterium tuberculosis resistant to almost all of the available drugs. Limited phase II trial with recombinant interferon-alpha2b in five chronic multidrug-resistant tuberculosis patients. Three million units of r-IFN-alpha2b were administered subcutaneously every week for 12 weeks. Before and after treatment, and during a 30-month follow-up period, the patients underwent clinical and radiological examination, together with bacteriological, immunological and routine laboratory testing. Two of the five patients became long-term sputum smear and culture negative after r-IFN-alpha2b therapy; one of the patients showed clinical improvement and negative smear after therapy, but remained culture positive. The other two patients showed no response. The results of this trial suggest that r-IFN-alpha2b should be evaluated further in multidrug-resistant tuberculosis in prospective controll...
The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease, 2009
Host defense factors may influence the development of active tuberculosis (TB). To test variants ... more Host defense factors may influence the development of active tuberculosis (TB). To test variants in solute carrier family 11A, member 1 (SLC11A1), for an association with TB. A mixed case-control study of TB cases, relatives or close contact controls, consisting of 474 African-Americans (243 families) and 381 Caucasians (192 families), examined 13 SLC11A1 polymorphisms for association with pulmonary TB using generalized estimating equations adjusting for age and sex. Two associations were observed in Caucasians (rs3731863, P = 0.03, and rs17221959, P = 0.04) and one in African-Americans (rs3731865, P = 0.05). Multilocus analyses between polymorphisms in SLC11A1 and 11 TB candidate genes detected interactions between SLC11A1 and inducible nitric oxide synthase (NOS2A) in Caucasians (rs3731863 [SLC11A1] x rs8073782 [NOS2A], P = 0.009; rs3731863 [SLC11A1] x rs17722851 [NOS2A], P = 0.007) and toll-like receptor 2 (TLR2) in African-Americans (rs3731865 [SLC11A1] x rs1816702, P = 0.005). ...
Your browser version may not work well with NCBI's web applications. More information here..... more Your browser version may not work well with NCBI's web applications. More information here... ...
Protective immunity against Mycobacterium tuberculosis requires the generation of cell-mediated i... more Protective immunity against Mycobacterium tuberculosis requires the generation of cell-mediated immunity. We investigated the expression and role of programmed death 1 (PD-1) and its ligands, molecules known to modulate T cell activation, in the regulation of IFN-␥ production and lytic degranulation during human tuberculosis. We demonstrated that specific Agstimulation increased CD3 ؉ PD-1 ؉ lymphocytes in peripheral blood and pleural fluid from tuberculosis patients in direct correlation with IFN-␥ production from these individuals. Moreover, M. tuberculosis-induced IFN-␥ participated in the up-regulation of PD-1 expression. Blockage of PD-1 or PD-1 and its ligands (PD-Ls: PD-L1, PD-L2) enhanced the specific degranulation of CD8 ؉ T cells and the percentage of specific IFN-␥-producing lymphocytes against the pathogen, demonstrating that the PD-1:PD-Ls pathway inhibits T cell effector functions during active M. tuberculosis infection. Furthermore, the simultaneous blockage of the inhibitory receptor PD-1 together with the activation of the costimulatory protein signaling lymphocytic activation molecule led to the promotion of protective IFN-␥ responses to M. tuberculosis, even in patients with weak cell-mediated immunity against the bacteria. Together, we demonstrated that PD-1 interferes with T cell effector functions against M. tuberculosis, suggesting that PD-1 has a key regulatory role during the immune response of the host to the pathogen.
We examined whether polymorphisms in interleukin-12B (IL12B) associate with susceptibility to pul... more We examined whether polymorphisms in interleukin-12B (IL12B) associate with susceptibility to pulmonary tuberculosis (PTB) in two West African populations (from The Gambia and Guinea-Bissau) and in two independent populations from North and South America. Nine polymorphisms (seven SNPs, one insertion/deletion, one microsatellite) were analyzed in 321 PTB cases and 346 controls from Guinea-Bissau and 280 PTB cases and 286 controls from The Gambia. For replication we studied 281 case and 179 control African-American samples and 221 cases and 144 controls of European ancestry from the US and Argentina. First-stage single locus analyses revealed signals of association at IL12B 39 UTR SNP rs3212227 (unadjusted allelic p = 0.04; additive genotypic p = 0.05, OR = 0.78, 95% CI [0.61-0.99]) in Guinea-Bissau and rs11574790 (unadjusted allelic p = 0.05; additive genotypic p = 0.05, OR = 0.76, 95% CI [0.58-1.00]) in The Gambia. Association of rs3212227 was then replicated in African-Americans (rs3212227 allelic p = 0.002; additive genotypic p = 0.05, OR = 0.78, 95% CI [0.61-1.00]); most importantly, in the African-American cohort, multiple significant signals of association (seven of the nine polymorphisms tested) were detected throughout the gene. These data suggest that genetic variation in IL12B, a highly relevant candidate gene, is a risk factor for PTB in populations of African ancestry, although further studies will be required to confirm this association and identify the precise mechanism underlying it. Citation: Morris GAJ, Edwards DRV, Hill PC, Wejse C, Bisseye C, et al. (2011) Interleukin 12B (IL12B) Genetic Variation and Pulmonary Tuberculosis: A Study of
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Papers by Eduardo Abbate