Proteínas de checkpoint imunológico como novo alvo da imunoterapia contra o câncer: revisão da literatura / Immune checkpoint proteins as new target for cancer immunotherapy: literature review

Uma nova era no tratamento do câncer está surgindo com o uso de anticorpos capazes de inibir pontos de bloqueio do sistema imunológico, chamados de "inibidores de checkpoint". Um novo conceito de "balas mágicas", que no início do século passado foram imaginadas por Paul Ehrlich como capazes de atuar diretamente na destruição de alvos tumorais, é representado agora por anticorpos direcionadas contra moléculas que bloqueiam a atividade antitumoral do sistema imunológico, como o antígeno-4 de linfócito T citotóxico (CTLA-4) e a proteína-1 de morte celular programada (PD-1). Essas novas imunoterapias vêm revolucionando a forma de tratar diferentes tipos de câncer. Nesta revisão selecionamos estudos sobre CTLA-4 e PD-1, seus ligantes em células apresentadoras de antígenos, assim como destacamos a importância da descoberta de antígenos tumorais e o papel do sistema imunológico na imunovigilância tumoral. Nesse estudo são discutidos aspectos relacionados aos efeitos de imunoterapias baseadas no uso de anticorpos monoclonais anti-CTLA-4 e anti-PD-1/ PD-L1, como o risco de serem estimuladas respostas direcionadas a tecidos saudáveis e outros efeitos adversos, bem como o uso de terapias combinadas que podem contribuir para melhorar a eficiência do tratamento do câncer.

A new era in cancer treatment is emerging with the use of antibodies directed against immune checkpoint proteins, known as "checkpoint inhibitors". A novel concept of "magic bullets", concepted by Paul Ehrlich at the beginning of the last century, as being capable of acting directly on the destruction of tumor targets, is now represented by antibodies directed against molecules which block the antitumor activity of the immune system, such as Cytotoxic T Lymphocyte Antigen-4 (CTLA-4) and Programmed Cell Death Protein-1 (PD-1). These new immunotherapies have revolutionized the treatment of different cancer types. Studies on CTLA-4, PD-1, and their ligands in antigen presenting cells are discussed in this review. The importance of tumor antigen discovery and the role of the immune system in immune surveillance of tumors were highlighted. Also in the present study, aspects related to the effects of immunotherapies based on the use of anti-CTLA-4 and anti-PD-1/ PD-L1 monoclonal antibodies are described, such as the risk of stimulating responses to normal tissues and other adverse effects, as well as the use of combination therapies which can improve the efficacy of cancer treatment.

Efeitos contrastantes da vitamina D sobre a resposta imune inata e adquirida e seu impacto na recuperação da tuberculose / Contrasting effects of Vitamin D on innate and acquired immune responses and its impact on tuberculosis recover

A vitamina D é um hormônio essencial para o organismo, podendo ser obtida da dieta ou, principalmente, gerada pela pele após exposição à luz solar ultravioleta B. Na sua forma ativa (1,25(oH)2D) ela controla a absorção de cálcio e fósforo do intestino para a corrente sanguínea e participa de diversos processos celulares e fisiológicos. A ligação da 1,25(oH)2D ao receptor da vitamina D (VDr) presente em diversas células, como as células do sistema imunológico, induz a transcrição de genes que podem, por exemplo, modular a resposta imune inata e adquirida. A deficiência de vitamina D ou do VDR é associada a problemas de saúde como desordens esqueléticas, hipertensão, doenças cardiovasculares, diabetes mellitus, dislipidemias, doenças autoimunes e doenças infecciosas. Neste sentido, a suplementação com vitamina D tem sido proposta como uma possível medida preventiva, podendo ser aplicada em muitas patologias, em especial na tuberculose. Principal causa de morte por um único agente infeccioso, a tuberculose é responsável por cerca de 1,3 milhões de óbitos por ano no mundo. Publicações recentes apontam efeitos diversos da vitamina D na resposta imune inata e adquirida. A 1,25(oH)2D3 na presença do interferon (IFN)-γ é capaz de aumentar a atividade bactericida do macrófago contra o M. tuberculosis, aumentando a produção de peptídios antimicrobianos e estimulando a autofagia, favorecendo assim a lise de bacilos localizados em fagossomos. Por outro lado, a vitamina D em linfócitos T mostra efeito tolerogênico que favorece o controle de respostas inflamatórias excessivas. Neste trabalho de revisão são apresentados estudos recentes envolvendo efeitos da vitamina D na resposta imune inata e adquirida. Além disso, considerações sobre deficiência de vitamina D e maior risco de contrair tuberculose, e efeitos contrastantes da suplementação com vitamina D na prevenção e tratamento da TB, são discutidos.

Vitamin D is an essential hormone for the body, and can be obtained from diet or, mainly, generated by the skin after exposure to ultraviolet B sunlight. In its active form (1.25(oH)2D) it controls the absorption of calcium and phosphorus from the intestine into the bloodstream and participates in several cellular and physiological processes. Binding of 1,25(oH)2D to the Vitamin D receptor (VDr) present in several cells, such as cells of the immune system, induces transcription of genes that can, for example, modulate the innate and adaptive immune response. Deficiency of Vitamin D or VDr is associated with health problems such as skeletal disorders, hypertension, cardiovascular disease, diabetes mellitus, dyslipidemias, autoimmune diseases and infectious diseases. In this sense, Vitamin D supplementation has been proposed as a possible preventive measure and can be applied in several pathologies, especially in tuberculosis. main cause of death by a single infectious agent, tuberculosis accounts for about 1.3 million deaths per year worldwide. recent publications point to contrasting functions of Vitamin D in the innate and acquired immune response. 1.25(oH)2D3 in the presence of interferon (IFN)-γ is capable of increasing the bactericidal activity of the macrophage against M. tuberculosis, increasing the production of antimicrobial peptides and stimulating autophagy, thus favoring the lysis of bacilli located in phagosomes. on the other hand, Vitamin D in T lymphocytes shows a tolerogenic effect that favors the control of excessive inflammatory responses. In this review, recent studies involving Vitamin D effects on the innate and acquired immune responses are presented. In addition, considerations about Vitamin D deficiency and increased risk of contracting tuberculosis, and contrasting effects of Vitamin D supplementation on the prevention and treatment of TB, are discussed.

Testes sorológicos anti-NDO-HSA, anti-LID-1 e anti-NDO-LID em contatos domiciliares de área não endêmica de hanseníase / Anti-NDO-HSA, anti-LID-1 and anti-NDO-LID serological tests in household contacts of a non-endemic leprosy area

Introdução: Diversos fatores podem interferir no desenvolvimento da hanseníase, entre eles fatores genéticos, convívio com o caso de hanseníase e classificação operacional do caso. Testes sorológicos que avaliam a reatividade de anticorpos IgM e IgG frente a antígenos específicos para o Mycobacterium leprae (M. leprae) podem atuar como auxiliares na vigilância dos contatos e/ou população de risco. Objetivo: Analisar o comportamento dos testes sorológicos anti-PGL-1 sintético (NDO-HSA), anti-LID-1 e anti-NDO-LID em área não endêmica de hanseníase e sua relação com características do caso de hanseníase. Material e métodos: Trata-se de um estudo transversal, do tipo analítico, realizado com 35 contatos domiciliares (CD) dos casos de hanseníase. A coleta de dados ocorreu no período de agosto/2016 a fevereiro/2017 por meio de visitas domiciliares. A reatividade de anticorpos IgM e IgG frente aos antígenos Natural disaccharide linked to human serum albumin via octyl (NDO-HSA), Leprosy IDRI diagnostic 1 (LID-1) e Natural disaccharideoctyl - Leprosy IDRI Diagnostic 1(NDO-LID) foi avaliada por ensaio imunoenzimático (ELISA). Os dados foram exportados e analisados no software StatisticalPackage for the Social Sciences (SPSS®) 24 for Windows. Resultados: Foi observada maior proporção de positividade aos testes em CD de casos multibacilares (MB), que residiam com o caso de hanseníase na época do diagnóstico e que tinham parentesco consanguíneo com o caso. Esses casos de hanseníase MB também apresentaram soropositividade frente aos antígenos testados. O valor do índice ELISA foi maior no grupo de CD de casos MB. Houve concordância moderada e significativa (K= 0,53; p< 0,0001) entre os testes anti-NDO-HSA e anti-NDO-LID, mas não foi detectada diferença entre os testes anti-NDO-HSA e anti-LID-1 (K= -0,05; p= 0,678). A correlação foi positiva entre os três antígenos, porém, entre LID-1 e NDO-HSA, não houve significância estatística (p<0,186). Conclusão: Os resultados sugerem que testes sorológicos em conjunto com as características avaliadas nos contatos domiciliares em área não endêmica de hanseníase,podem atuar como auxiliares na detecção de indivíduos infectados pelo M. leprae, contribuindo para vigilância dos contatos domiciliares

Introduction: Several factors may interfere in the development of leprosy, including genetic factors, conviviality with leprosy patients and operational classification of the case. Serological tests performed to evaluate the reactivity of IgM and IgG antibodies response against Mycobacterium leprae (M. leprae) specific antigens may be used as auxiliary tools for transmission surveillance and/or population at risk. Objective: To analyze the performance of anti-PGL-1 (NDO-HSA), anti-LID-1 and anti-NDO-LID serological tests in non-endemic area of leprosy and the relationship with characteristics of the leprosy case. Material and methods: This is a cross-sectional analytical study of 35 household contacts (HC) of leprosy cases. Data collection was carried out from August 2016 to February 2017 with home visits. The reactivity of IgM and IgG antibodies to Natural disaccharide linked to human serum albumin via octyl (NDO-HSA), Leprosy IDRI diagnostic 1 (LID-1) and Natural disaccharide octyl - Leprosy IDRI Diagnostic 1 (NDO-LID) was evaluated through enzyme-linked immunosorbent assay (ELISA). Data were exported and analyzed using Statistical Package for Social Sciences (SPSS®) 24 for Windows. Results: A higher proportion of positivity was observed in the HC tests of multibacillary (MB) leprosy cases who lived in the same dwelling with a leprosy case at the time of diagnosis and had a degree of kinship with the case. These multibacillary leprosy cases also showed seropositivity to the antigens tests. ELISA test index value was higher in the HC group of MB leprosy cases. There was moderate agreement (K = 0.53, p <0.0001) between anti-NDO-HSA and anti-NDO-LID tests, but no difference was found between anti-NDO-HSA and anti-LID -1 (K = -0.05, p = 0.678). Three antigens were positively correlated, but there was no statistical significance (p <0.186) between LID-1 and NDO-HSA. Conclusion: The results suggest that serological tests in combination with the characteristics assessed during household contacts in a non-endemic area may represent efficient auxiliary tools for the detection of M. leprae-infected individuals, providing a contribution to the surveillance of household contacts

Utility of immunoglobulin isotypes against LID-1 and NDO-LID for, particularly IgG1, confirming the diagnosis of multibacillary leprosy

BACKGROUND Leprosy remains a health problem in many countries, with difficulties in diagnosis resulting in delayed treatment and more severe disabilities. Antibodies against several Mycobacterium leprae antigens have, however, shown value as diagnostic and/or prognostic markers. OBJECTIVES The objective of this study was to evaluate serum immunoglobulin (Ig) IgM and IgG subclass reactivity against three M. leprae specific antigens: NDO-HSA, a conjugate formed by natural octyl disaccharide bound to human serum albumin; LID-1, the fusion protein product of the ml0405 and ml2331 genes; and NDO-LID, a combination of LID-1 and NDO. METHODS Sera from healthy controls, paucibacillary (PB) and multibacillary (MB) leprosy patients, and their respective household contacts, were evaluated for the presence of antigen-specific IgM, IgG, and IgG subclass antibodies by enzyme-linked immunosorbent assay (ELISA). The sensitivity and specificity of each ELISA were evaluated by receiver operating characteristic (ROC) curve analysis. FINDINGS Our data confirm that serum IgM antibodies against NDO-HSA and IgG antibodies against LID-1, as well as IgG/M antibodies against NDO-LID, are markedly increased in MB patients. For the first time, our data reveal a selective increase in IgG1 and IgG3 antibodies against LID-1 and NDO-LID in MB patients, demonstrating that these antibody isotypes are suitable for differentiation between MB and PB patients. ROC curve analysis indicates an improved capacity for diagnosing MB leprosy patients using the detection of IgG antibodies, particularly the IgG1 isotype, specific to LID-1 and NDO-LID over the performance levels attained with NDO-HSA. CONCLUSIONS Our findings indicate that serological tests based on the detection of antigen-specific IgG1 antibodies are a useful tool to differentiate MB from PB patients, and indicate the enhanced performance of the LID-1 and NDO-LID antigens in the serodiagnosis of leprosy.

Challenging Mycobacterium tuberculosi s dormancy mechanisms and their immunodiagnostic potential

ABSTRACT Mycobacterium tuberculosis is the etiologic agent of tuberculosis, one of the world's greatest cause of morbidity and mortality due to infectious disease. Many evolutionary mechanisms have contributed to its high level of adaptation as a host pathogen. Prior to become dormant, a group of about 50 genes related to metabolic changes are transcribed by the DosR regulon, one of the most complex and important systems of host-pathogen interaction. This genetic mechanism allows the mycobacteria to persist during long time periods, establishing the so-called latent infection. Even in the presence of a competent immune response, the host cannot eliminate the pathogen, only managing to keep it surrounded by an unfavorable microenvironment for its growth. However, conditions such as immunosuppression may reestablish optimal conditions for bacterial growth, culminating in the onset of active disease. The interactions between the pathogen and its host are still not completely elucidated. Nonetheless, many studies are being carried out in order to clarify this complex relationship, thus creating new possibilities for patient approach and laboratory screening.

Lower production of IL-17A and increased susceptibility to Mycobacterium bovis in mice coinfected with Strongyloides venezuelensis

The presence of intestinal helminths can down-regulate the immune response required to control mycobacterial infection. BALB/c mice infected with Mycobacterium bovis following an infection with the intestinal helminth Strongyloides venezuelensis showed reduced interleukin-17A production by lung cells and increased bacterial burden. Also, small granulomas and a high accumulation of cells expressing the inhibitory molecule CTLA-4 were observed in the lung. These data suggest that intestinal helminth infection could have a detrimental effect on the control of tuberculosis (TB) and render coinfected individuals more susceptible to the development of TB.

Effect of a change in treatment time on leprosy epidemiology in Juiz de Fora, Brazil

The impact of the reduction of treatment time for leprosy in Juiz de Fora, Brazil, from 1996 to 2004, was evaluated by examining 324 patients records. Although the time of treatment for multibacillary patients changed from 24 to 12 months, the prevalence of leprosy remained stable (~3 patients/10000 inhabitants). The incidence rate varied from 5.5 in period I (1996-1999) to 4.8 in period II (2000-2004). In both periods the multibacillary forms predominated, there being a slight reduction in cure rate (83 % to 79 %) and an increase in abandonment (6% to 11%). Interestingly, leprosy was more frequent in men in period I (62.2%), and itpredominated in women in period II (55.6%), when the detection of new cases from health counseling was greater. The change in the time of treatment did not significantly alter the prevalence or incidence of leprosywhich did, however, show new characteristics in the city.

Anti-mycobacterial treatment reduces high plasma levels of CXC-chemokines detected in active tuberculosis by cytometric bead array

Chemokines recruit and activate leukocytes, assisting granuloma formation. Herein, we evaluated plasma chemokines in patients with active tuberculosis (ATB) and after completing treatment (TTB) and compared them to BCG-vaccinated healthy controls (HC). Levels of chemokines were measured by cytometric bead array. Levels of CXCL8, CXCL9 and CXCL10 were higher in ATB patients compared to HC, but they decreased in TTB. Levels of CCL2 and CCL5 in ATB patients were similar to those observed in HC. Thus, the high levels of CXC-chemokines detected during ATB, which can modulate the trafficking of immune cells from the periphery to the site of infection, were reversed by anti-mycobacterial treatment.

Human serum antibody reactivity towards Paracoccidioides brasiliensis antigens treated with sodium metaperiodate / Reatividade de anticorpos de soros humanos a antígenos de Paracoccidioides brasiliensis tratados com metaperiodato sódico

In this study, we evaluated the profile of anti-Paracoccidioides brasiliensis immunoglobulin isotypes in serum from patients with the acute and chronic forms of paracoccidioidomycosis, using the whole Paracoccidioides brasiliensis antigen and the antigen treated with sodium metaperiodate. All the immunoglobulin isotypes present in the serum from patients with the acute and chronic forms of paracoccidioidomycosis presented higher reactivity towards the whole antigen than to the antigen treated with metaperiodate (P < 0.05). The reactivity of IgG and IgM to the antigen treated with metaperiodate was greater in serum from patients with the acute form of the disease (P < 0.05), while IgA was more reactive in serum from patients with the chronic form (P < 0.05). There was greater reactivity of IgG1 and IgG2 to the whole antigen and the antigen treated with metaperiodate in the serum from patients with paracoccidioidomycosis than there was in serum from patients with other parasitic infections (P < 0.05). Furthermore, IgG1 from patients with the acute form recognized the 19kDa, 27kDa and 31kDa antigens in the western blot test. Thus, the results suggest that modifications to the epitopes of Paracoccidioides brasiliensis antigens may help to improve the immunodiagnosis of paracoccidioidomycosis.

Neste trabalho, foi avaliado o perfil de isotipos de imunoglobulinas anti-Paracoccidioides brasiliensis em soros de pacientes com formas crônica e aguda de paracoccidiodomicoses usando antígeno total e tratado com meta-periodato. Todos os tipos de imunoglobulinas presentes nos soros de pacientes com formas aguda e crônica apresentaram alta reatividade ao antígeno total quando comparado ao tratado com meta-periodato (P < 0,05). Houve maior reatividade de IgG e IgM anti-antígeno tratado com meta-periodato em soros de pacientes com forma aguda da doença (P < 0,05), enquanto IgA foi mais reativa em soros da forma crônica (P < 0,05). Houve maior reatividade de IgG1 e IgG2 com antígeno total e tratado com meta-periodato em soros de pacientes comparados aos com outras parasitoses (P < 0,05). Além disso, IgG1 de pacientes com a forma aguda reconhecem antígenos de 19kDa, 27kDa e 31kDa por western blot. Assim, os resultados sugerem que alterações nos epitopos de antígenos de Paracoccidioides brasiliensis podem auxiliar no aprimoramento do imunodiagnóstico da paracoccidioidomicose.

Avaliação do uso da hidroxicloroquina no tratamento da osteoartrite sintomática de joelhos / Assessment of the use of hydroxychloroquine on knees' osteoarthritis treatment

OBJETIVO: Avaliar o efeito da hidroxicloroquina (HCQ) no tratamento da osteoartrite (OA) sintomática de joelhos. MÉTODOS: Dois grupos de pacientes com diagnóstico de OA sintomática de joelhos foram avaliados em estudo randomizado, controlado por placebo e duplo-cego, o primeiro constituído de 16 pacientes submetidos à terapêutica com HCQ, na dosagem de 400 mg/dia, durante quatro meses e o outro grupo constituído de 13 pacientes recebeu placebo por igual período. Ambos os grupos foram avaliados utilizando o Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), o índice algofuncional de Lequesne e a escala visual analógica (EVA). RESULTADOS: Não houve diferença entre os grupos nas subescalas do WOMAC em relação à dor (Wdor), p = 0,551, rigidez (Wrig), p = 0,512, e função (Wfunção), p = 0,293. Nas escalas EVA e Lequesne também não houve diferença estatisticamente significante com p = 0,461 e p = 0,803, respectivamente. CONCLUSÃO: Embora os dois grupos tenham apresentado melhora, não houve superioridade no tratamento da OA de joelhos no grupo submetido ao uso de HCQ em relação ao grupo placebo neste estudo.

OBJECTIVE: To assess the effectiveness of hydroxychloroquine (HCQ) on knee osteoarthritis (OA). METHODS: Two groups of patients with OA diagnosis have been assessed in a controlled, randomic, double-blind study, the first group consisted of 16 patients who received the therapeutics with HCQ, with the dosage of 400 milligrams per day during four months and the other one consisted of 13 patients who received the placebo during the same period of time. Both groups were assessed using the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), Lequèsne Algofunctional Index and the Visual Analogue Scale (VAS). RESULTS: There was not any difference between the groups on the WOMAC subscales in relation to the pain (p=0,551), stiffness (p=0.512) and function (p=0.293). On the VAS and Lequèsne scale, there was not any difference statistically significant with p=0.461 and p=0.803 respectively. CONCLUSION: Although both groups have presented improvement, there was not superiority on the knees' OA treatment in the group which underwent HCQ use in relation to the placebo group in this study.

Influência do baço, da asplenia e do implante esplênico autógeno no metabolismo lipídico de camundongos / Influence of the spleen, asplenism and autologous splenic implants on lipid metabolism in mice

OBJETIVO: Estudar a influência do baço, da asplenia e do implante esplênico autógeno no metabolismo lipídico, por meio da avaliação do lipidograma sérico de camundongos e da verificação do efeito do transplante autógeno de baço em diferentes locais do abdome. MÉTODO: Foram utilizados camundongos BALB/c distribuídos em sete grupos de 10 animais: controle normal (CN); controle obeso (CO); operação simulada (OS); esplenectomia total (ET); três grupos submetidos ao transplante autógeno do baço: omento maior (OM), retroperitônio (RP), tecido subcutâneo da parede abdominal (PA). Os animais, com exceção do grupo CN, foram submetidos a dieta com 1,25 por cento de colesterol. A intervenção cirúrgica foi realizada 30 dias após o início da dieta. A coleta de sangue ocorreu no 60° dia pós-operatório. Foram dosados os níveis de triglicérides, de colesterol total e de suas frações, bem como a glicemia. O baço, os implantes esplênicos e o fígado foram submetidos a estudo histológico. RESULTADOS: A dieta aumentou os níveis plasmáticos de colesterol total, HDL e LDL dos camundongos (p < 0,05 versus CN). Entre os animais em uso da dieta, não houve diferença no lipidograma dos grupos controles (CO e OS) quando comparados ao grupo esplenectomizado (ET), assim como em relação aos animais submetidos ao transplante autógeno do baço (OM, RP, PA). A capacidade de preservação da arquitetura histológica esplênica foi semelhante nos três locais de implante. Todos os animais que utilizaram a dieta enriquecida apresentaram esteatose hepática. CONCLUSÃO: De acordo com os resultados obtidos o baço não parece participar da regulação dos níveis de lipídeos plasmáticos em camundongos BALB/c.

BACKGROUND: This work evaluated the influence of the spleen and splenic remnants on lipid metabolism, by evaluating the impact of splenectomy on the lipidogram of mice and by studying the effect of autogenous spleen tissue implanted in different sites. METHODS: 70 BALB/c mice were divided into seven groups of 10 animals: normal control group, with no diet or surgery; fat control group, without surgery; surgical procedure sham group; total splenectomy group and three groups with implants in different sites: greater omentum, retroperitonium and abdominal subcutaneous tissue. The animals, except the normal control group, received food with 1.25 percent cholesterol. The surgical procedure was carried out 30 days after the beginning of the food administration. Two months after the operations, serum triglycerides, cholesterol and glycemia were studied. Histological assessments of the spleen or implants and the liver were carried out. RESULTS: The enriched food increased the plasmatic levels of total cholesterol, HDL, and mainly LDL of the mice (p<0.05). No significant difference was found in the lipidograms of the animals of the control groups when compared with the splenectomized ones, as well as in the animals submitted to the autogenous splenic tissue transplantation. The preservation of the splenic histological architecture was similar on the three implantation sites. All the animals receiving enriched food presented liver steatosis. CONCLUSION: The spleen, splenectomy and splenic implants do not influence lipidogram in BALB/c mice.

Diagnóstico imunológico da tuberculose: problemas e estratégias para o sucesso / Immunological diagnosis of tuberculosis: problems and strategies for success

A tuberculose continua sendo um grave problema social e de saúde, afetando milhões de pessoas anualmente. A vacina Bacille Calmette-Guerin (BCG), usada no controle profilático, é incapaz de conter a progressão da doença, que usualmente se manifesta através da queda da imunidade celular do indivíduo. O diagnóstico da tuberculose em seus estágios iniciais, aliado à poliquimioterapia, pode contribuir para o controle da disseminação da infecção. Os atuais métodos de diagnóstico apresentam problemas, como: baixa sensibilidade da baciloscopia; longo tempo de realização das culturas microbiológicas; e baixa especificidade do teste cutâneo com o derivado protéico purificado do M. tuberculosis. Novos métodos de diagnóstico que utilizam antígenos específicos (por exemplo, os conhecidos em inglês como o early secreted antigenic target 6-kDa e o culture filtrate protein 10-kDa), estão sendo testados. Os genes que codificam esses antígenos estão localizados na região de diferença 1 do M. tuberculosis, M. africanum e M. bovis, mas estão ausentes no M. bovis (BCG) e na maioria das micobactérias do meio ambiente. Métodos de diagnóstico baseados na produção de interferon-gama por linfócitos T, em resposta a esses antígenos, como o QuantiFERON-TB® e o T SPOT.TB®, estão sendo testados, e superam o teste cutâneo com o derivado protéico purificado nas seguintes características: maior sensibilidade; menor reatividade cruzada devido à vacinação com o BCG ou infecção por micobactérias do meio ambiente; e tempo de execução. A introdução de métodos de diagnóstico mais específicos e sensíveis, assim como um maior entendimento dos mecanismos moleculares e celulares que regulam a interação parasito-hospedeiro, pode contribuir para um eficiente combate à tuberculose.

Tuberculosis remains a serious social and public health problem, affecting millions of people annually. The bacille Calmette-Guerin (BCG) vaccine, used prophylactically, does not impede the progression of the disease, which usually manifests as decreased cellular immunity. Early diagnosis, together with polychemotherapy, can control the dissemination of the tuberculosis infection. The current diagnostic methods present certain problems. Such problems include the low sensitivity of sputum smear microscopy, the fact that performing microbiological cultures is quite time-consuming, and the low specificity of the skin test with the purified protein derivative of M. tuberculosis. New diagnostic methods, which use specific antigens such as the early secreted antigenic target 6-kDa and culture filtrate protein 10kDa, are being evaluated. The genes that encode these antigens are located in the DNA region of difference 1 of M. tuberculosis, M. africanum and M. bovis. However, they are absent from the M. bovis (BCG) and from most environmental mycobacteria. Diagnostic methods such as QuantiFERON-TB® and T SPOT.TB®, which are based on the production of interferon-gamma by T lymphocytes, in response to those antigens, are being tested and have been found to outstrip the purified protein derivative skin test in the following characteristics: greater sensitivity; lower cross-reactivity due to BCG vaccination or infection with environmental mycobacteria; and execution time. The introduction of diagnostic methods that are more specific and sensitive, together with gaining a better understanding of the molecular and cellular mechanisms that regulate the parasite-host interaction, can increase the efficiency of strategies devised to combat tuberculosis.