Novos aspectos da patogenia da tuberculose / The Pathogenesis of Tuberculosis: Novel Aspects

A tuberculose continua a assombrar a humanidade como uma das doenças infecciosas que mais incapacita e mata. Nosso objetivo foi rever a patogenia da tuberculose, um processo complexo, que envolve tanto o agente etiológico Mycobacterium tuberculosis como os mecanismos de defesa do hospedeiro. Os novos instrumentos de biologia molecular permitiram grandes avanços na compreensão da epidemiologia da doença, assim como na identificação de possíveis alvos farmacológicos e de moléculas que podem ser usadas no diagnóstico das diversas fases da infecção. Estudos da patogenia da tuberculose nos sítios ativos dos pulmões mostraram níveis significativamente mais elevados demediadores que prejudicam a imunidade do tipo Th1 e inata, incluindo mediadores intracelulares e extracelulares. Esses e outros achados têm permitido aplicações no manejo da tuberculose. A proteína early secretory antigenic target-6, presente em micobactérias patogênicas e ausente no BCG, permitiu o desenvolvimento de testes diagnósticos úteis na identificação de infecção tuberculosa latente mesmo em vacinados com BCG. Há uma correlação entre altos níveis de IL-10 ao final de tratamento antituberculose e recidiva da doença ao longo de avaliação, apontando um possível nexo entre essa citocina anti-inflamatória e o risco de recaída por tuberculose

Tuberculosis (TB) still looms as one of the most incapacitating and lethal infectious diseases worldwide. The objective of this article was to review the pathogenesis of tuberculosis, a complex process that involves the interaction between the etiologic agent Mycobacterium tuberculosis and host defense mechanisms. New molecular biology methods have allowed great advances in the understanding of tuberculosis epidemiology, as well as in the identiication of possible pharmacologic targets and molecules that can be used in the diagnosis during the various stages of the infection. Studies of the pathogenesis of tuberculosis at active disease sites in the lungs have demonstrated increased levels of mediators that impair Th1-mediated and innate immunity, including intracellular and extracellular mediators. Such indings have facilitated the application of new techniques in tuberculosis management. The discovery of early secretory antigenic target-6, which is present in pathogenic mycobacteria and absent from BCG, allowed the development of useful diagnostic tests for the identiication of latent tuberculosis infection even in BCG-vaccinated individuals. There is a correlation between high IL-10 levels at the end of anti-tuberculosis treatment and tuberculosis recurrence, showing a possible link between this anti-inlammatory cytokine and the risk of tuberculosis recurrence

Role of eosinophilic airway inflammation in models of asthma

Eosinophils play a central role in the establishment and outcome of bronchial inflammation in asthma. Animal models of allergy are useful to answer questions related to mechanisms of allergic inflammation. We have used models of sensitized and boosted guinea pigs to investigate the nature of bronchial inflammation in allergic conditions. These animals develop marked bronchial infiltration composed mainly of CD4+ T-lymphocytes and eosinophils. Further provocation with antigen leads to degranulation of eosinophils and ulceration of the bronchial mucosa. Eosinophils are the first cells to increase in number in the mucosa after antigen challenge and depend on the expression of alpha4 integrin to adhere to the vascular endothelium and transmigrate to the mucosa. Blockage of alpha4 integrin expression with specific antibody prevent not only the transmigration of eosinophils but also the development of bronchial hyperresponsiveness (BHR) to agonists in sensitized and challenged animals, clearly suggesting a role for this cell type in this altered functional site. Moreover, introduction of antibody against Major Basic Protein into the airways also prevents the development of BHR in similar model. BHR can also be suppressed by the use of FK506, an immunosuppressor that reduces in almost 100 per cent the infiltration of eosinophils into the bronchi of allergic animals. These data support the concept that eosinophil is the most important pro-inflammatory factor in bronchial inflammation associated with allergy.

Phenotypes of lung mononuclear phagocytes in HIV seronegative tuberculosis patients: evidence for new recruitment and cell activation

Mycobacterium tuberculosis preferentially resides in mononuclear phagocytes. The mechanisms by which mononuclear phagocytes keep M. tuberculosis in check or by which the microbe evades control to cause disease remain poorly understood. As an initial effort to delineate these mechanisms, we examined by immunostaining the phenotype of mononuclear phagocytes obtained from lungs of patients with active tuberculosis. From August 1994 to March 1995, consecutive patients who had an abnormal chest X-ray, no demonstrable acid-fast bacilli in sputum specimens and required a diagnostic bronchoalveolar lavage (BAL) were enrolled. Of the 39 patients enrolled, 21 had microbiologically diagnosed tuberculosis. Thirteen of the 21 tuberculosis patients were either HIV seronegative (n = 12) or had no risk factor for HIV and constituted the tuberculosis group. For comparison, M. tuberculosis negative patients who had BAL samples taken during this time (n = 9) or normal healthy volunteers (n = 3) served as control group. Compared to the control group, the tuberculosis group had significantly higher proportion of cells expressing markers of young monocytes (UCHM1) and RFD7, a marker for phagocytic cells, and increased expression of HLA-DR, a marker of cell activation. In addition, tuberculosis group had significantly higher proportion of cells expressing dendritic cell marker (RFD1) and epithelioid cell marker (RFD9). These data suggest that despite recruitment of monocytes probably from the peripheral blood and local cell activation, host defense of the resident lung cells is insufficient to control M. tuberculosis.