Networked T Cell Death following Macrophage Infection by Mycobacterium tuberculosis

<div><h3>Background</h3><p>Depletion of T cells following infection by <em>Mycobacterium tuberculosis</em> (Mtb) impairs disease resolution, and interferes with clinical test performance that relies on cell-mediated immunity. A number of mechanisms contribute to this T cell suppression, such as activation-induced death and trafficking of T cells out of the peripheral circulation and into the diseased lungs. The extent to which Mtb infection of human macrophages affects T cell viability however, is not well characterised.</p> <h3>Methodology/Principal Findings</h3><p>We found that lymphopenia (<1.5×10⁹ cells/l) was prevalent among culture-positive tuberculosis patients, and lymphocyte counts significantly improved post-therapy. We previously reported that Mtb-infected human macrophages resulted in death of infected and uninfected bystander macrophages. In the current study, we sought to examine the influence of infected human alveolar macrophages on T cells. We infected primary human alveolar macrophages (the primary host cell for Mtb) or PMA-differentiated THP-1 cells with Mtb H37Ra, then prepared cell-free supernatants. The supernatants of Mtb-infected macrophages caused dose-dependent, caspase-dependent, T cell apoptosis. This toxic effect of infected macrophage secreted factors did not require TNF-α or Fas. The supernatant cytotoxic signal(s) were heat-labile and greater than 50 kDa in molecular size. Although ESAT-6 was toxic to T cells, other Mtb-secreted factors tested did not influence T cell viability; nor did macrophage-free Mtb bacilli or broth from Mtb cultures. Furthermore, supernatants from <em>Mycobacterium bovis</em> Bacille de Calmette et Guerin (BCG)- infected macrophages also elicited T cell death suggesting that ESAT-6 itself, although cytotoxic, was not the principal mediator of T cell death in our system.</p> <h3>Conclusions</h3><p>Mtb-Infected macrophages secrete heat-labile factors that are toxic to T cells, and may contribute to the immunosuppression seen in tuberculosis as well as interfere with microbial eradication in the granuloma.</p> </div

Ionizing radiation modulates human macrophages towards a pro-inflammatory phenotype preserving their pro-invasive and pro-angiogenic capacities

In order to improve the efficacy of conventional radiotherapy, attention has been paid to immune cells, which not only modulate cancer cell response to therapy but are also highly recruited to tumours after irradiation. Particularly, the effect of ionizing radiation on macrophages, using therapeutically relevant doses, is not well understood. To evaluate how radiotherapy affects macrophage behaviour and macrophage-mediated cancer cell activity, human monocyte derived-macrophages were subjected, for a week, to cumulative ionizing radiation doses, as used during cancer treatment (2Gy/fraction/day). Irradiated macrophages remained viable and metabolically active, despite DNA damage. NF-kappaB transcription activation and increased Bcl-xL expression evidenced the promotion of pro-survival activity. A significant increase of pro-inflammatory macrophage markers CD80, CD86 and HLA-DR, but not CCR7, TNF and IL1B was observed after 10Gy cumulative doses, while anti-inflammatory markers CD163, MRC1, VCAN and IL-10 expression decreased, suggesting the modulation towards a more proinflammatory phenotype. Moreover, ionizing radiation induced macrophage morphological alterations and increased their phagocytic rate, without affecting matrix metalloproteases (MMP)2 and MMP9 activity. Importantly, irradiated macrophages promoted cancer cell-invasion and cancer cell-induced angiogenesis. Our work highlights macrophage ability to sustain cancer cell activities as a major concern that needs to be addressed to improve radiotherapy efficacy

Purinergic signalling links mechanical breath profile and alveolar mechanics with the pro-inflammatory innate immune response causing ventilation-induced lung injury

Severe pulmonary infection or vigorous cyclic deformation of the alveolar epithelial type I (AT I) cells by mechanical ventilation leads to massive extracellular ATP release. High levels of extracellular ATP saturate the ATP hydrolysis enzymes CD39 and CD73 resulting in persistent high ATP levels despite the conversion to adenosine. Above a certain level, extracellular ATP molecules act as danger-associated molecular patterns (DAMPs) and activate the pro-inflammatory response of the innate immunity through purinergic receptors on the surface of the immune cells. This results in lung tissue inflammation, capillary leakage, interstitial and alveolar oedema and lung injury reducing the production of surfactant by the damaged AT II cells and deactivating the surfactant function by the concomitant extravasated serum proteins through capillary leakage followed by a substantial increase in alveolar surface tension and alveolar collapse. The resulting inhomogeneous ventilation of the lungs is an important mechanism in the development of ventilation-induced lung injury. The high levels of extracellular ATP and the upregulation of ecto-enzymes and soluble enzymes that hydrolyse ATP to adenosine (CD39 and CD73) increase the extracellular adenosine levels that inhibit the innate and adaptive immune responses rendering the host susceptible to infection by invading microorganisms. Moreover, high levels of extracellular adenosine increase the expression, the production and the activation of pro-fibrotic proteins (such as TGF-β, α-SMA, etc.) followed by the establishment of lung fibrosis

Regulation and Repair of the Alveolar-Capillary Barrier in Acute Lung Injury

Considerable progress has been made in understanding the basic mechanisms that regulate fluid and protein exchange across the endothelial and epithelial barriers of the lung under both normal and pathological conditions. Clinically relevant lung injury occurs most commonly from severe viral and bacterial infections, aspiration syndromes, and severe shock. The mechanisms of lung injury have been identified in both experimental and clinical studies. Recovery from lung injury requires the reestablishment of an intact endothelial barrier and a functional alveolar epithelial barrier capable of secreting surfactant and removing alveolar edema fluid. Repair mechanisms include the participation of endogenous progenitor cells in strategically located niches in the lung. Novel treatment strategies include the possibility of cell-based therapy that may reduce the severity of lung injury and enhance lung repair

Purinergic signalling and immune cells

This review article provides a historical perspective on the role of purinergic signalling in the regulation of various subsets of immune cells from early discoveries to current understanding. It is now recognised that adenosine 5'-triphosphate (ATP) and other nucleotides are released from cells following stress or injury. They can act on virtually all subsets of immune cells through a spectrum of P2X ligand-gated ion channels and G protein-coupled P2Y receptors. Furthermore, ATP is rapidly degraded into adenosine by ectonucleotidases such as CD39 and CD73, and adenosine exerts additional regulatory effects through its own receptors. The resulting effect ranges from stimulation to tolerance depending on the amount and time courses of nucleotides released, and the balance between ATP and adenosine. This review identifies the various receptors involved in the different subsets of immune cells and their effects on the function of these cells

Avaliação da qualidade de vida com o instrumento SF-36 em lombalgia crônica

OBJETIVO: Avaliar a qualidade de vida através dos domínios do Instrumento SF-36 em portadores de lombalgia crônica inespecífica. MÉTODOS: Trinta portadores de lombalgia crônica inespecífica foram aleatorizados para três grupos (grupo Iso (Isostretching), grupo RPG (Reeducação Postural Global) e Iso+RPG), e avaliados quanto à dor e qualidade de vida antes e após as intervenções fisioterápicas e reavaliados novamente após 2 meses de acompanhamento. Após a aceitação do Termo de Consentimento Livre e Esclarecido os pacientes foram submetidos a procedimentos como: avaliação fisioterápica através do Instrumento de Avaliação da Coluna Vertebral, Escala Visual Analógica de Dor (EVA), Questionário de Qualidade de Vida através do Instrumento SF-36, antes da 1ª sessão e após três meses de tratamento, e reavaliados 2 meses após o tratamento. RESULTADOS: Mostraram que ambas as técnicas fisioterápicas diminuíram a dor (p<0,001), porém quando foram associadas as duas técnicas (Iso + RPG) a melhora da dor foi significativamente maior, e na avaliação após dois meses de acompanhamento o método de RPG foi mais eficaz. Quanto à avaliação da qualidade de vida, as técnicas fisioterápicas foram eficazes após as intervenções (P<0,001), porém o método do Iso foi mais eficaz quando os pacientes foram reavaliados no acompanhamento. CONCLUSÃO: As técnicas fisioterápicas utilizadas neste estudo foram eficazes para tratar a lombalgia crônica inespecífica apresentada pelos pacientes, pois diminuíram a algia que os mesmos apresentavam e melhoraram a qualidade de vida segundo os domínios do Instrumento SF-36. Nível de Evidência II, Ensaio Clínico Controlado e Randomizado. ____________________________________________________________________________________ ABSTRACTThe objective of this study was to evaluate the quality of life (QL) with the use of the SF-36 Questionnaire in patients with chronic nonspecific low back pain (CNLBP). Thirty patients with CNLBP were randomly assigned to one of three groups (Iso group (Isostretching), GPR group (Global Postural Reeducation), and the Iso+GPR group. Patients underwent physical therapy assessment with the use of the Vertebral Spine Assessment, the Visual Analog Scale of Pain (VASP), and the SF-36 life quality questionnaire before the first session (first assessment), after three months of treatment (second assessment) and reassessed two months after the final session in the follow-up (third assessment). The results indicated that both physical therapy techniques reduced pain (p<0.001); when the techniques (Iso+GPR) were combined, the reduction in pain was significantly greater; and, in the follow-up assessment, the GPR method was more efficient. As for the QL, physical therapy techniques were effective after the interventions (p<0.001), and the Iso method was more effective when patients were reassessed in the follow-up. We conclude that the physical therapy techniques used in this study were efficient to treat CNLBP in the patients since they reduced pain and increased QL according to the results of the SF-36 questionnaire. Level of Evidence II, Randomized Controlled Clinical Trial

Avaliação da qualidade de vida, da dor nas costas, da funcionalidade e de alterações da coluna vertebral de estudantes de fisioterapia

O objetivo deste estudo foi avaliar a qualidade de vida, dor nas costas, funcionalidade e as alterações da coluna vertebral de estudantes de fisioterapia. Participaram 42 universitários, sendo avaliada a coluna vertebral por meio do arcômetro, a dor nas costas por meio de um questionário multidimensional de dor, a qualidade de vida por meio do questionário SF-36 e funcionalidade a partir do Roland-Morris. Foi realizada estatística descritiva e teste qui-quadrado (α=0,05). Os resultados demonstraram: prevalência de alterações nas curvaturas da coluna vertebral de 38,1%; (n=16); alta prevalência de dor nas costas (69%; n=29); baixa prevalência de comprometimento da funcionalidade (3,4%; n=1); que não há associação entre as alterações nas curvaturas da coluna vertebral e funcionalidade e dor nas costas; e que os escores dos domínios do SF-36 foram maiores que 45, exceto o domínio "dor", cujo escore aproximado foi de 35. Conclui-se que quanto menor os níveis de intensidade da dor melhor o nível de qualidade de vida