Pulmonary Mycobacterial Granuloma

Shaler, Christopher R.; Kugathasan, Kapilan; McCormick, Sarah; Damjanovic, Daniela; Horvath, Carly; Small, Cherrie-Lee; Jeyanathan, Mangalakumari; Chen, Xiao; Yang, Ping‐Chang; Xing, Zhou

doi:10.1016/j.ajpath.2010.12.022

Cited by 20 publications

(19 citation statements)

References 68 publications

(90 reference statements)

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“…Conversely, Th2 cytokine IL-10 inhibits T cell proliferation by down regulating the production of IL-2 [11]. IL-10 is also known to contribute significantly to formation of a disorganized granuloma [2,12]. Several studies have demonstrated the immunosuppressive role of IL-10 cytokine in human and animal models [13,14].…”

Section: Introductionmentioning

confidence: 99%

IL-10 Modulates In Vitro Multinucleate Giant Cell Formation in Human Tuberculosis

Shrivastava

Bagchi

2013

PLoS ONE

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BackgroundMultinucleated giant cells (MGC) are the histologic hallmark of granuloma which is known to limit tuberculosis infection. Both Th1 and Th2 type of cytokines regulate the immune response occurring within the granulomas. The objective of the study was to determine whether tuberculosis patient monocytes differed in their MGC forming ability as compared to healthy controls.MethodsIn vitro MGC formation was carried out by treatment of monocytes with cytokine containing culture supernatant of ConA or PPD stimulated peripheral mononuclear cells. IL-2, TNF-α, IL-4, IL-10 and TGF-β cytokine levels were analysed in culture supernatants using ELISA. IL-4 and IL-10 were added to culture supernatant separately and simultaneously along with their respective neutralizing antibodies and their consequent effect on MGC formation was evaluated.Results MGC formation was significantly low in patient monocytes incubated with autologous culture supernatant as compared to control culture supernatant. Cytokine analysis of the culture supernatants revealed that while IL-4 levels were similar in patients and controls, increased IL-10 levels were found in patients. Exogenous addition of IL-10 resulted in reduced MGC formation. Contrastingly, when IL-4 was added exogenously, it led to increased MGC formation. The effects of both IL-10 and IL-4 were reversed upon addition of their respective antibodies.ConclusionThe findings suggest that one of the factors contributing to the disease could be the effect of cytokines on the functionality of monocytes, which are crucial in the fight against the organism. Significantly reduced MGC formation was observed on addition of IL-10. The findings imply an overriding role of IL-10 in MGC formation. The suppressive effect of IL-10 on MGC formation was further confirmed by addition of IL-10 neutralizing antibody.

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Section: Introductionmentioning

confidence: 99%

IL-10 Modulates In Vitro Multinucleate Giant Cell Formation in Human Tuberculosis

Shrivastava

Bagchi

2013

PLoS ONE

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“…In humans, high levels of IL-10 are found in lungs, serum, sputum, and bronchoalveolar lavage (BAL) fluid of patients with pulmonary tuberculosis (TB) (4,56). There are data suggesting a necessary role in control of TB (57)(58)(59)(60)(61), while others suggest that IL-10 plays no part in the dynamics (62)(63)(64)(65)(66)(67)(68). Our modeling studies predict a protective role for IL-10, balancing inflammation, limiting tissue damage, and regulating the dominant macrophage phenotype in the lymph node and lung (69)(70)(71).…”

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confidence: 99%

Macrophage Polarization Drives Granuloma Outcome during Mycobacterium tuberculosis Infection

et al. 2015

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c Mycobacterium tuberculosis, the causative agent of tuberculosis (TB), induces formation of granulomas, structures in which immune cells and bacteria colocalize. Macrophages are among the most abundant cell types in granulomas and have been shown to serve as both critical bactericidal cells and targets for M. tuberculosis infection and proliferation throughout the course of infection. Very little is known about how these processes are regulated, what controls macrophage microenvironment-specific polarization and plasticity, or why some granulomas control bacteria and others permit bacterial dissemination. We take a computational-biology approach to investigate mechanisms that drive macrophage polarization, function, and bacterial control in granulomas. We define a "macrophage polarization ratio" as a metric to understand how cytokine signaling translates into polarization of single macrophages in a granuloma, which in turn modulates cellular functions, including antimicrobial activity and cytokine production. Ultimately, we extend this macrophage ratio to the tissue scale and define a "granuloma polarization ratio" describing mean polarization measures for entire granulomas. Here we coupled experimental data from nonhuman primate TB granulomas to our computational model, and we predict two novel and testable hypotheses regarding macrophage profiles in TB outcomes. First, the temporal dynamics of granuloma polarization ratios are predictive of granuloma outcome. Second, stable necrotic granulomas with low CFU counts and limited inflammation are characterized by short NF-B signal activation intervals. These results suggest that the dynamics of NF-B signaling is a viable therapeutic target to promote M 1 polarization early during infection and to improve outcome.

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“…Mtb uses a variety of evasion strategies to resist attack from the host immune system, by blocking phagolysosome fusion and detoxifying reactive oxygen and nitrogen radicals [29]. In addition, virulent Mtb has multiple strategies to delay the early initial induction of T cell responses or to modulate antigen presentation to CD4+ T cells [27,29].…”

Section: Overview Of Tb Pathogenesismentioning

confidence: 99%

Host immune responses to mycobacterial antigens and their implications for the development of a vaccine to control tuberculosis

Yuk

2014

Clin Exp Vaccine Res

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Tuberculosis (TB) remains a worldwide health problem, causing around 2 million deaths per year. Despite the bacillus Calmette Guérin vaccine being available for more than 80 years, it has limited effectiveness in preventing TB, with inconsistent results in trials. This highlights the urgent need to develop an improved TB vaccine, based on a better understanding of host-pathogen interactions and immune responses during mycobacterial infection. Recent studies have revealed a potential role for autophagy, an intracellular homeostatic process, in vaccine development against TB, through enhanced immune activation. This review attempts to understand the host innate immune responses induced by a variety of protein antigens from Mycobacterium tuberculosis, and to identify future vaccine candidates against TB. We focus on recent advances in vaccine development strategies, through identification of new TB antigens using a variety of innovative tools. A new understanding of the host-pathogen relationship, and the usefulness of mycobacterial antigens as novel vaccine candidates, will contribute to the design of the next generation of vaccines, and to improving the host protective immune responses while limiting immunopathology during M. tuberculosis infection.

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Pulmonary Mycobacterial Granuloma

Cited by 20 publications

References 68 publications

IL-10 Modulates In Vitro Multinucleate Giant Cell Formation in Human Tuberculosis

IL-10 Modulates In Vitro Multinucleate Giant Cell Formation in Human Tuberculosis

Macrophage Polarization Drives Granuloma Outcome during Mycobacterium tuberculosis Infection

Host immune responses to mycobacterial antigens and their implications for the development of a vaccine to control tuberculosis

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