Search tips
Search criteria 


Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
Mucosal Immunol. Author manuscript; available in PMC 2012 March 25.
Published in final edited form as:
PMCID: PMC3311958

Macrophages and control of granulomatous inflammation in tuberculosis


The granuloma that forms in response to Mycobacterium tuberculosis must be carefully balanced in terms of immune responses to provide sufficient immune cell activation to inhibit the growth of the bacilli, yet modulate the inflammation to prevent pathology. There are likely many scenarios by which this balance can be reached, given the complexity of the immune responses induced by M. tuberculosis. In this review, we focus on the key role of the macrophage in balancing inflammation in the granuloma.


Tuberculosis remains a serious health threat worldwide. There were 9.4 million new cases of tuberculosis and 1.7 million deaths in 2009.1 Although this disease can be cured by drug treatment, the regimens involve several drugs and at least 6 months of therapy; obstacles to treatment include timely diagnosis, access to health care, compliance, side effects, and drug interactions. A vaccine, BCG (Bacillus Calmette-Guerin), which is an attenuated Mycobacterium bovis strain, has been used for nearly a century, but efficacy against adult disease is questionable. In fact, most of the deaths from tuberculosis occur in countries where BCG vaccination of infants is routine.1 Clearly, better diagnostic, preventive, and therapeutic strategies are necessary to gain control of this disease.

Tuberculosis is caused by Mycobacterium tuberculosis (Mtb). This bacterium has a complex cell wall, composed of long-chain fatty acids, glycolipids, peptidoglycan, and proteins, and a slow doubling time (18 –24 h). It is primarily a respiratory pathogen, and usually transmitted by the cough of a person with active disease. Primary tuberculosis can occur within the first year or so after exposure, and is the result of an uncontrolled initial infection. This could be because of an extremely virulent bacillus, large or repeated exposures, an immune response that is insufficient to control bacterial replication, or the induction of excessive pathology. The majority (90 %) of infected humans effectively contain, but do not eliminate, the bacteria and are defined as having “latent” infection. This is a clinical term, meaning a person is infected (as evidenced by T-cell reactivity to mycobacterial antigens) but is asymptomatic and not contagious. However, a latently infected human has a 10 % lifetime risk of reactivating the infection and presenting with active tuberculosis. Thus, the estimated 2 billion latently infected humans are an enormous reservoir of potential disease.

The factors that lead to containment of infection or progression to disease are not well understood and are multifactorial. Typically, tuberculosis presents as pulmonary disease, but with systemic manifestations, including anorexia and wasting. The old name for tuberculosis was “consumption,” as this disease appears to consume the patient. The wasting is partly because of production of inflammatory cytokines, such as tumor necrosis factor (TNF), known to cause cachexia. 2,3 Thus, the disease is driven by host and mycobacterial factors. A new complication in the setting of human immunodeficiency virus/Mtb co-infection also points to inflammation as an important contributor to tuberculosis: antiretroviral therapy that restores CD4 T-cell responses can occasionally have the paradoxical effect of unmasking or reactivating tuberculosis.46 This immune reconstitution inflammatory syndrome also supports that modulation of inflammation may be an essential component of management of tuberculosis.

We hypothesize that the balance of pro- and anti-inflammatory immune responses at the site of infection (the granuloma) is crucial to control of infection. Although there are numerous inflammatory mediators in tuberculosis, a key cell in the granuloma is the macrophage. Here, we focus on the macrophage as a major player in the balance of inflammation in the granuloma, necessary for inhibiting bacterial replication and for control of pathology.


Transmission occurs when droplet nuclei of Mtb expectorated via cough from someone with active tuberculosis are inhaled. The battle between pro- and anti-inflammatory signals begins in the airways with the initial contact of bacillus with host cells. Ingestion of intracellular bacteria by airway antigen-presenting cells (macrophages and dendritic cells) initiates the first important immune responses. Mtb induces proinflammatory cytokines interleukin (IL)-12, IL-1β, and TNF (reviewed in ref. 7). IL-12 plays a critical role in initiating a T helper 1 (TH1) T-cell response.8 TNF induces cytokine and chemokine production by macrophages, activates macrophages for killing, and modulates macrophage apoptosis.913 The anti-inflammatory cytokines such as IL-10 and TGF-β can also be produced by Mtb-infected macrophages, which downregulate proinflammatory cytokines and T-cell proliferation and activation, balancing the response between bacterial eradication and host survival.7,14

The alveolar macrophages, which line the airways, have been described as deficient in their interaction with Mtb;15 however, most humans who encounter Mtb do not become infected (as determined by immunologic reactivity), suggesting that in fact, the cells in the airways are quite robust in deterring productive infection with this bacillus. Alveolar macrophages have been considered to be anti-inflammatory in nature,15 which contributes to suppressing inflammation in the airways. How these cells, or other cells in the airways, are so successful at warding off infection, then, remains to be determined.


After the encounter of bacillus and macrophage in the airways, the infected macrophage may facilitate the spread of disease first by cellular necrosis to disseminate extracellular bacteria and by migration to distal sites in the lungs. Once in the parenchyma, the bacilli set off a slow inflammatory process by infected macrophages. These infected macrophages recruit uninfected macrophages to ultimately form a granuloma.1618

Dendritic cells in lungs or airways are also infected by Mtb, and migrate to thoracic lymph nodes, where a T-cell response is primed.19 This process is quite slow; studies in various animal models suggests that priming of T cells does not occur until 12–21 days postinfection.2023 Pulmonary inflammation due to interaction of bacillus with macrophages and other cells results in recruitment of monocytes, neutrophils, and primed T cells and B cells to lungs, culminating in formation of a granuloma. A granuloma is an organized and structured collection of immune cells that forms in response to chronic antigenic stimulation, in the context of macrophage-mediated factors. The granuloma is the classic pathologic feature of tuberculosis, and functions both as a niche in which the bacillus can grow or persist and an immunologic microenvironment in which cells with antimyco-bacterial functions interact to control and prevent dissemination of the infection.

Granulomas are observed in active, latent, and reactivation tuberculosis. Thus, the mere formation of a granuloma is insufficient for control of infection—rather, the granuloma must be functioning properly. In active tuberculosis, the host often has numerous granulomas that are incapable of controlling infection; bacteria, either extracellular or within macrophages or dendritic cells, then spread throughout the lung or disseminate to other organs, initiating new granuloma formation. In latent infection, there are usually one or a few granulomas in lungs and lymph nodes, although our knowledge of the true nature of latent infection in humans is limited, and these granulomas are capable of limiting the growth and spread of Mtb. One of the major gaps in our understanding of tuberculosis is what factors define a “functioning” granuloma, i.e., the type of granuloma that eliminates or exerts long-term control over the infection. Based on the variety of immune responses shown to contribute to control or exacerbation of tuberculosis, we assume that multiple combinations of responses may constitute a functioning granuloma (Figure 1 ), and these likely differ among individuals and even among granulomas in a single individual.

Figure 1
Balance of responses in the granuloma dictate bacterial control and pathology. There are a variety of combinations that can lead to an inflammatory granuloma in active tuberculosis (TB). Three possibilities are shown: (a) Active granuloma with high bacterial ...

Although granulomas are composed of a variety of cell types, the primary cellular component of the structure is the macrophage. The macrophage is the initiating cell for granuloma formation17,18 and the major cell type in most granulomas. Macrophages both harbor the majority of Mtb and have the effector functions to kill these bacilli. There are a variety of macrophage phenotypes in granulomas with various functions, including antimycobacterial effector mechanisms, pro- and anti-inflammatory cytokine production, and secretion of chemokines and proteins associated with tissue remodeling. Thus, this cell contributes to most aspects of inflammation and control of infection within the granuloma. This review will focus on the roles of the macrophage in promoting or controlling inflammation in tuberculosis granulomas, directly and through its interaction with other cells in the granuloma.


In humans, a spectrum of granulomas is observed in active tuberculosis and even latent infection. The classic granuloma in tuberculosis is the caseous granuloma, so called because the center of this granuloma has a “cheese-like ” appearance grossly. Histologically, this granuloma consists of epithelioid macrophages surrounding an acellular necrotic region, with a lymphocytic cuff, comprising both B and T cells.24 Neutrophils can also be observed within caseous granulomas. Caseous granulomas can range in size from 1 mm to > 2 cm. In chronic or latent infection, this type of granuloma can become calcified, with the calcification process beginning within the caseous center. A calcified granuloma generally represents a successful immune response and is associated with fewer inflammatory cells than other granulomas. Other types of granulomas include non-necrotizing granulomas, composed primarily of macrophages with a few lymphocytes, necrotic neutrophilic granulomas, and completely fibrotic granulomas. Peripheral fibrosis can be observed in some caseous granulomas. With all of these granulomas types, it is easy to imagine several microenvironments within and among granulomas for the microbe, as well as a range of immune microenvironments.


Tuberculosis is a human disease, but obtaining lung tissue (with granulomas) from people with tuberculosis is difficult. Thus, animal model systems are necessary for detailed studies of tuberculosis. Mice develop a chronic, progressive infection with Mtb; the granulomatous infiltration in lungs lacks the structured and organized appearance of human granulomas. 25 There have been reports of mouse strains developing granulomas that more closely represent human lesions,26 and these may be useful for a focused approach to granuloma biology in a system that is rich in reagents. In Guinea pigs and rabbits, some granulomas are more human-like and studies in these species have yielded important insights on the development and structure of granulomas.25 Infection of zebrafish with Mycobacterium marinum, an aquatic mycobacterial species, recapitulates a human caseous granuloma. 27 Studies in zebrafish embryos have allowed dynamic observation of granuloma formation and spread, 1618 and the use of genetic tools has enabled dissection of some of the factors important in granuloma formation and maintenance. 9,28 Non-human primates (primarily macaques) have been used as models for human tuberculosis. 21,2933 A full spectrum of granuloma types identical to human granulomas can be observed in Mtb-infected macaques, and immunologic tools are available for this model. Finally, computational models of granulomas provide the unique ability to study factors involved in tuberculosis that are not possible to study in experimental systems.12,34 Here, we draw on data from all the model systems in our discussion of granulomas in tuberculosis.


Monocytes migrate to the site of infection from blood, in response to inflammatory signals (cytokines and chemokines) that are often produced by macrophages as well.12 Only a fraction of macrophages in the granuloma are actually infected with Mtb, although this proportion is likely to be higher in a granuloma that is poorly functioning and not controlling the infection. It is difficult to estimate the fraction of cells infected in human granulomas, or the number of bacilli per cell because acid-fast staining for the microbe is notoriously inefficient in human and non-human primate tissues. Nonetheless, we consider the macrophage populations to consist of both infected and uninfected cells, both of which can be influenced by other factors (cells and soluble factors) in the granuloma. Mtb can have effects on macrophages from within by interacting with host receptors, such as Toll-like receptors in the phagosome.3542 It has been suggested that under some circumstances Mtb can escape the vacuole to reside in the cytoplasm,43,44 and that mycobacterial molecules can exit the phagosome and interact with cytoplasmic receptors to induce responses.4548 Mycobacteria and microbial factors can interact with cells from the outside as well, again through Toll-like receptors or other receptors. The variety of cytokines induced by interaction of Mtb with macrophages can then act on other cells within the granuloma, including macrophages, to induce various functional and phenotypic changes in cells that then modulate the environment of the granuloma.

In recent years, the complexity of macrophage populations has gained appreciation.49,50 For ease of discussion, macrophages differentiated in response to cytokine signals have been termed either classically activated macrophages (CAMs) or alternatively activated macrophages (AAMs).4952 CAMs arise in response to TH1 T-cell signals (interferon-γ and TNF). These macrophages produce proinflammatory cytokines (TNF and IL-12) and chemokines and are capable of killing bacilli; in mice, a marker for CAM is inducible nitric oxide synthase (iNOS). iNOS uses arginine as a substrate for production of nitric oxide that can kill Mtb. In mice, iNOS is essential for control of Mtb infection.5355 iNOS expression in human tuberculous lung macrophages has been reported,56,57 and we have detected iNOS expression in macrophages in macaque granulomas (J.T. Mattila and J.L. Flynn, personal communication).

AAMs are anti-inflammatory in nature, and were initially described as arising in response to TH2 cytokines IL-13 and IL-4.50,51 These macrophages can produce IL-10, TGF-β, and IL-6. In a TH2 environment, induction of the AAM phenotype is STAT-6 (signal transducer and activation of transcription 6) dependent.51 There are a set of genes and proteins used to characterize AAMs, with the primary marker being arginase.51 Arginase also uses arginine as a substrate and directly competes with iNOS for arginine, making the relative expression of these genes in a macrophage an important balancing feature for whether the macrophage will be pro- or anti-inflammatory, and directly affects the ability of a macrophage to kill Mtb (Figure 1).

There are several recent studies of AAMs in tuberculosis. Unlike parasitic and worm diseases, or asthma, where AAMs have been predominantly studied, tuberculosis induces a TH1-mediated immune response. It is difficult to measure IL-4 or IL-13 in tuberculous granulomas, and interruption of these genes in mice has little effect on Mtb infections, although there are a few reports that these cytokines can interfere with adequate control of tuberculosis.5860 The generation of AAMs in tuberculous (TH1) granulomas appears to have a different mechanism. Mtb induces arginase (Arg1) gene expression in a MyD88-dependent but STAT-6-independent fashion in murine macrophages.36 This Arg1 induction by mycobacteria was mediated by Toll-like receptor-induced IL-6, IL-10, and granulocyte colony-stimulating factor production by macrophages.61 However, only a subset of AAM markers were induced by these cytokines, suggesting perhaps an intermediate AAM phenotype compared with a TH2 environment. Other studies using a mouse that overexpressed IL-10 from macrophages supported that IL-10 can strongly induce arginase expression in the lungs of Mtb-infected mice.61 The latter study also suggested that IL-10 enhanced the sensitivity of macrophages to IL-4, exacerbating induction of AAMs even in the presence of very low IL-4 levels, as might occur in a granuloma. These mice had higher numbers of Mtb in the lungs, which was correlated with increased AAMs. Mice lacking arginase specifically in macrophages controlled Mtb infection better than wild-type mice, and Arg1 −/− macrophages had enhanced iNOS expression and increased killing of Mtb in vitro. Thus, although Mtb appears to have a different mechanism for induction of arginase than a TH2-mediated disease, arginase and AAM appear to inhibit control of Mtb infection.

Some studies have suggested that alveolar macrophages are inherently alternatively activated, and may allow Mtb bacilli to gain a foothold immediately upon entering the airway, as they are impaired in their ability to kill bacilli. 15 Gordon and Martinez51 have suggested that true AAMs require a signal of “activation” to attain the qualities of AAMs, and hence although alveolar macrophages before infection are not classically activated, they may not be true AAMs, either. There is clearly a spectrum of activation for macrophages, and incompletely activated cells may possess some but not all qualities of AAMs or CAMs, depending on the local cytokine environment.


The battle for control of Mtb infection occurs in granulomas, and the mechanisms that contribute to bacterial killing can also contribute to pathology. Excessive pathology also results in disease exacerbation. With a focus on macrophages, one can consider the balance of CAMs and AAMs to be crucial to the successful granuloma (Figure 1). Whereas CAMs are required for killing bacilli, the production of proinflammatory mediators and the continued recruitment and stimulation of T cells can lead to tissue damage and poor resolution of granulomas. Conversely, mouse data suggest that a granuloma with a substantial representation of AAMs would impair killing of bacteria, even while dampening inflammation and T-cell proliferation. The balance of CAMs and AAMs in a granuloma may be necessary to control infection and tissue damage. It also may be that CAMs and AAMs are spatially located differently in the human granuloma and play both roles—microbial killing and T-cell recruitment and activation where bacteria are more plentiful and downregulation of the T-cell environment where necessary to prevent tissue damage. Changes to location or numbers of macrophage types could affect the balance of the granuloma and lead to increased pathology or decreased bacterial killing (Figure 1). Location differences would not be apparent from the murine studies, as these granulomas have little of the organized structure of human granulomas.


Macrophages can differentiate in response to many factors, including cytokines, direct cell-to-cell contact with T cells, antibodies from B cells, and microbial factors (interacting through pattern recognition receptors). These factors in aggregate likely affect the balance of inflammation in a single granuloma. Because the factors that control inflammation are dynamic, each granuloma in a host could act independently in terms of inflammation and bacterial numbers; data from the macaque model supports this (P.L. Lin and J.L. Flynn, unpublished data).

T cells

T-cell responses are primary players in the inflammatory balance in the granuloma. 62,63 This includes cytotoxic T cells (which can kill infected cells), TH1 T cells that produce combinations of IL-2, interferon-γ, and TNF,64 TH17 cells producing IL-17, and regulatory T cells (Tregs) that can produce IL-10 or TGF-β and inhibit proliferation and cytokine production by other cells. It is not clear what controls the balance of T cells within a granuloma, and how dynamic the changes are over the course of infection. There is a strong TH1 response in most people infected with Mtb, regardless of whether they develop active disease or latent infection. Recent intriguing data demonstrated that the immuno-dominant T-cell epitopes are conserved in Mtb strains,65 leading to speculation that it is to the advantage of the bacillus to induce strong T-cell responses. Mtb heat-shock protein 70 can interact with the CD40 receptor on dendritic cells, leading to increased IL-12 production and TH1 responses, 66 again supporting that Mtb has evolved mechanisms for driving strong T-cell responses. 67 Robust T-cell responses are linked to cavitary disease,6870 a form of tuberculosis in which a granuloma is in direct contact with an airway, allowing bacteria to be more easily transmitted to a new host. Thus, regulation of TH1 responses may be necessary for optimal control of the infection and pathology.

TH17 responses in mice precede a strong TH1 response in the lungs, and increased TH17 cells can lead to enhanced recruitment of TH1 cells.7173 This appears to be important in vaccine-induced control of Mtb in mice,73 but the long-term role for TH17 cells in inducing or recruiting TH1 cells, and the effect this may have on the inflammatory balance in the granuloma in humans is not known. IL-17 also contributes to neutrophil recruitment in other systems, and neutrophils can increase the inflammatory nature of a granuloma. Excessive neutrophils have been implicated in active tuberculosis in humans.74 The data for the importance of TH17 cells in human tuberculosis are scarce so far (reviewed in ref. 75); BCG immunization does induce both TH1 and TH17 cells,76 but whether these are necessary for protection or contribute to pathology is not clear.

CD4+Foxp3+ Treg cells are important contributors to dampening inflammation. These cells are present in the granuloma of humans, non-human primates, and mice.7779 The loss of Foxp3 + Tregs in mice leads to higher bacterial loads.79 However, modulation of the Treg population in certain mice leads to increased mortality because of enhanced inflammation in the lungs.80 Tregs are good candidates for balancing immune responses through their interactions with T cells and necessary for preventing autoimmune diseases. Although Tregs are often only considered in their capacity to downregulate effector T-cell responses, and therefore exacerbate the infection, in chronic or persistent infections, these cells may be crucial players in preventing pathology. In macaques, Tregs rapidly left the blood and appeared in the airways following Mtb infection. 78 Surprisingly, those monkeys with high levels of Tregs in blood before infection (presumably resulting in higher levels in lungs postinfection) were more likely to develop latent, rather than active tuberculosis. Thus, these cells may modulate the granuloma environment, and downregulate inflammation, which somehow contributes to the success of the granuloma in containing the infection (Figure 1).

The importance of regulating the T-cell response to control granulomatous inflammation is also demonstrated by the phenotype of programmed death-1 (PD-1) knockout mice. PD-1 is an exhaustion marker for T cells and engagement of PD-1 inhibits T-cell responses. In PD-1-deficient mice, the effector CD4 T-cell response was substantially enhanced, but the mice succumbed quickly because of increased pathology and higher bacterial load. 81,82 The mechanisms by which this occurs in the PD-1 knockout mice are not clear, and may be because of enhanced necrosis in the lungs due to strong T-cell responses, providing the right environment for robust growth of the bacilli. These data support that increased CD4 TH1 cells do not necessarily enhance control of infection, and that the lack of regulation of T cells by several different mechanisms exacerbates pathology.

B cells

B cells are a major cellular component of granulomas in humans, non-human primates, and mice infected with Mtb8386 (J.L. Flynn, J. Chan and J. Phuah, unpublished data). In Mtb- infected mice, B cells constitute 5–7% of total leukocytes present in lungs.84 They form discrete aggregates suggestive of tertiary lymphoid tissues with features of germinal center B cells,87,88 which are in close proximity to macrophages84 (Figure 1). Emerging evidence in mice indicates that B cells are required for optimal immunity against Mtb, modulating susceptibility, cytokine production, histopathology, neutrophilic infiltration, as well as T-cell responses. 89 How B cells regulate the immune response to Mtb is just beginning to be addressed. B cells can produce antibodies, cytokines, and present antigens,89 which potentially regulate other immune cells in the granuloma in a direct or indirect fashion. In particular, the macrophage is subject to regulation by B cells.

There are B-cell subsets with distinct immunologic function,9092 including signature cytokine profiles, much like in the T-cell TH1/TH2 paradigm.90,92 The functional relevance of the different cytokine profiles is underscored by the ability of distinct effector B-cell subsets to bias the development of T cells along the TH1 or TH2 lineage.90,92 In infectious diseases model, AAM macrophages are conducive to persistence of certain pathogens.93 Recently, B1 cells, a subset of B lymphocytes, have been shown to promote the polarization of macrophages to a unique phenotype, including upregulation of IL-10 production, down-regulation of TNF, IL-1β, and CCL3 (chemokine (C-C motif) ligand 3), as well as expression of typical AAM markers such as Ym1 and Fizz1.94 The key factor mediating polarization is IL-10.95 It is possible that by regulating macrophage functions, B cells can affect immune responses to the tubercle bacillus.

By virtue of their ability to produce antibodies, B cells are requisite to formation of immune complexes with potent immunoregulatory roles. For example, ligation of Fcγ receptors (FcγRs) on macrophages by immune complexes can have remarkable immunological effects. Ligation of FcγRs by antibody-coated Leishmania results in increased IL-10 and decreased IL-12 production by macrophages, 96 enhancing leishmanial growth in macrophages. As a result, the phenomenon has been termed “antibody-dependent enhancement (ADE) of microbial infection.”96 ADE was originally observed in viral pathogens, most notably the Dengue virus, 97101 and can be dependent on the nature of the immune complex.102 Whether ADE is applicable to in vivo Mtb infection, where immune complexes are known to exist,103,104 remains to be determined. Plasma cells, B cells that produce large quantities of antibodies, are found in macaque granulomas (J. Phuah and J.L. Flynn, unpublished data). Mice infected with monoclonal antibody-coated Mtb displayed improved outcome.105 The FcγRIIB-deficient knockout strain has increased control of Mtb infection, concomitant with an enhanced Th1 T-cell response. 106 Furthermore, although immune complex engagement of activating FcγR has been reported to a major mechanism underlying IL-10-enhancing ADE, immune complex-treated Mtb-infected FcγRIIB knockout macrophages produce enhanced IL-12p40.106 Thus, through antibody production, B cells can modulate host immune responses by different mechanisms, one of which could be regulation of macrophage via FcgR engagement with immune complexes.

Through antibody production and modulation of macrophages, modulation of T cells,89,91 as well as direct cytokine production, B cells have the ability to contribute to the inflammatory balance in the granuloma (Figure 1). Although neglected to date, the role of B cells in regulating the immune response during Mtb infection warrants further investigation.


Mtb orchestrates a complex set of immune responses in humans, with the most common outcome being lifetime control of the infection. However, when the balance of immune responses is disturbed, primary tuberculosis or reactivation of latent infection can occur. Here we explored the macrophage as a key mediator of inflammatory control in the granuloma, as it is the cell that interacts most frequently with the bacillus and the other key cells within the granuloma. Thus, it acts as the central control cell for events within the granuloma, dictating the outcome of infection. Strategies for modulating the macrophages may be useful in preventing disease, but must be approached carefully, as we do not understand the balance of cells and mediators necessary to kill bacilli, yet prevent lung pathology. These are important areas for further study.


We acknowledge support from the NIH (J.L.F.: AI37859, HL092883; J.L.F. and J.C.: AI50732, HL71241) and the Bill and Melinda Gates Foundation (J.L.F. and P.L.L.).



The authors declared no conflict of interest.


1. Global Tuberculosis Control WHO Report 2010. World Health Organization; Geneva: 2010.
2. van Lettow M, van der Meer JW, West CE, van Crevel R, Semba RD. Interleukin-6 and human immunodeficiency virus load, but not plasma leptin concentration, predict anorexia and wasting in adults with pulmonary tuberculosis in Malawi. J Clin Endocrinol Metab. 2005;90:4771–4776. [PubMed]
3. Santucci N, et al. A clinical correlate of the dysregulated immuno-endocrine response in human tuberculosis. Neuroimmunomodulation. 2010;17:184–187. [PubMed]
4. Lawn SD, Myer L, Edwards D, Bekker LG, Wood R. Short-term and long-term risk of tuberculosis associated with CD4 cell recovery during antiretroviral therapy in South Africa. AIDS. 2009;23:1717–1725. [PMC free article] [PubMed]
5. Lawn SD, Wilkinson RJ, Lipman MC, Wood R. Immune reconstitution and “unmasking” of tuberculosis during antiretroviral therapy. Am J Respir Crit Care Med. 2008;177:680–685. [PMC free article] [PubMed]
6. Meintjes G, et al. Tuberculosis-associated immune reconstitution inflammatory syndrome: case definitions for use in resource-limited settings. Lancet Infect Dis. 2008;8:516–523. [PMC free article] [PubMed]
7. van Crevel R, Ottenhoff TH, van der Meer JW. Innate immunity to Mycobacterium tuberculosis. Clin Microbiol Rev. 2002;15:294–309. [PMC free article] [PubMed]
8. Cooper AM, Solache A, Khader SA. Interleukin-12 and tuberculosis: an old story revisited. Curr Opin Immunol. 2007;19:441–447. [PMC free article] [PubMed]
9. Clay H, Volkman HE, Ramakrishnan L. Tumor necrosis factor signaling mediates resistance to mycobacteria by inhibiting bacterial growth and macrophage death. Immunity. 2008;29:283–294. [PMC free article] [PubMed]
10. Algood HM, Lin PL, Flynn JL. Tumor necrosis factor and chemokine interactions in the formation and maintenance of granulomas in tuberculosis. Clin Infect Dis. 2005;41 (Suppl 3):S189–S193. [PubMed]
11. Algood HM, et al. TNF influences chemokine expression of macrophages in vitro and that of CD11b+ cells in vivo during Mycobacterium tuberculosis infection. J Immunol. 2004;172:6846–6857. [PubMed]
12. Ray JC, Flynn JL, Kirschner DE. Synergy between individual TNF-dependent functions determines granuloma performance for controlling Mycobacterium tuberculosis infection. J Immunol. 2009;182:3706–3717. [PMC free article] [PubMed]
13. Lee J, Remold HG, Ieong MH, Kornfeld H. Macrophage apoptosis in response to high intracellular burden of Mycobacterium tuberculosis is mediated by a novel caspase-independent pathway. J Immunol. 2006;176:4267–4274. [PubMed]
14. Marino S, Myers A, Flynn JL, Kirschner DE. TNF and IL-10 are major factors in modulation of the phagocytic cell environment in lung and lymph node in tuberculosis: a next-generation two-compartmental model. J Theor Biol. 2010;265:586–598. [PMC free article] [PubMed]
15. Day J, Friedman A, Schlesinger LS. Modeling the immune rheostat of macrophages in the lung in response to infection. Proc Natl Acad Sci USA. 2009;106:11246–11251. [PubMed]
16. Davis JM, et al. Real-time visualization of mycobacterium-macrophage interactions leading to initiation of granuloma formation in zebrafish embryos. Immunity. 2002;17:693–702. [PubMed]
17. Clay H, et al. Dichotomous role of the macrophage in early Mycobacterium marinum infection of the zebrafish. Cell Host Microbe. 2007;2:29–39. [PMC free article] [PubMed]
18. Davis JM, Ramakrishnan L. The role of the granuloma in expansion and dissemination of early tuberculous infection. Cell. 2009;136:37–49. [PMC free article] [PubMed]
19. Wolf AJ, et al. Mycobacterium tuberculosis infects dendritic cells with high frequency and impairs their function in vivo. J Immunol. 2007;179:2509–2519. [PubMed]
20. Chackerian AA, Alt JM, Perera TV, Dascher CC, Behar SM. Dissemination of Mycobacterium tuberculosis is influenced by host factors and precedes the initiation of T-cell immunity. Infect Immun. 2002;70:4501–4509. [PMC free article] [PubMed]
21. Lin PL, et al. Early events in Mycobacterium tuberculosis infection in cynomolgus macaques. Infect Immun. 2006;74:3790–3803. [PMC free article] [PubMed]
22. Wolf AJ, et al. Initiation of the adaptive immune response to Mycobacterium tuberculosis depends on antigen production in the local lymph node, not the lungs. J Exp Med. 2008;205:105–115. [PMC free article] [PubMed]
23. Winslow GM, Cooper A, Reiley W, Chatterjee M, Woodland DL. Early T-cell responses in tuberculosis immunity. Immunol Rev. 2008;225:284–299. [PMC free article] [PubMed]
24. Flynn JL, Klein E. Pulmonary Tuberculosis in Monkeys. In: Leong J, Datois V, Dick T, editors. A Color Atlas of Comparative Pulmonary Tuberculosis Histopathology. Taylor & Francis Publishers; Boca Raton, FL: 2011. pp. 83–106.
25. Flynn JL, Tsenova L, Izzo A, Kaplan G. Experimental animal models of tuberculosis. In: Kaufmann SHE, Britton WJ, editors. Handbook of Tuberculosis: Immunology and Cell Biology. Vol. 2. Wiley-VCH; Weinheim: 2008. pp. 389–417.
26. Pichugin AV, Yan BS, Sloutsky A, Kobzik L, Kramnik I. Dominant role of the sst1 locus in pathogenesis of necrotizing lung granulomas during chronic tuberculosis infection and reactivation in genetically resistant hosts. Am J Pathol. 2009;174:2190–2201. [PubMed]
27. Pozos TC, Ramakrishnan L. New models for the study of Mycobacterium-host interactions. Curr Opin Immunol. 2004;16:499–505. [PubMed]
28. Tobin DM, et al. The lta4h locus modulates susceptibility to mycobacterial infection in zebrafish and humans. Cell. 2010;140:717–730. [PMC free article] [PubMed]
29. Lin PL, et al. TNF neutralization results in disseminated disease during acute and latent M. tuberculosis infection with normal granuloma structure. Arthritis Rheum. 2010;62:340–350. [PMC free article] [PubMed]
30. Lin PL, et al. Quantitative comparison of active and latent tuberculosis in the cynomolgus macaque model. Infect Immun. 2009;77:4631–4642. [PMC free article] [PubMed]
31. Mehra S, et al. Transcriptional reprogramming in nonhuman primate (rhesus macaque) tuberculosis granulomas. PLoS One. 2010;5:e12266. [PMC free article] [PubMed]
32. Langermans JA, et al. Divergent effect of bacillus Calmette-Guerin (BCG) vaccination on Mycobacterium tuberculosis infection in highly related macaque species: implications for primate models in tuberculosis vaccine research. Proc Natl Acad Sci USA. 2001;98:11497–11502. [PubMed]
33. Chen CY, et al. A critical role for CD8 T cells in a nonhuman primate model of tuberculosis. PLoS Pathog. 2009;5:e1000392. [PMC free article] [PubMed]
34. Fallahi-Sichani M, El-Kebir M, Marino S, Kirschner DE, Linderman JJ. Multiscale computational modeling reveals a critical role for TNF-α receptor 1 dynamics in tuberculosis granuloma formation. J Immunol. 2011;186:3472–3483. [PMC free article] [PubMed]
35. Drage MG, et al. TLR2 and its co-receptors determine responses of macrophages and dendritic cells to lipoproteins of Mycobacterium tuberculosis. Cell Immunol. 2009;258:29–37. [PMC free article] [PubMed]
36. El Kasmi KC, et al. Toll-like receptor-induced arginase 1 in macrophages thwarts effective immunity against intracellular pathogens. Nat Immunol. 2008;9:1399–1406. [PMC free article] [PubMed]
37. Velez DR, et al. Variants in toll-like receptors 2 and 9 influence susceptibility to pulmonary tuberculosis in Caucasians, African-Americans, and West Africans. Hum Genet. 2010;127:65–73. [PMC free article] [PubMed]
38. Ito T, et al. TLR9 activation is a key event for the maintenance of a mycobacterial antigen-elicited pulmonary granulomatous response. Eur J Immunol. 2007;37:2847–2855. [PubMed]
39. Numata K, et al. Overexpression of suppressor of cytokine signaling-3 in T cells exacerbates acetaminophen-induced hepatotoxicity. J Immunol. 2007;178:3777–3785. [PubMed]
40. Pompei L, et al. Disparity in IL-12 release in dendritic cells and macrophages in response to Mycobacterium tuberculosis is due to use of distinct TLRs. J Immunol. 2007;178:5192–5199. [PubMed]
41. Hawn TR, et al. A common human TLR1 polymorphism regulates the innate immune response to lipopeptides. Eur J Immunol. 2007;37:2280–2289. [PubMed]
42. Thuong NT, et al. A polymorphism in human TLR2 is associated with increased susceptibility to tuberculous meningitis. Genes Immun. 2007;8:422–428. [PubMed]
43. van der Wel N, et al. M. tuberculosis and M. leprae translocate from the phagolysosome to the cytosol in myeloid cells. Cell. 2007;129:1287–1298. [PubMed]
44. McDonough KA, Kress Y, Bloom BR. Pathogenesis of tuberculosis: interaction of Mycobacterium tuberculosis with macrophages. Infect Immun. 1993;61:2763–2773. [PMC free article] [PubMed]
45. Carlsson F, et al. Host-detrimental role of Esx-1-mediated inflammasome activation in mycobacterial infection. PLoS Pathog. 2010;6:e1000895. [PMC free article] [PubMed]
46. Leber JH, et al. Distinct TLR- and NLR-mediated transcriptional responses to an intracellular pathogen. PLoS Pathog. 2008;4:e6. [PMC free article] [PubMed]
47. McElvania Tekippe E, et al. Granuloma formation and host defense in chronic Mycobacterium tuberculosis infection requires PYCARD/ASC but not NLRP3 or caspase-1. PLoS One. 2010;5:e12320. [PMC free article] [PubMed]
48. DiGiuseppe Champion PA, Champion MM, Manzanillo P, Cox JS. ESX-1 secreted virulence factors are recognized by multiple cytosolic AAA ATPases in pathogenic mycobacteria. Mol Microbiol. 2009;73:950–962. [PMC free article] [PubMed]
49. Gordon S, Taylor PR. Monocyte and macrophage heterogeneity. Nat Rev Immunol. 2005;5:953–964. [PubMed]
50. Martinez FO, Sica A, Mantovani A, Locati M. Macrophage activation and polarization. Front Biosci. 2008;13:453–461. [PubMed]
51. Gordon S, Martinez FO. Alternative activation of macrophages: mechanism and functions. Immunity. 2010;32:593–604. [PubMed]
52. Martinez FO, Helming L, Gordon S. Alternative activation of macrophages: an immunologic functional perspective. Annu Rev Immunol. 2009;27:451–483. [PubMed]
53. MacMicking JD, et al. Identification of nitric oxide synthase as a protective locus against tuberculosis. Proc Natl Acad Sci USA. 1997;94:5243–5248. [PubMed]
54. Flynn JL, Scanga CA, Tanaka KE, Chan J. Effects of aminoguanidine on latent murine tuberculosis. J Immunol. 1998;160:1796–1803. [PubMed]
55. Scanga CA, et al. The inducible nitric oxide synthase locus confers protection against aerogenic challenge of both clinical and laboratory strains of Mycobacterium tuberculosis in mice. Infect Immun. 2001;69:7711–7717. [PMC free article] [PubMed]
56. Nathan C. Inducible nitric oxide synthase in the tuberculous human lung. Am J Respir Crit Care Med. 2002;166:130–131. [PubMed]
57. Choi HS, Rai PR, Chu HW, Cool C, Chan ED. Analysis of nitric oxide synthase and nitrotyrosine expression in human pulmonary tuberculosis. Am J Respir Crit Care Med. 2002;166:178–186. [PubMed]
58. Harris J, et al. T helper 2 cytokines inhibit autophagic control of intracellular Mycobacterium tuberculosis. Immunity. 2007;27:505–517. [PubMed]
59. Buccheri S, et al. IL-4 depletion enhances host resistance and passive IgA protection against tuberculosis infection in BALB/c mice. Eur J Immunol. 2007;37:729–737. [PubMed]
60. Roy E, Brennan J, Jolles S, Lowrie DB. Beneficial effect of anti-interleukin-4 antibody when administered in a murine model of tuberculosis infection. Tuberculosis (Edinb) 2008;88:197–202. [PubMed]
61. Qualls JE, et al. Arginine usage in mycobacteria-infected macrophages depends on autocrine-paracrine cytokine signaling. Sci Signal. 2010;3:ra62. [PMC free article] [PubMed]
62. Cooper AM. Cell-mediated immune responses in tuberculosis. Annu Rev Immunol. 2009;27:393–422. [PubMed]
63. Cooper AM, Khader SA. The role of cytokines in the initiation, expansion, and control of cellular immunity to tuberculosis. Immunol Rev. 2008;226:191–204. [PubMed]
64. Mattila JT, Diedrich CR, Lin PL, Phuah J, Flynn JL. Simian immunodeficiency virus-induced changes in T cell cytokine responses in cynomolgus macaques with latent Mycobacterium tuberculosis infection are associated with timing of reactivation. J Immunol. 2011;186:3527–3537. [PMC free article] [PubMed]
65. Comas I, et al. Human T cell epitopes of Mycobacterium tuberculosis are evolutionarily hyperconserved. Nat Genet. 2010;42:498–503. [PMC free article] [PubMed]
66. Lazarevic V, Myers AJ, Scanga CA, Flynn JL. CD40, but not CD40L, is required for the optimal priming of T cells and control of aerosol M. tuberculosis infection. Immunity. 2003;19:823–835. [PubMed]
67. Flynn JL, Chan J. What’s good for the host is good for the bug. Trends Microbiol. 2005;13:98–102. [PubMed]
68. Jones BE, et al. Chest radiographic findings in patients with tuberculosis with recent or remote infection. Am J Respir Crit Care Med. 1997;156:1270–1273. [PubMed]
69. Jones BE, et al. CD4 cell counts in human immunodeficiency virus-negative patients with tuberculosis. Clin Infect Dis. 1997;24:988–991. [PubMed]
70. Perlman DC, et al. Variation of chest radiographic patterns in pulmonary tuberculosis by degree of human immunodeficiency virus-related immunosuppression. The Terry Beirn Community Programs for Clinical Research on AIDS (CPCRA) The AIDS Clinical Trials Group (ACTG) Clin Infect Dis. 1997;25:242–246. [PubMed]
71. Lin Y, et al. Interleukin-17 is required for T helper 1 cell immunity and host resistance to the intracellular pathogen Francisella tularensis. Immunity. 2009;31:799–810. [PMC free article] [PubMed]
72. Khader SA, Gaffen SL, Kolls JK. Th17 cells at the crossroads of innate and adaptive immunity against infectious diseases at the mucosa. Mucosal Immunol. 2009;2:403–411. [PMC free article] [PubMed]
73. Khader SA, et al. IL-23 and IL-17 in the establishment of protective pulmonary CD4+ T cell responses after vaccination and during Mycobacterium tuberculosis challenge. Nat Immunol. 2007;8:369–377. [PubMed]
74. Berry MP, et al. An interferon-inducible neutrophil-driven blood transcriptional signature in human tuberculosis. Nature. 2010;466:973–977. [PMC free article] [PubMed]
75. Cooper AM. Editorial: Be careful what you ask for: is the presence of IL-17 indicative of immunity? J Leukoc Biol. 2010;88:221–223. [PubMed]
76. Burl S, et al. Delaying bacillus Calmette-Guerin vaccination from birth to 4 1/2 months of age reduces postvaccination Th1 and IL-17 responses but leads to comparable mycobacterial responses at 9 months of age. J Immunol. 2010;185:2620–2628. [PubMed]
77. Rahman S, et al. Compartmentalization of immune responses in human tuberculosis: few CD8+ effector T cells but elevated levels of FoxP3+ regulatory t cells in the granulomatous lesions. Am J Pathol. 2009;174:2211–2224. [PubMed]
78. Green AM, et al. CD4(+) regulatory T cells in a cynomolgus macaque model of Mycobacterium tuberculosis infection. J Infect Dis. 2010;202:533–541. [PMC free article] [PubMed]
79. Scott-Browne J, et al. Expansion and function of Foxp3-expressing T regulatory cells in tuberculosis. J Exp Med. 2007;204:2159–2169. [PMC free article] [PubMed]
80. Windish HP, et al. Aberrant TGF-beta signaling reduces T regulatory cells in ICAM-1-deficient mice, increasing the inflammatory response to Mycobacterium tuberculosis. J Leukoc Biol. 2009;86:713–725. [PubMed]
81. Lazar-Molnar E, et al. Programmed death-1 (PD-1)-deficient mice, are extraordinarily sensitive to tuberculosis. Proc Natl Acad Sci USA. 2010;107:13402–13407. [PubMed]
82. Barber DL, Mayer-Barber KD, Feng CG, Sharpe AH, Sher A. CD4 T cells promote rather than control tuberculosis in the absence of PD-1-mediated inhibition. J Immunol. 2011;186:1598–1607. [PubMed]
83. Gonzalez-Juarrero M, et al. Temporal and spatial arrangement of lymphocytes within lung granulomas induced by aerosol infection with Mycobacterium tuberculosis. Infect Immun. 2001;69:1722–1728. [PMC free article] [PubMed]
84. Tsai MC, et al. Characterization of the tuberculous granuloma in murine and human lungs: cellular composition and relative tissue oxygen tension. Cell Microbiol. 2006;8:218–232. [PubMed]
85. Turner J, Frank AA, Brooks JV, Gonzalez-Juarrero M, Orme IM. The progression of chronic tuberculosis in the mouse does not require the participation of B lymphocytes or interleukin-4. Exp Gerontol. 2001;36:537–545. [PubMed]
86. Ulrichs T, et al. Human tuberculous granulomas induce peripheral lymphoid follicle-like structures to orchestrate local host defence in the lung. J Pathol. 2004;204:217–228. [PubMed]
87. Kahnert A, et al. Mycobacterium tuberculosis triggers formation of lymphoid structure in murine lungs. J Infect Dis. 2007;195:46–54. [PubMed]
88. Maglione PJ, Xu J, Chan J. B cells moderate inflammatory progression and enhance bacterial containment upon pulmonary challenge with Mycobacterium tuberculosis. J Immunol. 2007;178:7222–7234. [PubMed]
89. Maglione PJ, Chan J. How B cells shape the immune response against Mycobacterium tuberculosis. Eur J Immunol. 2009;39:676–686. [PMC free article] [PubMed]
90. Harris DP, et al. Reciprocal regulation of polarized cytokine production by effector B and T cells. Nat Immunol. 2000;1:475–482. [PubMed]
91. Lund FE, Randall TD. Effector and regulatory B cells: modulators of CD4(+) T cell immunity. Nat Rev Immunol. 2010;10:236–247. [PMC free article] [PubMed]
92. Mosmann T. Complexity or coherence? Cytokine secretion by B cells. Nat Immunol. 2000;1:465–466. [PubMed]
93. Benoit M, Desnues B, Mege JL. Macrophage polarization in bacterial infections. J Immunol. 2008;181:3733–3739. [PubMed]
94. Wong SC, et al. Macrophage polarization to a unique phenotype driven by B cells. Eur J Immunol. 2010;40:2296–2307. [PubMed]
95. Davila S, et al. Genetic association and expression studies indicate a role of toll-like receptor 8 in pulmonary tuberculosis. PLoS Genet. 2008;4:e1000218. [PMC free article] [PubMed]
96. Halstead SB, Mahalingam S, Marovich MA, Ubol S, Mosser DM. Intrinsic antibody-dependent enhancement of microbial infection in macrophages: disease regulation by immune complexes. Lancet Infect Dis. 2010;10:712–722. [PMC free article] [PubMed]
97. Halstead SB, Chow JS, Marchette NJ. Immunological enhancement of dengue virus replication. Nat New Biol. 1973;243:24–26. [PubMed]
98. Halstead SB, O’Rourke EJ. Dengue viruses and mononuclear phagocytes. I Infection enhancement by non-neutralizing antibody. J Exp Med. 1977;146:201–217. [PMC free article] [PubMed]
99. Halstead SB, O’Rourke EJ. Antibody-enhanced dengue virus infection in primate leukocytes. Nature. 1977;265:739–741. [PubMed]
100. Kliks SC, Halstead SB. An explanation for enhanced virus plaque formation in chick embryo cells. Nature. 1980;285:504–505. [PubMed]
101. Kliks SC, Halstead SB. Role of antibodies and host cells in plaque enhancement of Murray Valley encephalitis virus. J Virol. 1983;46:394–404. [PMC free article] [PubMed]
102. Mahalingam S, Lidbury BA. Suppression of lipopolysaccharide-induced antiviral transcription factor (STAT-1 and NF-kappa B) complexes by antibody-dependent enhancement of macrophage infection by Ross River virus. Proc Natl Acad Sci USA. 2002;99:13819–13824. [PubMed]
103. Brostoff J, Lenzini L, Rottoli P, Rottoli L. Immune complexes in the spectrum of tuberculosis. Tubercle. 1981;62:169–173. [PubMed]
104. Sai Baba KS, Moudgil KD, Jain RC, Srivastava LM. Complement activation in pulmonary tuberculosis. Tubercle. 1990;71:103–107. [PubMed]
105. Teitelbaum R, et al. A mAb recognizing a surface antigen of Mycobacterium tuberculosis enhances host survival. Proc Natl Acad Sci USA. 1998;95:15688–15693. [PubMed]
106. Maglione PJ, Xu J, Casadevall A, Chan J. Fc gamma receptors regulate immune activation and susceptibility during Mycobacterium tuberculosis infection. J Immunol. 2008;180:3329–3338. [PubMed]