What is the difference between granuloma and tubercle

In addition to the classical Th1 response, a Thtype response is also triggered by mycobacterial infection. IL is a proinflammatory cytokine driving the recruitment of effector cells, such as neutrophils, and participating in the activation of macrophages. They limit the intensity of the immune response to the bacteria in a manner that seems to be independent of IL, as shown in depletion studies in mice and, ex vivo, in human PBMCs.

They are thought to play an important role in the establishment of persistent infection. They display susceptibility to virulent mycobacteria and the infectious phenotype is dependent on the size of the inoculum [ 65 , 79 , 82 ]. They have marked central necrotic zones not seen in wild-type mice. This seems to be due to a lack of apoptosis induction in infected cells, resulting in the degeneration of these cells and an increase in neutrophil infiltration into the lesions [ 79 , 83 ].

Cooper et al. In humans, Mtb - specific CTL have been found [ 87 ] and shown to direct the granulysin-mediated lysis of the bacteria [ 88 ]. This would contribute to the stability of the granuloma [ 68 ].

There is some debate about their role in the antimycobacterial response in mice [ 80 , 81 , 89 ]. This compartment also expands rapidly upon restimulation, in a reminiscent manner of memory cells [ 91 , 92 ]. These cells were first described in granulomas more than 20 years ago and seem to be involved in the formation and development of these structures [ 80 , 94 , 95 ]. Saunders et al. The infected macrophages therefore degenerate, resulting in high levels of inflammation and tissue damage.

Conversely, in mice infected with the 2— strain of M. This IL production is dependent on antigenic stimulation and exposure to IL [ 76 , 98 ]. In a study of tissue from patients with BCG lymphadenitis, Kim et al. However, Falini et al. The subcutaneous injection of deproteinated mycobacterial cell wall into mice has been shown to induce granuloma-like structures with a high NKT-cell content, these T cells being activated by the recognition of bacterial PIMs [ ].

However, granuloma formation in the lungs of NKT KO mice infected intranasally with Mtb seemed to be as efficient as that in wild-type mice [ ]. Dieli et al. This suggests that NKT cells may play an anti-inflammatory role in the mycobacterial granuloma [ ]. The treatment of Mtb-infected mice with -galactosyl-ceramide, a potent activator of NKT cells, has been shown to decrease bacterial load and to improve the survival of the animals.

The lung lesions of the treated mice were less necrotic and contained a larger number of lymphocytes [ ]. Necrotic granulomas have been shown to express the SapC gene strongly. This gene encodes a protein involved in ceramide metabolism and in the transfer of mycobacterial lipid antigens from intralysosomal membranes to CD1d [ ]. Further studies are required to determine the exact ligands of NKT cells and the effect of these cells on the immune response in the context of mycobacterial infection.

The response to mycobacterial infection is based mostly on cellular immunity, with the role of humoral immunity in protection against TB remains a matter of debate [ , ].

Nonetheless, B cells have been implicated in the organisation and development of granulomatous lesions in the lung. The lungs of mice with no B cells contain fewer granulomas than those of wild-type mice, and these granulomas are much smaller with little cellular infiltrate. These changes are not correlated with differences in the ability to contain the infection, as the lungs of wild-type mice and mice with no B cells contain similar numbers of bacteria [ , ].

An absence of B cells has also been shown to have no effect on tuberculosis progression during the chronic phase, over a period of days [ ]. B cells form aggregates in both mice [ 64 , ] and humans [ 64 , ]. These aggregates resemble the follicular structures of the lymph nodes. However, these B-cell clusters are associated principally with monocytes in mice and with T lymphocytes in humans. These structures are more frequently found in patients with latent tuberculosis and are thus associated with good immune control of the disease [ ].

Cells of the B-1 subset are present in the peritoneal and pleural cavities. X-linked immunodeficient Xid mice lacking B-1 cells are more susceptible to BCG infection than their wild-type counterparts. Thus, B-1 cells appear to be involved in granuloma formation and the inflammatory state, at least through their downregulation of MCP-1 secretion.

However, the presence of these cells within the granuloma has not been demonstrated [ ]. B-1 cells have recently been shown to polarise anti-inflammatory macrophages resembling the AAMs found in tuberculous granulomas. This polarisation seems to be driven principally by IL secretion [ ]. The granuloma tends to become necrotic in susceptible individuals, facilitating bacterial spread by coughing. It is assumed that apoptosis kills the bacteria and promotes antigen presentation, thereby stimulating T cells, whereas the necrosis of infected cells releases the bacteria and promotes inflammation and tissue damage see [ ].

It remains unclear why some individuals have necrotic lesions whilst others do not progress beyond latent infection, and the factors triggering necrosis have yet to be identified.

The tuberculous granulomas of mice induced by commonly used strains do not display caseous necrosis, whereas this feature is observed in other animal models, such as guinea pigs, rabbits, and macaques, and in mice infected with certain strains of M.

Caseous necrosis is associated with a hypoxic state of the lesions [ 64 , , ]. In the model of M. In humans, transcriptional analyses of microdissected tuberculous granulomas have shown that caseation is associated with an increase in lipid metabolism. This is consistent with a role for foamy macrophages in the formation of the central necrotic zone [ 35 , ]. There are good reasons to think that neutrophils also play a role in necrosis.

It remains unclear whether these cells are protective or damaging, but, when Mtb-infected animals are repeatedly challenged with mycobacterial antigens, the lesions become necrotic and contain a higher proportion of granulocytes [ ].

Early diagnosis and appropriate treatment of TB are important, to reduce transmission and favour the elimination of the bacterium. Diagnosis and follow up have recently been improved by the development of imaging techniques using radiopharmaceutical compounds.

FDG-PET can be used not only for diagnosis, but also for monitoring throughout tuberculosis treatments, particularly in cases of multidrug-resistant infections. Soussan et al. Sathekge et al. In this review, they pointed out that one of the key problems in tuberculosis diagnosis is the invasive nature of the methods used [ ]. The development of new, safe and noninvasive methods for imaging is therefore likely to prove highly beneficial.

We now have various experimental models that should help to unveil the mysteries of the complex host-pathogen relationships taking place in the mycobacterial granuloma. Granuloma formation seems to be primarily a host-defence mechanism for containing the bacteria, but it also shelters the bacteria, providing them with a niche in which they can persist in a latent form until an opportunity arises for re-activation and spread.

An understanding of the physiopathology of granulomas is critical for the design of new vaccines and antituberculous drugs. Granulomas are not restricted to mycobacterial infections, being found in many different kinds of bacterial, fungal or viral infections, and even in noninfectious inflammatory diseases [ 4 ]. Thus, the knowledge obtained about mycobacterial granulomas and some of the models used to study them may be useful in the fight against other diseases.

This is an open access article distributed under the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Article of the Year Award: Outstanding research contributions of , as selected by our Chief Editors. Read the winning articles. Journal overview. Special Issues. Academic Editor: E. Received 09 Dec Revised 16 Apr Accepted 30 Apr Published 03 Jul Abstract One of the main features of the immune response to M.

Introduction Almost 20 people develop tuberculosis and four people die from the disease every minute, somewhere in the world [ 1 ]. Figure 1. Formation and maturation of lung tuberculous granulomas. Following inhalation of contaminated aerosols, M. Tuberculosis moves to the lower respiratory tract where it is recognized by alveolar macrophages. This recognition is mediated by a set of surface receptors see text , which drive the uptake of the bacteria and trigger innate immune signalling pathways leading to the production of various chemokines and cytokines a.

Epithelial cells and neutrophils can also produce chemokines in response to bacterial products not represented. This promotes recruitment of other immune cells more macrophages, dendritic cells, and lymphocytes to the infection site b.

B lymphocytes tend to aggregate in follicular-type structures adjacent to the granuloma c , see text for details. The bacteria can survive for decades inside the granuloma in a latent state. Due to some environmental e. A necrotic zone called caseum due to its milky appearance will develop in the centre of the granuloma d.

Ultimately the structure will disintegrate allowing exit of the bacteria, which will spread in other parts of the lungs and more lesions will be formed. Infection will also be transmitted to other individuals due to release of the infected droplets by coughing e.

Model Advantages Drawbacks Monkey Granuloma similar to humans. Difficult to handle. Restricted availability of reagents. Easy to handle. Genetic manipulation difficult. Mice Easy to handle. Granulomas often differ in many ways from Model of choice for genetic studies.

Zebrafish embryo Easy to handle. Good for real-time experiments and live imaging the larvae are transparent. Good for studies of the initial steps of granuloma formation and the role of innate immunity. No lymphocytes present in the embryo. Some important elements present in the lung compartment but not in PBMCs may be lacking.

Possible to study the early steps of granuloma formation. Flexible e. Highly dependent on the initial parameter settings and cannot take previously unknown information into account. Study of the early steps of granuloma formation possible. Table 1. Models for studying Mtb infection and the granulomatous response. Recruitment of neutrophils. Epithelial cells of the lung. Recruitment of macrophages and other immune cells. Recruitment of immune cells. Recruitment and priming of IFN- -producing T cells.

Migration of DC from the lung to draining lymph nodes. CXCL13 Dendritic cells, stromal cells of the lymph nodes. Recruitment of B cells and formation of the granuloma-associated follicular structures. Activation of macrophages. Induction of NO synthesis and bacterial killing. Induction of chemokine production.

Critical for granuloma formation. IL-1 Macrophages, DCs. Recruitment and activation of phagocytes. Involved in neutrophil recruitment and macrophage activation. Polarisation of macrophages towards the AAM type. Table 2. Main chemokines and cytokines involved in the granulomatous response. References S. Gonzalez-Cano, R. View at: Google Scholar M.

Sandor, J. Weinstock, and T. Cooper, K. Mayer-Barber, and A. Jo, C. Yang, C. Choi, and C. Kirschner, D. Young, and J. Gonzalez-Juarrero, O.

Turner, J. Turner, P. Marietta, J. Brooks, and I. Puissegur, C. Botanch, J. Duteyrat, G. Delsol, C. Caratero, and F. Flynn, J. Chan, and P. Huynh, S. Joshi, and E. Day, M. Koch, G. Nouailles et al.

Davis, H. Clay, J. Lewis, N. Ghori, P. The Bottom Line: Does M. Therefore, while a mycobacteria-focused view on granulomas was long overdue Russell, ; Ramakrishnan, , this should by no means neutralize the evidence in favor of the protective infection-sequestrating granuloma: — T cells transfer protective immunity and granuloma formation Orme and Collins, Conflict of Interest Statement The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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Fuller, C. In situ study of abundant expression of proinflammatory chemokines and cytokines in pulmonary granulomas that develop in cynomolgus macaques experimentally infected with Mycobacterium tuberculosis. Chemokine response in mice infected with Mycobacterium tuberculosis. Cooper, A. Download references. The author would like to acknowledge the work of past and present members of the laboratory, most notably E.

Rhoades, R. Geisel and K. You can also search for this author in PubMed Google Scholar. Mycobacterium bovis. Mycobacterium tuberculosis.

David G. Russell's homepage. The ancestral species or strain that underwent divergent evolution to produce several new species or strains. The process by which a tuberculous granuloma decays into a structureless mass of cellular debris. Cytokines involved in specific inflammatory responses.

They also express a T-cell receptor that recognizes CD1b which binds glycolipids not peptides. A subpopulation of T cells that express the CD4 receptor and respond to antigens presented on the surface of host cells that bear major histocompatibility complex class II molecules.

A subpopulation of T cells that express the CD8 receptor. Member of a large family of secreted proteins that bind immune cells through specific receptors. Cytokine production results in the activation of an intracellular-signalling cascade that commonly regulates processes such as immune function and inflammation.

The formation of new blood vessels in a developing tissue. This process is stimulated by the production of vascular endothelial growth factor. The term is used most frequently in cancer biology in which the tumour develops its own blood supply through neovascularization.

A macrophage loaded with lipid droplets. Such cells are often observed in tissues with chronic proinflammatory stimulus. The tuberculoma is the granuloma that is formed during tuberculosis infection. This term is most frequently used by clinicians and has replaced the more traditional 'tubercle'. A pathway for the recycling of cellular contents, in which materials inside the cell are packaged into vesicles and are then targeted to the vacuole or lysosome for bulk turnover.

Fibrosis is frequently seen at sites of chronic inflammatory stimulation. A technique to screen large numbers of distinct mutants for those that fail to survive an animal infection. Each mutant is tagged with a unique DNA sequence called a signature tag , which allows a specific mutant to be tracked within a large pool of bacteria.

Reprints and Permissions. Who puts the tubercle in tuberculosis?. Nat Rev Microbiol 5, 39—47 Download citation. Published : 11 December Issue Date : 01 January Anyone you share the following link with will be able to read this content:. Sorry, a shareable link is not currently available for this article. Provided by the Springer Nature SharedIt content-sharing initiative.

Scientific Reports Virchows Archiv Applied Microbiology and Biotechnology Infectious Diseases of Poverty Communications Biology Advanced search. Skip to main content Thank you for visiting nature. Key Points Mycobacterium tuberculosis probably evolved from a founder strain similar to the TB-like strains found today in central Africa, and invaded mankind prior to the spread of humans out of Africa.

Abstract Tuberculosis TB , an illness that mainly affects the respiratory system, is one of the world's most pernicious diseases. Access through your institution.

Buy or subscribe. Rent or Buy article Get time limited or full article access on ReadCube. Figure 1: Trafficking of Mycobacterium tuberculosis bacilli in cells. Figure 2: Release and trafficking of bacterial lipids. Figure 3: The lipid-bead granuloma model.

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Google Scholar 36 Sturgill-Koszycki, S. Russell Authors David G. Russell View author publications. Ethics declarations Competing interests The author declares no competing financial interests. Glossary Founder strain The ancestral species or strain that underwent divergent evolution to produce several new species or strains. Caseation The process by which a tuberculous granuloma decays into a structureless mass of cellular debris.

Chemokine Cytokines involved in specific inflammatory responses. Cytokine Member of a large family of secreted proteins that bind immune cells through specific receptors. Neovascularization The formation of new blood vessels in a developing tissue. Foamy macrophage A macrophage loaded with lipid droplets. Giant cell A giant, multinucleate macrophage. Curiel, T. Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival.

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