Tuberculosis pathophysiology: Difference between revisions

Jump to navigation Jump to search
VisualWikitext
No edit summary
Line 1: Line 1:
<div style="-webkit-user-select: none;">
<div style="-webkit-user-select: none;">
{|class="infobox" style="position: fixed; top: 65%; right: 10px; margin: 0 0 0 0; border: 0; float: right;
{| class="infobox" style="position: fixed; top: 65%; right: 10px; margin: 0 0 0 0; border: 0; float: right;"
|-
|-
| {{#ev:youtube|https://https://www.youtube.com/watch?v=yR51KVF4OX0|350}}
|{{#ev:youtube|https://https://www.youtube.com/watch?v=yR51KVF4OX0|350}}
|-
|-
|}
|}
Line 10: Line 10:


==Overview==
==Overview==
''M. tuberculosis'' is acquired by inhaled aerosols produced by patients with active disease. The mycobacterium thrives in the upper lung lobes given the high oxygen content. Tuberculosis is a prototypical granulomatous infection. The [[granuloma]] prevents the dissemination of [[M. tuberculosis|mycobacteria]] and provides a pathway for [[immune cell]] communication.  Within the [[granuloma]], [[CD4|CD4 T lymphocytes]] secrete [[cytokines]] such as [[interferon gamma]] that activate local [[macrophages]].
''M. tuberculosis'' infection occurs through inhalation of aerosols produced by patients with active disease The mycobacterium prefers to live in the upper lung lobes due to the high amount of oxygen. Tuberculosis is a prototypical granulomatous infection. The [[granuloma]] encloses mycobacteria and prevents their spreading and facilitates immune [[immune cell]] communication.  Within the [[granuloma]], [[CD4|CD4 T lymphocytes]] release [[cytokines]] such as [[interferon gamma]] that activate local [[macrophages]].


==Pathogenesis==
==Pathogenesis==
The ''M. tuberculosis'' bacterium is acquired by inhaled aerosols generated by individuals with active pulmonary disease. They travel to the terminal airways and alveoli (commonly at the middle lobes, upper regions of lower lobes, and lower regions of upper lobes) and are phagocytosed by alveolar macrophages. The initial immune response generated by these macrophages recruits further macrophages, neutrophils, and monocytes, leading to primary containment of the bacilli. Despite having a very low infectious dose (ID<200 bacteria), 90% of immunocompetent individuals that acquire ''M. tuberculosis'' do not develop [[symptoms]].  In most cases, the bacteria may either be eliminated or be harbored in a latent state by an immune formation known as a granuloma.  The [[granuloma]] is a structured, radial aggregation of immune cells that prevents the dissemination of [[M. tuberculosis|mycobacteria]] and provides a pathway for [[immune cell]] communication.<ref name="Mandell">{{cite book | last = Mandell | first = Gerald | title = Mandell, Douglas, and Bennett's principles and practice of infectious diseases | publisher = Churchill Livingstone/Elsevier | location = Philadelphia, PA | year = 2010 | isbn = 0443068399 }}</ref>  The initial focus of [[infection]] in the lung is a single region in 75% of the cases, and is called the [[Ghon focus]]. Besides the alveolar [[macrophages]],  other [[immune cells]] such as blood [[monocytes]] (tissue [[macrophages]]) and [[lymphocytes]] also migrate to the [[Ghon focus]] aiding in the termination of the infection or initiation of a granulomatous containment.<ref name="Mandell"></ref><ref name=Herrmann_2005>{{cite journal |author=Herrmann J, Lagrange P |title=Dendritic cells and Mycobacterium tuberculosis: which is the Trojan horse? |journal=Pathol Biol (Paris) |volume=53 |issue=1 |pages=35–40 |year=2005 | pmid = 15620608}}</ref>
The ''M. tuberculosis'' bacterium is acquired by inhaled aerosols generated by individuals with active pulmonary disease. They pass to the terminal bronchioles and alveoli (commonly at the middle lobes, upper regions of lower lobes, and lower regions of upper lobes) and are phagocytosed by alveolar macrophages. The initial immune response by these macrophages attracts further macrophages, neutrophils, and monocytes, surrounding the bacilli. Despite having a very low infectious dose (ID<200 bacteria), 90% of immunocompetent individuals that acquire ''M. tuberculosis'' do not develop [[symptoms]].  In most cases, the bacteria may either be eliminated or be harbored in a latent state by an immune formation known as a granuloma.  The [[granuloma]] is a structured, radial aggregation of immune cells that prevents the dissemination of [[M. tuberculosis|mycobacteria]] and provides a pathway for [[immune cell]] communication.<ref name="Mandell">{{cite book | last = Mandell | first = Gerald | title = Mandell, Douglas, and Bennett's principles and practice of infectious diseases | publisher = Churchill Livingstone/Elsevier | location = Philadelphia, PA | year = 2010 | isbn = 0443068399 }}</ref>  The initial focus of [[infection]] in the lung is a single region in 75% of the cases, and is called the [[Ghon focus]]. Besides the alveolar [[macrophages]],  other [[immune cells]] such as blood [[monocytes]] (tissue [[macrophages]]) and [[lymphocytes]] also migrate to the [[Ghon focus]] aiding in the termination of the infection or initiation of a granulomatous containment.<ref name="Mandell"></ref><ref name="Herrmann_2005">{{cite journal |author=Herrmann J, Lagrange P |title=Dendritic cells and Mycobacterium tuberculosis: which is the Trojan horse? |journal=Pathol Biol (Paris) |volume=53 |issue=1 |pages=35–40 |year=2005 | pmid = 15620608}}</ref>


===Primary Infection===
===Primary Infection===
In an [[immunocompetent]] person, the infected [[macrophages]] are transported through the [[lymph]] to the regional [[lymph nodes]].  In [[immunocompromised]] patients, these [[macrophages]] may reach different parts of the body, through the [[bloodstream]]. Despite this wide initial dissemination, most patients resolve those foci of infection without any signs or symptoms of disease.  However, during the dissemination of the infected [[macrophages]],  tissues that are more prone to bacterial replication, represent potential metastatic foci. These tissues include:<ref name="Mandell"></ref><ref name=Herrmann_2005>{{cite journal |author=Herrmann J, Lagrange P |title=Dendritic cells and Mycobacterium tuberculosis: which is the Trojan horse? |journal=Pathol Biol (Paris) |volume=53 |issue=1 |pages=35–40 |year=2005 | pmid = 15620608}}</ref>
In an [[immunocompetent]] person, the infected [[macrophages]] pass through the [[lymph]] to the regional [[lymph nodes]].  In [[immunocompromised]] patients, these [[macrophages]] may bw transported to different parts of the body, through the [[bloodstream|blood]]. In spite of the initial dissemination, those foci of infection usually resolve without any clinical manifestations of disease.  However, during the dissemination of the infected [[macrophages]],  tissues that are more prone to bacterial replication, represent potential metastatic foci. These tissues include:<ref name="Mandell"></ref><ref name="Herrmann_2005">{{cite journal |author=Herrmann J, Lagrange P |title=Dendritic cells and Mycobacterium tuberculosis: which is the Trojan horse? |journal=Pathol Biol (Paris) |volume=53 |issue=1 |pages=35–40 |year=2005 | pmid = 15620608}}</ref>
* Apical-posterior regions of the lungs
* [[Lymph nodes]]
* [[Kidneys]]
* [[Vertebral bodies]]
* Extremities of long bones
* Juxta ependymal [[meningeal]] regions


Although all parts of the body can be affected by TB, the [[heart]], [[skeletal muscle]]s, [[pancreas]] and [[thyroid]] are rarely affected.<ref>{{cite journal |author=Agarwal R, Malhotra P, Awasthi A, Kakkar N, Gupta D |url=http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=15857515 |title=Tuberculous dilated cardiomyopathy: an under-recognized entity? |journal=BMC Infect Dis |volume=5 |issue=1 |pages=29 |year=2005 |pmid=15857515}}</ref> In a small number of cases, when there is a large concentration of [[antigens]] in the primary focus, the development of the [[immune response]] and hypersensitivity may lead to the [[necrosis]] and calcification of this infection site. These primary calcified foci are called '''Ranke complex'''.<ref name="Mandell"></ref><ref name=Grosset>{{cite journal |author=Grosset J |title=Mycobacterium tuberculosis in the extracellular compartment: an underestimated adversary |journal=Antimicrob Agents Chemother |volume=47 |issue=3 |pages=833-6 |year=2003 | pmid = 12604509}}</ref>
*Apical-posterior regions of the lungs
*[[Lymph nodes]]
*[[Kidneys]]
*[[Vertebral bodies]]
*Extremities of long bones
*Juxta ependymal [[meningeal]] regions
 
Although TB can target all body parts, the [[heart]], [[skeletal muscle]]s, [[pancreas]] and [[thyroid]] are rarely affected.<ref>{{cite journal |author=Agarwal R, Malhotra P, Awasthi A, Kakkar N, Gupta D |url=http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=15857515 |title=Tuberculous dilated cardiomyopathy: an under-recognized entity? |journal=BMC Infect Dis |volume=5 |issue=1 |pages=29 |year=2005 |pmid=15857515}}</ref> In a few cases, when the [[antigens]] concentration in the primary focus is high, the development of the [[immune response]] and hypersensitivity may result in the [[necrosis]] and calcification of this infection site. These primary calcified foci are called '''Ranke complex'''.<ref name="Mandell"></ref><ref name="Grosset">{{cite journal |author=Grosset J |title=Mycobacterium tuberculosis in the extracellular compartment: an underestimated adversary |journal=Antimicrob Agents Chemother |volume=47 |issue=3 |pages=833-6 |year=2003 | pmid = 12604509}}</ref>


===Progression of the Primary Infection===
===Progression of the Primary Infection===
Initial foci of [[infection]] may evolve into large [[pulmonary]] [[lymph nodes]].  These may lead to:<ref name="Mandell"></ref>
Initial foci of [[infection]] may reach the large [[pulmonary]] [[lymph nodes]].  These may lead to:<ref name="Mandell"></ref>
* [[Bronchial]] collapse
* Formation of [[atelectasis]]
* Erosion of the [[bronchus]], with further spread of infection


More commonly in non-caucasian children, with inferior resistance to tuberculosis, the primary focus of infection may evolve to constitute progressive primary disease, with advancing [[pneumonia]].   The infection may lead to the formation of cavitations with spread of the infection through the [[bronchi]].  This may also occur in [[HIV]] and elderly patients.<ref name="Mandell"></ref><ref name="pmid3990748">{{cite journal| author=Stead WW, Lofgren JP, Warren E, Thomas C| title=Tuberculosis as an endemic and nosocomial infection among the elderly in nursing homes. | journal=N Engl J Med | year= 1985 | volume= 312 | issue= 23 | pages= 1483-7 | pmid=3990748 | doi=10.1056/NEJM198506063122304 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=3990748  }} </ref><ref name="pmid2274719">{{cite journal| author=Murray JF| title=Cursed duet: HIV infection and tuberculosis. | journal=Respiration | year= 1990 | volume= 57 | issue= 3 | pages= 210-20 | pmid=2274719 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=2274719  }} </ref> In young children, the dissemination of infection before the onset of hypersensitivity may lead to '''military tuberculosis'''.  Bacteria may disseminate directly from the primary focus, or from the ''Weigart focus'' (metastatic focus adjacent to a [[pulmonary vein]]) through the blood.<ref name="Mandell"></ref><ref name=Kim_2003>{{cite journal |author=Kim J, Park Y, Kim Y, Kang S, Shin J, Park I, Choi B |title=Miliary tuberculosis and acute respiratory distress syndrome |journal=Int J Tuberc Lung Dis |volume=7 |issue=4 |pages=359-64 |year=2003 | pmid = 12733492}}</ref>  In younger patients, serofibrinous [[pleurisy]] is more prone to occur following the rupture of subpleural foci of infection into the [[pleural space]].<ref name="Mandell"></ref>  The most severe consequence of the dissemination of bacteria from primary or metastatic foci, through the blood and lymph, is the seeding of the postero-apical regions of the lung.  Here bacteria are able to replicate without the opposition of the [[immune system]], potentially leading pulmonary tuberculosis.<ref name="Mandell"></ref>
*[[Bronchial]] collapse
*Formation of [[atelectasis]]
*[[bronchus|Bronchial]] erosion, with more spread of infection
 
Usually occurs in non-caucasian children, with low resistance to tuberculosis, the primary focus of infection may evolve to constitute progressive primary disease, with advancing [[pneumonia]]. The infection may result in cavity formation with transmission of the infection through the [[bronchi]].  This can occur in [[HIV]] and elderly patients.<ref name="Mandell"></ref><ref name="pmid3990748">{{cite journal| author=Stead WW, Lofgren JP, Warren E, Thomas C| title=Tuberculosis as an endemic and nosocomial infection among the elderly in nursing homes. | journal=N Engl J Med | year= 1985 | volume= 312 | issue= 23 | pages= 1483-7 | pmid=3990748 | doi=10.1056/NEJM198506063122304 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=3990748  }} </ref><ref name="pmid2274719">{{cite journal| author=Murray JF| title=Cursed duet: HIV infection and tuberculosis. | journal=Respiration | year= 1990 | volume= 57 | issue= 3 | pages= 210-20 | pmid=2274719 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=2274719  }} </ref> In young children, the dissemination of infection preceding the onset of hypersensitivity response can result in '''military tuberculosis'''.  Bacteria can disseminate directly from the primary focus, or from the ''Weigart focus'' (metastatic focus adjacent to a [[pulmonary vein]]) through the blood.<ref name="Mandell"></ref><ref name="Kim_2003">{{cite journal |author=Kim J, Park Y, Kim Y, Kang S, Shin J, Park I, Choi B |title=Miliary tuberculosis and acute respiratory distress syndrome |journal=Int J Tuberc Lung Dis |volume=7 |issue=4 |pages=359-64 |year=2003 | pmid = 12733492}}</ref>  In younger patients, serofibrinous [[pleurisy]] usually occurs after the rupture of subpleural foci of infection into the [[pleural space]].<ref name="Mandell"></ref>  The most serious consequence of the dissemination of bacteria from primary or metastatic foci, through the blood and lymph, is the seeding of the postero-apical regions of the lung.  Here bacteria are able to replicate hidden from the [[immune system]], potentially leading pulmonary tuberculosis.<ref name="Mandell"></ref>


==Immunopathogenesis==
==Immunopathogenesis==
The immune response against tuberculosis consists of both innate and acquired systems, with cell-mediated immunity predominating over humoral immunity.
The immune response generated against tuberculosis includes both innate and acquired immune systems, but the cell-mediated immunity predominating over humoral immunity.
===Innate Immune Response===
===Innate Immune Response===
The immune response against ''[[M. tuberculosis]]'' is minimal during the first weeks, allowing it to replicate in the alveolar spaces and [[macrophages]],  constituting the [[Ghon focus]], or metastatic foci.  Recognition and phagocytosis of the ''M. tuberculosis'' bacilli occurs via the following receptors on macrophages:<ref name="pmid10358769">{{cite journal| author=Aderem A, Underhill DM| title=Mechanisms of phagocytosis in macrophages. | journal=Annu Rev Immunol | year= 1999 | volume= 17 | issue=  | pages= 593-623 | pmid=10358769 | doi=10.1146/annurev.immunol.17.1.593 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10358769  }} </ref>
In the first weeks, The immune response against ''[[M. tuberculosis]]'' is minimal, allowing it to replicate in the alveolar spaces and [[macrophages]],  forming the [[Ghon focus]], or metastatic foci.  Macrophages recognize and phagocytose the ''M. tuberculosis'' bacilli occurs by the following receptors on the surface of macrophages:<ref name="pmid10358769">{{cite journal| author=Aderem A, Underhill DM| title=Mechanisms of phagocytosis in macrophages. | journal=Annu Rev Immunol | year= 1999 | volume= 17 | issue=  | pages= 593-623 | pmid=10358769 | doi=10.1146/annurev.immunol.17.1.593 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10358769  }} </ref>
 
*Toll-like Receptor 2 (TLR2)
*Toll-like Receptor 2 (TLR2)
*TLR4
*TLR4
Line 48: Line 51:


===Acquired Immunity and Granuloma Formation===
===Acquired Immunity and Granuloma Formation===
Although the granuloma creates an immune microenvironment in which the infection can be controlled, it also provides the mycobacterium with a niche in which it can survive. Within the granuloma, the bacilli can modulate the immune response to ensure their survival over long periods of time.  One of the most important factors required for the establishment of infection is a balance between the pro-inflammatory and anti-inflammatory cytokines produced to reduce or control bacterial proliferation.  TNF-α and IFN-γ are particularly important in promoting the formation and function of the granuloma, whereas IL-10 is one of the main negative regulators of this response.  The granuloma contains mostly blood-derived macrophages, epithelioid cells (differentiated macrophages), and multinucleated giant cells (also known as Langhans giant cells), surrounded by T lymphocytes.  Caseous granulomas are typical of tuberculosis. These structures are formed by epithelioid macrophages surrounding a cellular necrotic region with a rim of lymphocytes of the T- and B-cell types.  Other types of granuloma include non-necrotizing granulomas, which consist primarily of macrophages with a few lymphocytes, necrotic neutrophilic granulomas, and completely fibrotic granulomas.<ref name="pmid22811737">{{cite journal| author=Silva Miranda M, Breiman A, Allain S, Deknuydt F, Altare F| title=The tuberculous granuloma: an unsuccessful host defense mechanism providing a safe shelter for the bacteria? | journal=Clin Dev Immunol | year= 2012 | volume= 2012 | issue=  | pages= 139127 | pmid=22811737 | doi=10.1155/2012/139127 | pmc=PMC3395138 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22811737  }} </ref>
Although the granuloma can control the infection, it also provides the mycobacterium with a niche in which it can survive. Within the granuloma, the bacilli can modulate the immune response so that they can survive for a long time.  It is crucial to establish the infection by keeping a balance between the pro-inflammatory and anti-inflammatory cytokines released to decrease or control bacterial proliferation.  TNF-α and IFN-γ are particularly important for granuloma formation, whereas IL-10 is one of the main negative regulators of this response.  The granuloma is mainly formed of blood-derived macrophages (derived from monocytes), epithelioid cells (differentiated macrophages), and multinucleated giant cells (also known as Langhans giant cells), surrounded by T lymphocytes.  Caseous granulomas are characteristic of tuberculosis. The caseous granulomas include epithelioid macrophages surrounding a cellular necrotic region with some lymphocytes.  Other types of granuloma include non-necrotizing granulomas, which contain mainly macrophages and a few lymphocytes, necrotic neutrophilic granulomas, and completely fibrotic granulomas.<ref name="pmid22811737">{{cite journal| author=Silva Miranda M, Breiman A, Allain S, Deknuydt F, Altare F| title=The tuberculous granuloma: an unsuccessful host defense mechanism providing a safe shelter for the bacteria? | journal=Clin Dev Immunol | year= 2012 | volume= 2012 | issue=  | pages= 139127 | pmid=22811737 | doi=10.1155/2012/139127 | pmc=PMC3395138 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22811737  }} </ref>


Many different chemokines are involved in granuloma formation. Some are produced by the epithelial cells of the respiratory tract, and others are produced by the immune cells themselves. In particular, the chemokines binding to the CCR2 receptor (CCL2/MCP-1, CCL12, and CCL13) are important for the early recruitment of macrophages. Osteopontin, which is produced by macrophages and lymphocytes, promotes the adhesion and recruitment of these cells.  CCL19 and, possibly, CCL21 are involved in the recruitment and priming of IFN--producing T cells.  CXCL13 is involved in B-cell recruitment and the formation of follicular structures.  The expression of the CC and CXC chemokines is deregulated at the transcriptional level in TNF-deficient mice, and the lack of these chemokines prevents the recruitment of macrophages and CD4+ T cells, accounting for the critical role of TNF- in granuloma formation.<ref name="pmid22811737">{{cite journal| author=Silva Miranda M, Breiman A, Allain S, Deknuydt F, Altare F| title=The tuberculous granuloma: an unsuccessful host defense mechanism providing a safe shelter for the bacteria? | journal=Clin Dev Immunol | year= 2012 | volume= 2012 | issue=  | pages= 139127 | pmid=22811737 | doi=10.1155/2012/139127 | pmc=PMC3395138 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22811737  }} </ref>
Many different chemokines are involved in granuloma formation. Some are released from the respiratory tract epithelium, and others are released from the immune cells themselves. The chemokines that bind to the CCR2 receptor (CCL2/MCP-1, CCL12, and CCL13) are important for the early recruitment of macrophages. Osteopontin, which is released from macrophages and lymphocytes, facilitates the adhesion and recruitment of these cells.  CCL19 and CCL21 are involved in the recruit IFN--producing T cells.  CXCL13 is important for B-cell recruitment and the formation of follicular structures.  The expression of the CC and CXC chemokines is inhibited at the transcriptional level in TNF-deficient mice, and the lack of these chemokines prevents the recruitment of macrophages and CD4+ T cells, emphasizing on the crucial role of TNF- in granuloma formation.<ref name="pmid22811737">{{cite journal| author=Silva Miranda M, Breiman A, Allain S, Deknuydt F, Altare F| title=The tuberculous granuloma: an unsuccessful host defense mechanism providing a safe shelter for the bacteria? | journal=Clin Dev Immunol | year= 2012 | volume= 2012 | issue=  | pages= 139127 | pmid=22811737 | doi=10.1155/2012/139127 | pmc=PMC3395138 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22811737  }} </ref>


[[File:Granuloma_Formation_in_Tuberculosis.jpg|thumb|center|800px|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 signaling 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 the recruitment of other immune cells (more macrophages, dendritic cells, and lymphocytes) to the infection site (b). They organize in a spherical structure with infected macrophages in the middle surrounded by various categories of lymphocytes (mainly CD4+, CD8+, and γ/δ T cells). Macrophages (MP) can fuse to form MGCs or differentiate into lipid-rich foamy cells (FM). 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.g., HIV infection, malnutrition, etc.) or genetic factors, the bacteria will reactivate and provoke the death of the infected macrophages. A necrotic zone (called caseum due to its milky appearance) will develop in the center of the granuloma (d). Ultimately the structure will disintegrate allowing the exit of the bacteria, which will spread in other parts of the lungs, and more lesions will be formed. The infection will also be transmitted to other individuals due to the release of the infected droplets by coughing (e).<ref name="pmid22811737">{{cite journal| author=Silva Miranda M, Breiman A, Allain S, Deknuydt F, Altare F| title=The tuberculous granuloma: an unsuccessful host defense mechanism providing a safe shelter for the bacteria? | journal=Clin Dev Immunol | year= 2012 | volume= 2012 | issue=  | pages= 139127 | pmid=22811737 | doi=10.1155/2012/139127 | pmc=PMC3395138 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22811737  }} </ref>]]
[[File:Granuloma_Formation_in_Tuberculosis.jpg|thumb|center|800px|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 signaling 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 the recruitment of other immune cells (more macrophages, dendritic cells, and lymphocytes) to the infection site (b). They organize in a spherical structure with infected macrophages in the middle surrounded by various categories of lymphocytes (mainly CD4+, CD8+, and γ/δ T cells). Macrophages (MP) can fuse to form MGCs or differentiate into lipid-rich foamy cells (FM). 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.g., HIV infection, malnutrition, etc.) or genetic factors, the bacteria will reactivate and provoke the death of the infected macrophages. A necrotic zone (called caseum due to its milky appearance) will develop in the center of the granuloma (d). Ultimately the structure will disintegrate allowing the exit of the bacteria, which will spread in other parts of the lungs, and more lesions will be formed. The infection will also be transmitted to other individuals due to the release of the infected droplets by coughing (e).<ref name="pmid22811737">{{cite journal| author=Silva Miranda M, Breiman A, Allain S, Deknuydt F, Altare F| title=The tuberculous granuloma: an unsuccessful host defense mechanism providing a safe shelter for the bacteria? | journal=Clin Dev Immunol | year= 2012 | volume= 2012 | issue=  | pages= 139127 | pmid=22811737 | doi=10.1155/2012/139127 | pmc=PMC3395138 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22811737  }} </ref>]]


===Molecular Pathogenesis===
===Molecular Pathogenesis===
*Alveolar [[macrophages]] and [[dendritic cells]] present [[mycobacterial]] [[antigens]] on their surfaces through class II [[major histocompatibility complex]].  These [[antigens]] will be recognized by [[CD4]] lymphocytes through αβ T-cell receptors.  CD4 lymphocytes, once activated, release [[lymphokines]] that attract more [[macrophages]] to the site of infection. 
*Interferon gamma (IFN-γ) and tumor necrosis factor alpha (TNF-α) signaling activates further macrophages which engulf the tuberculosis bacilli. <ref name=Tuberculosis>{{cite web | title = Tumor Necrosis Factor alpha| url =http://erj.ersjournals.com/content/36/5/1185.long }}</ref>
*Metalloproteinase converts the transmembrane protein to soluble TNF-α. This binds with the receptor TNFR1 and TNFR2 and through caspase dependant pathways induce apoptosis.
*TNF along with the synergistic action of interferon-gamma increases the phagocytic activity of the macrophages and causes the intracellular killing of the pathogens by reactive nitrogen and oxygen intermediates.
*Neutralization of the TNF-α activity causes the persistence of mycobacterial activities within the granuloma in latent infection. Thus they are required for the formation and maintenance of granuloma in tuberculosis.
*TNF stimulates the production of CCL2, CCL3, CCL4, CCL5, CCL8 cytokines and increases CD54 causing focussed accumulation of immune cells and plays a pivotal role in the generation of granuloma and maintaining the integrity of the granuloma. <ref name=Tuberculosis>{{cite web | title = Tumor Necrosis Factor and Tuberculosis| url =http://www.nature.com/jidsp/journal/v12/n1/full/5650027a.htm }}</ref>
*During [[lymphocyte]] activation, [[immune cells]] produce large amounts of lytic enzymes, which when released, lead to the [[necrosis]] of tissues.


*Alveolar [[macrophages]] and [[dendritic cells]] present [[mycobacterial]] [[antigens]] on their surfaces through class II [[major histocompatibility complex]].  These [[antigens]] are recognized by [[CD4]] lymphocytes through αβ T-cell receptors. Following that, CD4 lymphocytes produce [[lymphokines]] that recruit more [[macrophages]] to the site of infection.
*Interferon gamma (IFN-γ) and tumor necrosis factor alpha (TNF-α) signaling activates further macrophages which engulf the tuberculosis bacilli. <ref name="Tuberculosis">{{cite web | title = Tumor Necrosis Factor alpha| url =http://erj.ersjournals.com/content/36/5/1185.long }}</ref>
*Metalloproteinase converts the transmembrane protein to soluble TNF-α. This binds with the receptor TNFR1 and TNFR2 and induces apoptosis through caspase-dependent pathways
*TNF along with the synergistic action of interferon-gamma enhances the phagocytic activity of the macrophages and leads to the intracellular killing of organisms by reactive nitrogen and oxygen intermediates.
*Neutralization of the TNF-α activity results in the survival of mycobacteria within the granuloma in latent infection. Thus they are required for the formation and maintenance of granuloma.
*TNF stimulates the production of CCL2, CCL3, CCL4, CCL5, CCL8 cytokines and increases CD54 leading to accumulation of immune cells and is the main factor for the formation and maintenance of granuloma. <ref name="Tuberculosis">{{cite web | title = Tumor Necrosis Factor and Tuberculosis| url =http://www.nature.com/jidsp/journal/v12/n1/full/5650027a.htm }}</ref>
*During [[lymphocyte]] activation, [[immune cells]] produce large amounts of lytic enzymes resulting in tissue [[necrosis]].


[[File:TNF alpha.png|thumb|center|500px| <SMALL><SMALL> ''[(http://en.wikipedia.org/wiki/Tumor_necrosis_factor_alpha#mediaviewer/File:TNF_signaling.jpg)]''<ref name="TNF Alpha">{{Cite web | title = TNF Alpha |http://en.wikipedia.org/wiki/Tumor_necrosis_factor_alpha#mediaviewer/File:TNF_signaling.jpg url = }}</ref></SMALL></SMALL>]]
 
[[File:TNF alpha.png|thumb|center|500px| <SMALL><SMALL> ''[(http://en.wikipedia.org/wiki/Tumor_necrosis_factor_alpha#mediaviewer/File:TNF_signaling.jpg<nowiki>)]</nowiki>''<ref name="TNF Alpha">{{Cite web | title = TNF Alpha |http://en.wikipedia.org/wiki/Tumor_necrosis_factor_alpha#mediaviewer/File:TNF_signaling.jpg url = }}</ref></SMALL></SMALL>]]


Once within [[alveolar]] [[macrophages]], ''[[M. tuberculosis]]'' uses multiple mechanisms in order to survive:<ref name="Mandell"></ref>
Once within [[alveolar]] [[macrophages]], ''[[M. tuberculosis]]'' uses multiple mechanisms in order to survive:<ref name="Mandell"></ref>
* [[Urease]] - prevents acidification of macrophageal [[lysosomes]], limiting action of cellular [[enzymes]]
 
* Secretion of [[antioxidant]]s, for suppression of [[reactive oxygen species]], such as:
*[[Urease]] - prevents acidification of macrophageal [[lysosomes]], limiting action of cellular [[enzymes]]
:* [[Catalase]]
*Secretion of [[antioxidant]]s, for suppression of [[reactive oxygen species]], such as:
:* [[Superoxide dismutase]]
 
:* [[Thioredoxin]]
:*[[Catalase]]
:*[[Superoxide dismutase]]
:*[[Thioredoxin]]


==Transmission==
==Transmission==
After contact with a patient that has the active form of the disease, and inhalation of the ''[[M. tuberculosis]]'' the risk of developing active tuberculosis is low, with a life-time projected risk of about 10%.<ref name="pmid23460002">{{cite journal| author=Glaziou P, Falzon D, Floyd K, Raviglione M| title=Global epidemiology of tuberculosis. | journal=Semin Respir Crit Care Med | year= 2013 | volume= 34 | issue= 1 | pages= 3-16 | pmid=23460002 | doi=10.1055/s-0032-1333467 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23460002  }} </ref>  The probability of [[transmission]] from one person to another depends on the number of [[infectious]] droplets expelled by the carrier, the effectiveness of ventilation, the duration of the exposure, and the [[virulence]] of the strain of ''M. tuberculosis''.<ref>{{cite web|url=http://www.mayoclinic.com/health/tuberculosis/DS00372/DSECTION=3|title=Causes of Tuberculosis|accessdate=2007-10-19|date=2006-12-21|last=|first=|publisher=[[Mayo Clinic]]}}</ref>  The probability of transmitting the disease is highest during the first years, after the person has been infected, decreasing hence forth.<ref name="pmid21420161">{{cite journal| author=Lawn SD, Zumla AI| title=Tuberculosis. | journal=Lancet | year= 2011 | volume= 378 | issue= 9785 | pages= 57-72 | pmid=21420161 | doi=10.1016/S0140-6736(10)62173-3 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21420161  }} </ref>
Following contact with a patient having the active form of the disease, and inhalation of the ''[[M. tuberculosis]],'' the risk of developing active tuberculosis is low, and the life-time risk of about 10%.<ref name="pmid23460002">{{cite journal| author=Glaziou P, Falzon D, Floyd K, Raviglione M| title=Global epidemiology of tuberculosis. | journal=Semin Respir Crit Care Med | year= 2013 | volume= 34 | issue= 1 | pages= 3-16 | pmid=23460002 | doi=10.1055/s-0032-1333467 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23460002  }} </ref>  The probability of [[transmission]] from one person to another depends on the number of [[infectious]] droplets expelled by the carrier, the ventilation, the duration of the exposure, and the [[virulence]] of the ''M. tuberculosis strain''.<ref>{{cite web|url=http://www.mayoclinic.com/health/tuberculosis/DS00372/DSECTION=3|title=Causes of Tuberculosis|accessdate=2007-10-19|date=2006-12-21|last=|first=|publisher=[[Mayo Clinic]]}}</ref>  The probability of transmitting the disease is highest during the first years, after the person has been infected, decreasing hence forth.<ref name="pmid21420161">{{cite journal| author=Lawn SD, Zumla AI| title=Tuberculosis. | journal=Lancet | year= 2011 | volume= 378 | issue= 9785 | pages= 57-72 | pmid=21420161 | doi=10.1016/S0140-6736(10)62173-3 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21420161  }} </ref>


In rare occasions, the bacteria may be transmitted through other routes, besides the [[pulmonary]]. In these cases, the formation of foci in local [[lymph nodes]] is always involved.  These alternative routes of [[transmission]] include:<ref name="Mandell"></ref>
Rarely, the mycobacteria can be transmitted by different ways, other than the [[pulmonary]]. In these cases, the formation of foci in the regional [[lymph nodes]] is usually occurs.  The other routes of [[transmission]] are:<ref name="Mandell"></ref>
* [[Skin]] abrasions
 
* [[Oropharynx]]
*[[Skin]] abrasions
* [[Intestine]]
*[[Oropharynx]]
* [[Genitalia]]
*[[Intestine]]
*[[Genitalia]]


==Associated Conditions==
==Associated Conditions==
===AIDS===
===AIDS===
Tuberculosis influences the progression of [[HIV]] [[viral replication|replication]] in infected patients, leading to an increase in the [[mortality rate]].<ref name="pmid23425167">{{cite journal| author=Zumla A, Raviglione M, Hafner R, von Reyn CF| title=Tuberculosis. | journal=N Engl J Med | year= 2013 | volume= 368 | issue= 8 | pages= 745-55 | pmid=23425167 | doi=10.1056/NEJMra1200894 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23425167  }} </ref>
Tuberculosis affects the progression of [[HIV]] [[viral replication|replication]], increasing in the [[mortality rate]].<ref name="pmid23425167">{{cite journal| author=Zumla A, Raviglione M, Hafner R, von Reyn CF| title=Tuberculosis. | journal=N Engl J Med | year= 2013 | volume= 368 | issue= 8 | pages= 745-55 | pmid=23425167 | doi=10.1056/NEJMra1200894 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23425167  }} </ref>


On the other hand, [[HIV]] infected patients, particularly those with low counts of [[CD4|CD4 lymphocytes]], have increased risk of reactivation of latent tuberculosis.  Additionally, when recently infected with ''[[M. tuberculosis]]'', these patients tend to rapidly progress into active disease.<ref name="Mandell"></ref><ref name="pmid1345800">{{cite journal| author=Daley CL, Small PM, Schecter GF, Schoolnik GK, McAdam RA, Jacobs WR et al.| title=An outbreak of tuberculosis with accelerated progression among persons infected with the human immunodeficiency virus. An analysis using restriction-fragment-length polymorphisms. | journal=N Engl J Med | year= 1992 | volume= 326 | issue= 4 | pages= 231-5 | pmid=1345800 | doi=10.1056/NEJM199201233260404 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=1345800  }} </ref><ref name="pmid8280411">{{cite journal| author=Bouvet E, Casalino E, Mendoza-Sassi G, Lariven S, Vallée E, Pernet M et al.| title=A nosocomial outbreak of multidrug-resistant Mycobacterium bovis among HIV-infected patients. A case-control study. | journal=AIDS | year= 1993 | volume= 7 | issue= 11 | pages= 1453-60 | pmid=8280411 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8280411  }} </ref>  It is still not known if [[AIDS]] influences the risk of [[infection]], when in contact with the ''[[M. tuberculosis]]''.<ref name="Mandell"></ref>
Moreover, [[HIV]] infected patients, especilly those with low [[CD4|CD4 lymphocytes]] counts, have are more prone to reactivation of latent tuberculosis.  Furthermore, when recently infected with ''[[M. tuberculosis]]'', these patients rapidly progress into active disease.<ref name="Mandell"></ref><ref name="pmid1345800">{{cite journal| author=Daley CL, Small PM, Schecter GF, Schoolnik GK, McAdam RA, Jacobs WR et al.| title=An outbreak of tuberculosis with accelerated progression among persons infected with the human immunodeficiency virus. An analysis using restriction-fragment-length polymorphisms. | journal=N Engl J Med | year= 1992 | volume= 326 | issue= 4 | pages= 231-5 | pmid=1345800 | doi=10.1056/NEJM199201233260404 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=1345800  }} </ref><ref name="pmid8280411">{{cite journal| author=Bouvet E, Casalino E, Mendoza-Sassi G, Lariven S, Vallée E, Pernet M et al.| title=A nosocomial outbreak of multidrug-resistant Mycobacterium bovis among HIV-infected patients. A case-control study. | journal=AIDS | year= 1993 | volume= 7 | issue= 11 | pages= 1453-60 | pmid=8280411 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8280411  }} </ref>  It is still not fully understood whether [[AIDS]] has an impact on the risk of [[infection]], when in contact with the ''[[M. tuberculosis]]''.<ref name="Mandell"></ref>
 
Patients with [[AIDS]] are more susceptible to developing [[pulmonary]] and [[extrapulmonary tuberculosis]].  Extrapulmonary disease in those patients has unique manifestations, such as:<ref name="Mandell"></ref>
 
*Higher frequency of disseminated disease<ref name="pmid1956280">{{cite journal| author=Shafer RW, Kim DS, Weiss JP, Quale JM| title=Extrapulmonary tuberculosis in patients with human immunodeficiency virus infection. | journal=Medicine (Baltimore) | year= 1991 | volume= 70 | issue= 6 | pages= 384-97 | pmid=1956280 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=1956280  }} </ref>
*Rapid progression of the disease with widespread [[pulmonary]] infiltrates
*[[DIC]] and acute [[respiratory failure]]
*Tuberculous [[pleuritis]] occurs bilaterally
*Abdominal and mediastinal [[lymphadenopathy]] are common
*Increased risk of [[Immune reconstitution inflammatory syndrome]] ([[IRIS]])<ref name="pmid18652998">{{cite journal| author=Meintjes G, Lawn SD, Scano F, Maartens G, French MA, Worodria W et al.| title=Tuberculosis-associated immune reconstitution inflammatory syndrome: case definitions for use in resource-limited settings. | journal=Lancet Infect Dis | year= 2008 | volume= 8 | issue= 8 | pages= 516-23 | pmid=18652998 | doi=10.1016/S1473-3099(08)70184-1 | pmc=PMC2804035 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18652998  }} </ref>
*Common [[abscesses]] of:<ref name="Mandell"></ref>


Patients with [[AIDS]] have increased risk of developing [[pulmonary]] and [[extrapulmonary tuberculosis]].  Extrapulmonary disease in this group of patients has characteristic manifestations, such as:<ref name="Mandell"></ref>
* Higher frequency of disseminated disease<ref name="pmid1956280">{{cite journal| author=Shafer RW, Kim DS, Weiss JP, Quale JM| title=Extrapulmonary tuberculosis in patients with human immunodeficiency virus infection. | journal=Medicine (Baltimore) | year= 1991 | volume= 70 | issue= 6 | pages= 384-97 | pmid=1956280 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=1956280  }} </ref>
* Rapid progression of the disease with widespread [[pulmonary]] infiltrates
* [[DIC]] and acute [[respiratory failure]]
* When present, tuberculous [[pleuritis]] occurs bilaterally
* Abdominal and mediastinal [[lymphadenopathy]] are common
* Increased risk of [[Immune reconstitution inflammatory syndrome]] ([[IRIS]])<ref name="pmid18652998">{{cite journal| author=Meintjes G, Lawn SD, Scano F, Maartens G, French MA, Worodria W et al.| title=Tuberculosis-associated immune reconstitution inflammatory syndrome: case definitions for use in resource-limited settings. | journal=Lancet Infect Dis | year= 2008 | volume= 8 | issue= 8 | pages= 516-23 | pmid=18652998 | doi=10.1016/S1473-3099(08)70184-1 | pmc=PMC2804035 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18652998  }} </ref>
* Common [[abscesses]] of:<ref name="Mandell"></ref>
:*[[Pancreas]]
:*[[Pancreas]]
:*[[Liver]]
:*[[Liver]]
Line 104: Line 113:
==Gallery==
==Gallery==
<gallery>
<gallery>
 
File:TB1.jpg|Left lateral margin of a tongue of a tuberculosis patient, which had been retracted in order to reveal the lesion that had been caused by the Gram-positive bacterium Mycobacterium tuberculosis<SMALL><SMALL>''[http://phil.cdc.gov/phil/ Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.]''<ref name="PHIL">{{Cite web | title = Public Health Image Library (PHIL), Centers for Disease Control and Prevention | url = http://phil.cdc.gov/phil/}}</ref></SMALL></SMALL>
Image:TB1.jpg|Left lateral margin of a tongue of a tuberculosis patient, which had been retracted in order to reveal the lesion that had been caused by the Gram-positive bacterium Mycobacterium tuberculosis<SMALL><SMALL>''[http://phil.cdc.gov/phil/ Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.]''<ref name="PHIL">{{Cite web | title = Public Health Image Library (PHIL), Centers for Disease Control and Prevention | url = http://phil.cdc.gov/phil/}}</ref></SMALL></SMALL>
File:TB2.jpg|<SMALL><SMALL>''Light photomicrograph revealing some of the histopathologic cytoarchitectural characteristics seen in a mycobacterial skin infection.[ http://phil.cdc.gov/phil/<nowiki> Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.]</nowiki>''<ref name="PHIL">{{Cite web | title = Public Health Image Library (PHIL), Centers for Disease Control and Prevention | url = http://phil.cdc.gov/phil/}}</ref></SMALL></SMALL>
 
File:Leprosy-35.jpg| Light photomicrograph revealing some of the histopathologic cytoarchitectural characteristics seen in a mycobacterial skin infection <SMALL><SMALL>''[http://phil.cdc.gov/phil/ Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.]''<ref name="PHIL">{{Cite web | title = Public Health Image Library (PHIL), Centers for Disease Control and Prevention | url = http://phil.cdc.gov/phil/}}</ref></SMALL></SMALL>
Image:TB2.jpg|<SMALL><SMALL>''Light photomicrograph revealing some of the histopathologic cytoarchitectural characteristics seen in a mycobacterial skin infection.[ http://phil.cdc.gov/phil/  Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.]''<ref name="PHIL">{{Cite web | title = Public Health Image Library (PHIL), Centers for Disease Control and Prevention | url = http://phil.cdc.gov/phil/}}</ref></SMALL></SMALL>
File:Leprosy-36.jpg| Light photomicrograph revealing some of the histopathologic cytoarchitectural characteristics seen in a mycobacterial skin infection <SMALL><SMALL>''[http://phil.cdc.gov/phil/ Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.]''<ref name="PHIL">{{Cite web | title = Public Health Image Library (PHIL), Centers for Disease Control and Prevention | url = http://phil.cdc.gov/phil/}}</ref></SMALL></SMALL>
 
File:Leprosy-37.jpg| Light photomicrograph revealing some of the histopathologic cytoarchitectural characteristics seen in a mycobacterial skin infection <SMALL><SMALL>''[http://phil.cdc.gov/phil/ Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.]''<ref name="PHIL">{{Cite web | title = Public Health Image Library (PHIL), Centers for Disease Control and Prevention | url = http://phil.cdc.gov/phil/}}</ref></SMALL></SMALL>
Image:Leprosy-35.jpg| Light photomicrograph revealing some of the histopathologic cytoarchitectural characteristics seen in a mycobacterial skin infection <SMALL><SMALL>''[http://phil.cdc.gov/phil/ Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.]''<ref name="PHIL">{{Cite web | title = Public Health Image Library (PHIL), Centers for Disease Control and Prevention | url = http://phil.cdc.gov/phil/}}</ref></SMALL></SMALL>
File:Leprosy-38.jpg| Light photomicrograph revealing some of the histopathologic cytoarchitectural characteristics seen in a mycobacterial skin infection <SMALL><SMALL>''[http://phil.cdc.gov/phil/ Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.]''<ref name="PHIL">{{Cite web | title = Public Health Image Library (PHIL), Centers for Disease Control and Prevention | url = http://phil.cdc.gov/phil/}}</ref></SMALL></SMALL>
 
File:TB3.jpg| Photomicrograph describing tuberculosis of the placenta.<SMALL><SMALL>''[http://phil.cdc.gov/phil/ Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.]''<ref name="PHIL">{{Cite web | title = Public Health Image Library (PHIL), Centers for Disease Control and Prevention | url = http://phil.cdc.gov/phil/}}</ref></SMALL></SMALL>
Image:Leprosy-36.jpg| Light photomicrograph revealing some of the histopathologic cytoarchitectural characteristics seen in a mycobacterial skin infection <SMALL><SMALL>''[http://phil.cdc.gov/phil/ Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.]''<ref name="PHIL">{{Cite web | title = Public Health Image Library (PHIL), Centers for Disease Control and Prevention | url = http://phil.cdc.gov/phil/}}</ref></SMALL></SMALL>
File:TB4.jpg| Histopathology of tuberculosis, endometrium. Ziehl-Neelsen stain.<SMALL><SMALL>''[http://phil.cdc.gov/phil/ Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.]''<ref name="PHIL">{{Cite web | title = Public Health Image Library (PHIL), Centers for Disease Control and Prevention | url = http://phil.cdc.gov/phil/}}</ref></SMALL></SMALL>
 
File:TB5.jpg| Histopathology of tuberculosis, placenta.<SMALL><SMALL>''[http://phil.cdc.gov/phil/ Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.]''<ref name="PHIL">{{Cite web | title = Public Health Image Library (PHIL), Centers for Disease Control and Prevention | url = http://phil.cdc.gov/phil/}}</ref></SMALL></SMALL>
Image:Leprosy-37.jpg| Light photomicrograph revealing some of the histopathologic cytoarchitectural characteristics seen in a mycobacterial skin infection <SMALL><SMALL>''[http://phil.cdc.gov/phil/ Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.]''<ref name="PHIL">{{Cite web | title = Public Health Image Library (PHIL), Centers for Disease Control and Prevention | url = http://phil.cdc.gov/phil/}}</ref></SMALL></SMALL>
File:Miliar TB.JPG|Miliar Tuberculosis
 
File:Renal TB.jpg|Renal Tuberculosis lesion
Image:Leprosy-38.jpg| Light photomicrograph revealing some of the histopathologic cytoarchitectural characteristics seen in a mycobacterial skin infection <SMALL><SMALL>''[http://phil.cdc.gov/phil/ Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.]''<ref name="PHIL">{{Cite web | title = Public Health Image Library (PHIL), Centers for Disease Control and Prevention | url = http://phil.cdc.gov/phil/}}</ref></SMALL></SMALL>
 
Image:TB3.jpg| Photomicrograph describing tuberculosis of the placenta.<SMALL><SMALL>''[http://phil.cdc.gov/phil/ Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.]''<ref name="PHIL">{{Cite web | title = Public Health Image Library (PHIL), Centers for Disease Control and Prevention | url = http://phil.cdc.gov/phil/}}</ref></SMALL></SMALL>
 
Image:TB4.jpg| Histopathology of tuberculosis, endometrium. Ziehl-Neelsen stain.<SMALL><SMALL>''[http://phil.cdc.gov/phil/ Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.]''<ref name="PHIL">{{Cite web | title = Public Health Image Library (PHIL), Centers for Disease Control and Prevention | url = http://phil.cdc.gov/phil/}}</ref></SMALL></SMALL>
 
Image:TB5.jpg| Histopathology of tuberculosis, placenta.<SMALL><SMALL>''[http://phil.cdc.gov/phil/ Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.]''<ref name="PHIL">{{Cite web | title = Public Health Image Library (PHIL), Centers for Disease Control and Prevention | url = http://phil.cdc.gov/phil/}}</ref></SMALL></SMALL>
 
Image:Miliar TB.JPG|Miliar Tuberculosis
 
Image:Renal TB.jpg|Renal Tuberculosis lesion
</gallery>
</gallery>


Revision as of 03:41, 25 January 2021

https://https://www.youtube.com/watch?v=yR51KVF4OX0%7C350}}

Tuberculosis Microchapters

Home

Patient Information

Overview

Historical Perspective

Classification

Pathophysiology

Causes

Differentiating Tuberculosis from other Diseases

Epidemiology and Demographics

Risk Factors

Screening

Natural History, Complications and Prognosis

Children

HIV Coinfection

Diagnosis

History and Symptoms

Physical Examination

Laboratory Findings

Electrocardiogram

Chest X Ray

CT

MRI

Echocardiography or Ultrasound

Other Imaging Findings

Other Diagnostic Studies

Treatment

Medical Therapy

Special Conditions
Drug-resistant

Surgery

Primary Prevention

Secondary Prevention

Cost-Effectiveness of Therapy

Future or Investigational Therapies

Case Studies

Case #1

Tuberculosis pathophysiology On the Web

Most recent articles

Most cited articles

Review articles

CME Programs

Powerpoint slides

Images

American Roentgen Ray Society Images of Tuberculosis pathophysiology

All Images
X-rays
Echo & Ultrasound
CT Images
MRI

Ongoing Trials at Clinical Trials.gov

US National Guidelines Clearinghouse

NICE Guidance

FDA on Tuberculosis pathophysiology

CDC on Tuberculosis pathophysiology

Tuberculosis pathophysiology in the news

Blogs on Tuberculosis pathophysiology

Directions to Hospitals Treating Tuberculosis

Risk calculators and risk factors for Tuberculosis pathophysiology

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Mashal Awais, M.D.[2], João André Alves Silva, M.D. [3]

Overview

M. tuberculosis infection occurs through inhalation of aerosols produced by patients with active disease The mycobacterium prefers to live in the upper lung lobes due to the high amount of oxygen. Tuberculosis is a prototypical granulomatous infection. The granuloma encloses mycobacteria and prevents their spreading and facilitates immune immune cell communication. Within the granuloma, CD4 T lymphocytes release cytokines such as interferon gamma that activate local macrophages.

Pathogenesis

The M. tuberculosis bacterium is acquired by inhaled aerosols generated by individuals with active pulmonary disease. They pass to the terminal bronchioles and alveoli (commonly at the middle lobes, upper regions of lower lobes, and lower regions of upper lobes) and are phagocytosed by alveolar macrophages. The initial immune response by these macrophages attracts further macrophages, neutrophils, and monocytes, surrounding the bacilli. Despite having a very low infectious dose (ID<200 bacteria), 90% of immunocompetent individuals that acquire M. tuberculosis do not develop symptoms. In most cases, the bacteria may either be eliminated or be harbored in a latent state by an immune formation known as a granuloma. The granuloma is a structured, radial aggregation of immune cells that prevents the dissemination of mycobacteria and provides a pathway for immune cell communication.[1] The initial focus of infection in the lung is a single region in 75% of the cases, and is called the Ghon focus. Besides the alveolar macrophages, other immune cells such as blood monocytes (tissue macrophages) and lymphocytes also migrate to the Ghon focus aiding in the termination of the infection or initiation of a granulomatous containment.[1][2]

Primary Infection

In an immunocompetent person, the infected macrophages pass through the lymph to the regional lymph nodes. In immunocompromised patients, these macrophages may bw transported to different parts of the body, through the blood. In spite of the initial dissemination, those foci of infection usually resolve without any clinical manifestations of disease. However, during the dissemination of the infected macrophages, tissues that are more prone to bacterial replication, represent potential metastatic foci. These tissues include:[1][2]

Although TB can target all body parts, the heart, skeletal muscles, pancreas and thyroid are rarely affected.[3] In a few cases, when the antigens concentration in the primary focus is high, the development of the immune response and hypersensitivity may result in the necrosis and calcification of this infection site. These primary calcified foci are called Ranke complex.[1][4]

Progression of the Primary Infection

Initial foci of infection may reach the large pulmonary lymph nodes. These may lead to:[1]

Usually occurs in non-caucasian children, with low resistance to tuberculosis, the primary focus of infection may evolve to constitute progressive primary disease, with advancing pneumonia. The infection may result in cavity formation with transmission of the infection through the bronchi. This can occur in HIV and elderly patients.[1][5][6] In young children, the dissemination of infection preceding the onset of hypersensitivity response can result in military tuberculosis. Bacteria can disseminate directly from the primary focus, or from the Weigart focus (metastatic focus adjacent to a pulmonary vein) through the blood.[1][7] In younger patients, serofibrinous pleurisy usually occurs after the rupture of subpleural foci of infection into the pleural space.[1] The most serious consequence of the dissemination of bacteria from primary or metastatic foci, through the blood and lymph, is the seeding of the postero-apical regions of the lung. Here bacteria are able to replicate hidden from the immune system, potentially leading pulmonary tuberculosis.[1]

Immunopathogenesis

The immune response generated against tuberculosis includes both innate and acquired immune systems, but the cell-mediated immunity predominating over humoral immunity.

Innate Immune Response

In the first weeks, The immune response against M. tuberculosis is minimal, allowing it to replicate in the alveolar spaces and macrophages, forming the Ghon focus, or metastatic foci. Macrophages recognize and phagocytose the M. tuberculosis bacilli occurs by the following receptors on the surface of macrophages:[8]

  • Toll-like Receptor 2 (TLR2)
  • TLR4
  • TLR9
  • Dectin-1
  • DC-SIGN
  • Mannose receptor
  • Complement receptors
  • NOD2

Acquired Immunity and Granuloma Formation

Although the granuloma can control the infection, it also provides the mycobacterium with a niche in which it can survive. Within the granuloma, the bacilli can modulate the immune response so that they can survive for a long time. It is crucial to establish the infection by keeping a balance between the pro-inflammatory and anti-inflammatory cytokines released to decrease or control bacterial proliferation. TNF-α and IFN-γ are particularly important for granuloma formation, whereas IL-10 is one of the main negative regulators of this response. The granuloma is mainly formed of blood-derived macrophages (derived from monocytes), epithelioid cells (differentiated macrophages), and multinucleated giant cells (also known as Langhans giant cells), surrounded by T lymphocytes. Caseous granulomas are characteristic of tuberculosis. The caseous granulomas include epithelioid macrophages surrounding a cellular necrotic region with some lymphocytes. Other types of granuloma include non-necrotizing granulomas, which contain mainly macrophages and a few lymphocytes, necrotic neutrophilic granulomas, and completely fibrotic granulomas.[9]

Many different chemokines are involved in granuloma formation. Some are released from the respiratory tract epithelium, and others are released from the immune cells themselves. The chemokines that bind to the CCR2 receptor (CCL2/MCP-1, CCL12, and CCL13) are important for the early recruitment of macrophages. Osteopontin, which is released from macrophages and lymphocytes, facilitates the adhesion and recruitment of these cells. CCL19 and CCL21 are involved in the recruit IFN--producing T cells. CXCL13 is important for B-cell recruitment and the formation of follicular structures. The expression of the CC and CXC chemokines is inhibited at the transcriptional level in TNF-deficient mice, and the lack of these chemokines prevents the recruitment of macrophages and CD4+ T cells, emphasizing on the crucial role of TNF- in granuloma formation.[9]

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 signaling 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 the recruitment of other immune cells (more macrophages, dendritic cells, and lymphocytes) to the infection site (b). They organize in a spherical structure with infected macrophages in the middle surrounded by various categories of lymphocytes (mainly CD4+, CD8+, and γ/δ T cells). Macrophages (MP) can fuse to form MGCs or differentiate into lipid-rich foamy cells (FM). 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.g., HIV infection, malnutrition, etc.) or genetic factors, the bacteria will reactivate and provoke the death of the infected macrophages. A necrotic zone (called caseum due to its milky appearance) will develop in the center of the granuloma (d). Ultimately the structure will disintegrate allowing the exit of the bacteria, which will spread in other parts of the lungs, and more lesions will be formed. The infection will also be transmitted to other individuals due to the release of the infected droplets by coughing (e).[9]

Molecular Pathogenesis

  • Alveolar macrophages and dendritic cells present mycobacterial antigens on their surfaces through class II major histocompatibility complex. These antigens are recognized by CD4 lymphocytes through αβ T-cell receptors. Following that, CD4 lymphocytes produce lymphokines that recruit more macrophages to the site of infection.
  • Interferon gamma (IFN-γ) and tumor necrosis factor alpha (TNF-α) signaling activates further macrophages which engulf the tuberculosis bacilli. [10]
  • Metalloproteinase converts the transmembrane protein to soluble TNF-α. This binds with the receptor TNFR1 and TNFR2 and induces apoptosis through caspase-dependent pathways
  • TNF along with the synergistic action of interferon-gamma enhances the phagocytic activity of the macrophages and leads to the intracellular killing of organisms by reactive nitrogen and oxygen intermediates.
  • Neutralization of the TNF-α activity results in the survival of mycobacteria within the granuloma in latent infection. Thus they are required for the formation and maintenance of granuloma.
  • TNF stimulates the production of CCL2, CCL3, CCL4, CCL5, CCL8 cytokines and increases CD54 leading to accumulation of immune cells and is the main factor for the formation and maintenance of granuloma. [10]
  • During lymphocyte activation, immune cells produce large amounts of lytic enzymes resulting in tissue necrosis.


[(http://en.wikipedia.org/wiki/Tumor_necrosis_factor_alpha#mediaviewer/File:TNF_signaling.jpg)][11]

Once within alveolar macrophages, M. tuberculosis uses multiple mechanisms in order to survive:[1]

Transmission

Following contact with a patient having the active form of the disease, and inhalation of the M. tuberculosis, the risk of developing active tuberculosis is low, and the life-time risk of about 10%.[12] The probability of transmission from one person to another depends on the number of infectious droplets expelled by the carrier, the ventilation, the duration of the exposure, and the virulence of the M. tuberculosis strain.[13] The probability of transmitting the disease is highest during the first years, after the person has been infected, decreasing hence forth.[14]

Rarely, the mycobacteria can be transmitted by different ways, other than the pulmonary. In these cases, the formation of foci in the regional lymph nodes is usually occurs. The other routes of transmission are:[1]

Associated Conditions

AIDS

Tuberculosis affects the progression of HIV replication, increasing in the mortality rate.[15]

Moreover, HIV infected patients, especilly those with low CD4 lymphocytes counts, have are more prone to reactivation of latent tuberculosis. Furthermore, when recently infected with M. tuberculosis, these patients rapidly progress into active disease.[1][16][17] It is still not fully understood whether AIDS has an impact on the risk of infection, when in contact with the M. tuberculosis.[1]

Patients with AIDS are more susceptible to developing pulmonary and extrapulmonary tuberculosis. Extrapulmonary disease in those patients has unique manifestations, such as:[1]

Gallery

References

  1. ↑ 1.00 1.01 1.02 1.03 1.04 1.05 1.06 1.07 1.08 1.09 1.10 1.11 1.12 1.13 1.14 Mandell, Gerald (2010). Mandell, Douglas, and Bennett's principles and practice of infectious diseases. Philadelphia, PA: Churchill Livingstone/Elsevier. ISBN 0443068399.
  2. ↑ 2.0 2.1 Herrmann J, Lagrange P (2005). "Dendritic cells and Mycobacterium tuberculosis: which is the Trojan horse?". Pathol Biol (Paris). 53 (1): 35–40. PMID 15620608.
  3. ↑ Agarwal R, Malhotra P, Awasthi A, Kakkar N, Gupta D (2005). "Tuberculous dilated cardiomyopathy: an under-recognized entity?". BMC Infect Dis. 5 (1): 29. PMID 15857515.
  4. ↑ Grosset J (2003). "Mycobacterium tuberculosis in the extracellular compartment: an underestimated adversary". Antimicrob Agents Chemother. 47 (3): 833–6. PMID 12604509.
  5. ↑ Stead WW, Lofgren JP, Warren E, Thomas C (1985). "Tuberculosis as an endemic and nosocomial infection among the elderly in nursing homes". N Engl J Med. 312 (23): 1483–7. doi:10.1056/NEJM198506063122304. PMID 3990748.
  6. ↑ Murray JF (1990). "Cursed duet: HIV infection and tuberculosis". Respiration. 57 (3): 210–20. PMID 2274719.
  7. ↑ Kim J, Park Y, Kim Y, Kang S, Shin J, Park I, Choi B (2003). "Miliary tuberculosis and acute respiratory distress syndrome". Int J Tuberc Lung Dis. 7 (4): 359–64. PMID 12733492.
  8. ↑ Aderem A, Underhill DM (1999). "Mechanisms of phagocytosis in macrophages". Annu Rev Immunol. 17: 593–623. doi:10.1146/annurev.immunol.17.1.593. PMID 10358769.
  9. ↑ 9.0 9.1 9.2 Silva Miranda M, Breiman A, Allain S, Deknuydt F, Altare F (2012). "The tuberculous granuloma: an unsuccessful host defense mechanism providing a safe shelter for the bacteria?". Clin Dev Immunol. 2012: 139127. doi:10.1155/2012/139127. PMC 3395138. PMID 22811737.
  10. ↑ 10.0 10.1 "Tumor Necrosis Factor alpha".
  11. ↑ "TNF Alpha". Missing or empty |url= (help)
  12. ↑ Glaziou P, Falzon D, Floyd K, Raviglione M (2013). "Global epidemiology of tuberculosis". Semin Respir Crit Care Med. 34 (1): 3–16. doi:10.1055/s-0032-1333467. PMID 23460002.
  13. ↑ "Causes of Tuberculosis". Mayo Clinic. 2006-12-21. Retrieved 2007-10-19.
  14. ↑ Lawn SD, Zumla AI (2011). "Tuberculosis". Lancet. 378 (9785): 57–72. doi:10.1016/S0140-6736(10)62173-3. PMID 21420161.
  15. ↑ Zumla A, Raviglione M, Hafner R, von Reyn CF (2013). "Tuberculosis". N Engl J Med. 368 (8): 745–55. doi:10.1056/NEJMra1200894. PMID 23425167.
  16. ↑ Daley CL, Small PM, Schecter GF, Schoolnik GK, McAdam RA, Jacobs WR; et al. (1992). "An outbreak of tuberculosis with accelerated progression among persons infected with the human immunodeficiency virus. An analysis using restriction-fragment-length polymorphisms". N Engl J Med. 326 (4): 231–5. doi:10.1056/NEJM199201233260404. PMID 1345800.
  17. ↑ Bouvet E, Casalino E, Mendoza-Sassi G, Lariven S, Vallée E, Pernet M; et al. (1993). "A nosocomial outbreak of multidrug-resistant Mycobacterium bovis among HIV-infected patients. A case-control study". AIDS. 7 (11): 1453–60. PMID 8280411.
  18. ↑ Shafer RW, Kim DS, Weiss JP, Quale JM (1991). "Extrapulmonary tuberculosis in patients with human immunodeficiency virus infection". Medicine (Baltimore). 70 (6): 384–97. PMID 1956280.
  19. ↑ Meintjes G, Lawn SD, Scano F, Maartens G, French MA, Worodria W; et al. (2008). "Tuberculosis-associated immune reconstitution inflammatory syndrome: case definitions for use in resource-limited settings". Lancet Infect Dis. 8 (8): 516–23. doi:10.1016/S1473-3099(08)70184-1. PMC 2804035. PMID 18652998.
  20. ↑ 20.0 20.1 20.2 20.3 20.4 20.5 20.6 20.7 20.8 "Public Health Image Library (PHIL), Centers for Disease Control and Prevention".

Template:WH Template:WS

Retrieved from "https://www.wikidoc.org/index.php?title=Tuberculosis_pathophysiology&oldid=1685607"