Tuberculosis pathophysiology

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

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 mycobacteria and provides a pathway for immune cell communication. Within the granuloma, CD4 T lymphocytes secrete 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 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 mycobacteria and provides a pathway for immune cell communication. 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.

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:

• 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 muscles, pancreas and thyroid are rarely affected. 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.

Progression of the Primary Infection

Initial foci of infection may evolve into large pulmonary lymph nodes. These may lead to:

• 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. 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. In younger patients, serofibrinous pleurisy is more prone to occur following the rupture of subpleural foci of infection into the pleural space. 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.

Immunopathogenesis

The immune response against tuberculosis consists of both innate and acquired systems, with cell-mediated immunity predominating over humoral immunity.

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:

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

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 nonnecrotising granulomas, which consist primarily of macrophages with a few lymphocytes, necrotic neutrophilic granulomas, and completely fibrotic granulomas.

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.

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). They organise 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 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).

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.
• 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 maintanence 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.
• During lymphocyte activation, immune cells produce large amounts of lytic enzymes, which when released, lead to the necrosis of tissues.

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

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

• Urease - prevents acidification of macrophageal lysosomes, limiting action of cellular enzymes
• Secretion of antioxidants, for suppression of reactive oxygen species, such as:

• Catalase
• Superoxide dismutase
• Thioredoxin

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%. 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. The probability of transmitting the disease is highest during the first years, after the person has been infected, decreasing hence forth.

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:

• Skin abrasions
• Oropharynx
• Intestine
• Genitalia

Associated Conditions

AIDS

Tuberculosis influences the progression of HIV replication in infected patients, leading to an increase in the mortality rate.

On the other hand, HIV infected patients, particularly those with low counts of 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. It is still not known if AIDS influences the risk of infection, when in contact with the M. tuberculosis.

Patients with AIDS have increased risk of developing pulmonary and extrapulmonary tuberculosis. Extrapulmonary disease in this group of patients has characteristic manifestations, such as:

• Higher frequency of disseminated disease
• 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)
• Common abscesses of:

• Pancreas
• Liver
• Spleen
• Chest wall
• Abdominal wall

Gallery

• 
  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 tuberculosisAdapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.
• 
  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.]
• 
  Light photomicrograph revealing some of the histopathologic cytoarchitectural characteristics seen in a mycobacterial skin infection Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.
• 
  Light photomicrograph revealing some of the histopathologic cytoarchitectural characteristics seen in a mycobacterial skin infection Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.
• 
  Light photomicrograph revealing some of the histopathologic cytoarchitectural characteristics seen in a mycobacterial skin infection Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.
• 
  Light photomicrograph revealing some of the histopathologic cytoarchitectural characteristics seen in a mycobacterial skin infection Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.
• 
  Photomicrograph describing tuberculosis of the placenta.Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.
• 
  Histopathology of tuberculosis, endometrium. Ziehl-Neelsen stain.Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.
• 
  Histopathology of tuberculosis, placenta.Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.
• 
  Miliar Tuberculosis
• 
  Renal Tuberculosis lesion

References