Tuberculosis pathophysiology

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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. 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 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:

• 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 muscles, pancreas and thyroid are rarely affected. 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.

Progression of the Primary Infection

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

• Bronchial collapse
• Formation of atelectasis
• 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. 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. In younger patients, serofibrinous pleurisy usually occurs after the rupture of subpleural foci of infection into the pleural space. 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.

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:

• 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.

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.

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).

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.
• 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.
• 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)]

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

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

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:

• Skin abrasions
• Oropharynx
• Intestine
• Genitalia

Associated Conditions

AIDS

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

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. It is still not fully understood whether AIDS has an impact on the risk of infection, when in contact with the M. tuberculosis.

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

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

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

Gallery

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  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.

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  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.]

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  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.

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  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.

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  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.

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  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.

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  Photomicrograph describing tuberculosis of the placenta.Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.

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  Histopathology of tuberculosis, endometrium. Ziehl-Neelsen stain.Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.

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  Histopathology of tuberculosis, placenta.Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.

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  Miliar Tuberculosis

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  Renal Tuberculosis lesion

References