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Immunology of Tuberculosis: Host-Pathogen Dynamics
The immunology of Tuberculosis (TB) involves a complex interplay between Mycobacterium tuberculosis and the host immune system. This interaction determines disease progression, from initial infection to latent or active states. Understanding host-pathogen dynamics, immune evasion strategies, and diagnostic responses is crucial for effective management and prevention of this global health challenge.
Key Takeaways
Host immune response dictates TB infection outcome.
Few individuals progress to primary active disease.
Immunosuppression triggers latent TB reactivation.
Tuberculin test differentiates DTH from latent infection.
What are the fundamental aspects of Tuberculosis immunology?
The fundamental aspects of Tuberculosis immunology involve understanding how Mycobacterium tuberculosis (M.tb) interacts with the immune system, the nature of delayed-type hypersensitivity, and the varied outcomes in different host immune states. The respiratory system employs both innate and adaptive immunity to defend against pathogens. TB remains the second most common infectious cause of death globally, often linked with HIV, and is transmitted primarily through the inhalation of aerosols and dust. M.tb's waxy outer coat, composed of mycolic acid, contributes to its resilience and ability to evade initial immune responses.
- M.tb infection involves a critical immune encounter.
- Delayed-type hypersensitivity is a key immune response.
- Immune outcomes vary in competent versus compromised hosts.
- Interferon gamma release assays (IGRA) detect M.tb exposure.
- Tuberculin tests gauge immunity but have limitations.
- Respiratory system employs both innate and adaptive immunity.
- TB is the second most common infectious cause of death.
- Transmission occurs via aerosol inhalation.
How does Mycobacterium tuberculosis interact with and evade the host immune system?
Mycobacterium tuberculosis interacts with the host by employing specific virulence factors to evade immune detection and destruction. Its waxy outer coat, for instance, blocks phagocyte enzymes, allowing M.tb to remain undetected. Catalase-peroxidase helps the bacterium resist the host's oxidative response, while Lipoarabinomannan (LAM) induces cytokines and interferes with antigen presentation. M.tb also actively evades intracellular killing by resisting reactive oxygen intermediates, inhibiting phagosome-lysosome fusion and acidification, and even escaping the phagosomal compartment. Weeks after infection, M.tb peptides are presented to Th1 (CD4) lymphocytes, leading to the release of IFN-γ and TNF, which enhance macrophage killing and activation.
- Waxy outer coat blocks phagocyte enzymes, making M.tb undetected.
- Catalase-peroxidase resists host oxidative responses.
- Lipoarabinomannan (LAM) induces cytokines and interferes with antigen presentation.
- M.tb evades intracellular killing by resisting reactive oxygen intermediates (ROIs).
- It inhibits phagosome-lysosome fusion and acidification.
- M.tb can escape the phagosomal compartment.
- Weeks after infection, M.tb peptides activate Th1 (CD4) lymphocytes.
- IFN-γ and TNF release enhance macrophage killing and activation.
What are the typical clinical courses and outcomes of Tuberculosis infection?
The clinical course of Tuberculosis infection varies significantly, starting with immediate clearance in 90% of exposures. For others, it can lead to immediate onset primary disease, latent infection, or reactivation. In primary disease, bacilli establish in the lungs and proliferate within macrophages, forming nodular granulomatous structures called tubercles. These can enlarge, leading to lymphadenopathy and the formation of a Ghon complex. Lung destruction in primary disease is progressive, driven by TNF-alpha, reactive oxygen/nitrogen intermediates, and cytotoxic cells, resulting in characteristic caseating necrosis. Granulomas can spread mechanically, and other forms like miliary TB (hematogenous spread) and chronic TB exist, with chronic TB having high mortality without treatment.
- Immediate clearance occurs in 90% of exposures.
- Primary disease involves bacilli proliferation in macrophages.
- Macrophages form nodular granulomatous structures called tubercles.
- Ghon complex includes tubercles and enlarged lymph nodes.
- Ranke complex represents healed, fibrotic or calcified tubercles.
- Lung destruction is driven by TNF-alpha and cytotoxic cells.
- Caseating necrosis is a characteristic "cheese-like" tissue death.
- Miliary TB involves hematogenous spread and millet seed lesions.
- Chronic TB has high mortality without treatment.
When does latent Tuberculosis occur, and what causes its reactivation?
Latent Tuberculosis occurs when there is a stable balance between the M.tb infection and the host's immune system, primarily involving the activation of CD4+ (Th1) lymphocytes. This state is characterized by a non-replicating bacilli population and an immune response to secreted antigens, often showing resistance to anti-Mtb drugs. Reactivation disease involves the proliferation of these dormant bacteria, occurring in 5-10% of latent cases. It is strongly associated with immunosuppression, which can stem from conditions like HIV infection, end-stage renal disease, diabetes mellitus, malignant lymphoma, corticosteroid use, TNF-alpha inhibitors, or the natural diminution of cell-mediated immunity with age. Reactivation typically presents as localized disease, often in the lung apices, with less regional lymph node involvement.
- Latent TB involves a balance between the host immune system and infection.
- Activation of CD4+ (Th1) lymphocytes is crucial in latency.
- Low induction of CD8+ lymphocytes is observed.
- Non-replicating bacilli populations characterize latent infection.
- Immune response to secreted antigens is present.
- Resistance to anti-Mtb drugs can occur.
- Reactivation involves the proliferation of dormant bacteria.
- 5-10% of latent cases reactivate, often due to immunosuppression.
- Immunosuppression factors include HIV, diabetes, and corticosteroid use.
- Reactivation disease typically occurs at the lung apices.
- Granulomas are now seen as both host protective and potentially aiding bacilli survival.
Which diagnostic and immune tests are used to detect Tuberculosis infection?
Several diagnostic and immune tests are employed to detect Tuberculosis infection, each with specific applications and limitations. The Tuberculin Test, also known as the Mantoux test, is a delayed hypersensitivity skin test involving the intradermal injection of PPD. However, it is non-specific for M.tb, unreliable in immunocompromised states, and can yield false-positive results in individuals vaccinated with BCG. In contrast, the IFN-γ Release Assay (IGRA) measures interferon-gamma released from T cells stimulated by M.tb specific antigens like ESAT-6 and CFP-10. These antigens are absent in the BCG vaccine strain, allowing IGRA to differentiate latent infection from BCG vaccination. While a delayed-type hypersensitivity (DTH) response is observed, it does not directly correlate with protection against TB.
- The Tuberculin Test (Mantoux) is a delayed hypersensitivity skin test.
- It is non-specific for M.tb and unreliable in immunocompromised individuals.
- BCG vaccination can cause false-positive tuberculin test results.
- IFN-γ Release Assays (IGRA) measure IFN-γ from T cells.
- IGRA uses M.tb specific antigens like ESAT-6 and CFP-10.
- IGRA differentiates latent infection from BCG vaccination.
- DTH response does not correlate with protection against TB.
Frequently Asked Questions
What is the primary mode of TB transmission?
Tuberculosis primarily spreads through the inhalation of airborne aerosols and dust containing Mycobacterium tuberculosis bacteria, released by infected individuals when coughing or sneezing.
How does M.tb evade the host immune system?
M.tb uses virulence factors like its waxy coat and Lipoarabinomannan to block phagocyte enzymes, resist oxidative stress, and inhibit phagosome-lysosome fusion, allowing it to survive inside host cells.
What is the significance of a Ghon complex?
A Ghon complex indicates primary TB infection, consisting of a calcified lung lesion (tubercle) and enlarged regional lymph nodes. It often heals into a Ranke complex, signifying resolved infection.
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