Immunopathology in Human Tuberculosis

Tuberculosis (TB) is a chronic infectious disease caused by Mycobacterium tuberculosis (Mtb). The immune response to TB is complex, involving both protective and pathological mechanisms. While immune activation is essential for controlling infection, excessive or dysregulated responses contribute to tissue damage and disease progression. This document explores the immunopathological aspects of TB and their implications for disease outcome and treatment.

Innate Immune Response

1. Recognition of Mtb
   • Mtb is recognized by pattern recognition receptors (PRRs) on macrophages and dendritic cells, including Toll-like receptors (TLRs) and NOD-like receptors (NLRs).
   • The interaction leads to phagocytosis and activation of inflammatory pathways.
2. Granuloma Formation
   • A hallmark of TB pathology, granulomas consist of macrophages, T cells, dendritic cells, and fibroblasts.
   • They help contain Mtb but can also serve as reservoirs for latent infection.
3. Macrophage Activation and Cytokine Signaling
   • Activated macrophages produce tumor necrosis factor-alpha (TNF-α), interleukin-12 (IL-12), and interferon-gamma (IFN-γ), crucial for controlling bacterial replication.
   • Mtb evades immune destruction by inhibiting phagosome-lysosome fusion and manipulating host signaling pathways.

Adaptive Immune Response

1. T Cell-Mediated Immunity
   • CD4+ T cells secrete IFN-γ, which enhances macrophage killing capacity.
   • CD8+ T cells contribute by lysing infected cells and producing cytokines.
   • Regulatory T cells (Tregs) modulate the immune response to prevent excessive inflammation.
2. Humoral Response
   • Although antibodies are produced in TB, their protective role remains unclear.
   • B cells may contribute to immune regulation and granuloma maintenance.

Immunopathology and Tissue Damage

1. Caseous Necrosis and Cavitation
   • Uncontrolled immune activation leads to tissue necrosis and formation of cavities in the lungs, facilitating bacterial transmission.
   • Excessive TNF-α and reactive oxygen species (ROS) contribute to cell death and breakdown of granulomas.
2. Latent vs. Active TB
   • In latent TB, immune control prevents bacterial spread but does not eliminate infection.
   • Reactivation occurs due to immune suppression, as seen in HIV co-infection or malnutrition.

Immunotherapeutic Approaches

1. Host-Directed Therapies (HDTs)
   • Targeting immune pathways to reduce inflammation and enhance bacterial clearance.
   • Examples include TNF inhibitors, autophagy enhancers, and cytokine modulation.
2. Vaccine Development
   • Bacillus Calmette-Guérin (BCG) provides partial protection, but novel vaccines aim to improve efficacy.
   • Subunit and live-attenuated vaccines are in development to enhance T cell responses.

Conclusion

The immunopathology of TB highlights the delicate balance between protective immunity and excessive inflammation. Understanding host-pathogen interactions is crucial for developing better therapies and vaccines to control TB effectively.

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