Mycobacterium tuberculosis (Mtb) and Immune Response

Cell-Mediated Immune Response

Macrophages and dendritic cells consume Mtb antigens, and then transport them to CD4+ T cells through molecules in the class II major histocompatibility complex (MHC II). Active T cells release IFN- and also augment the antimicrobial properties of macrophages by activating the production of cytotoxic molecules, including nitric oxide (NO) (NOX2) and reactive oxygen species to form granulomas that block the infection; Mtb is encapsulated in structures formed when immune cells, such as macrophages, dendritic and B cells pool together.

Antibodies and Their Use in Tuberculosis

Although the immune response to TB is largely cell-based, the immune system also contains antibodies. Antibodies to Mtb typically produce IgM, IgG and Iga. From available evidence, the antibody response in TB patients is incredibly heterogeneous, with variations in antibody type and specificity attributed directly to Mtb load, immune tolerance and symptoms.

Figure 2. Role of Antibodies in Phagocytic Modulation of M. tuberculosis Interaction with Macrophages (Source: G Jacobs, A.J., et al., 2016)

To identify TB, antibody responses are used to separate LTBI from active TB. Once antibodies to Mtb are detected in the blood (e.g., IgG and IgM), it's diagnostically possible to identify an Mtb infection. Antibody testing is moderately sensitive and specific in diagnosing LTBI (although false negatives and false positives sometimes occur).

Antibodies form a major part of the TB immune system beyond diagnosis. Antibodies that are bound to Fc receptors on the host cell kill Mtb by being absorbed by macrophages or other immune cells in the process known as antibody-dependent cellular cytotoxicity (ADCC). In addition, the opsonizing role of antibodies increases phagocytic activity and immune cells' capacity to flush out the infection.

Figure 3. IgA+ and IgG+ Plasma Cells in the Lungs of Tuberculosis Patients (Source: Zimmermann, N., et al., 2016)

Drug Resistance Mechanisms

Mtb resistance, notably multidrug-resistant TB (MDR-TB) and extensively drug-resistant TB (XDR-TB), is a global problem in TB control. Mtb develops antibiotic resistance via gene mutations that modify targets proteins or enzymes and prevent them from working. Second, immune evasion pathways are the major driver of Mtb's long-term persistence in the host, creating chronic or latent infection. Mtb may escape immune detection by changing its surface antigens or avoiding recognition by the immune system.

Intuition and adaptive immunity play an increasingly complex role in tuberculosis immunity. While the immune system can in most cases regulate Mtb replication, some host conditions (immune diseases, diabetes, HIV infection, etc.) can promote vulnerability and aid the transition from passive infection to active disease. It is now well-understood that antibodies play a key role in the TB immune response via antibody-mediated cytotoxicity and opsonization of cells. Such research opens up new avenues for TB diagnosis, vaccine discovery and new therapies.