Impact of DM on immunity to LTBI [TB0092]

Latent tuberculosis infection (LTBI) is characterized by an infection with Mycobacterium tuberculosis (M.tb) without symptoms of active TB. M.tb's success lies in its ability to remain asymptomatic in a latent state, reactivating only in a minority over months, years, or even decades. The risk of reactivation varies with age at infection and any concurrent health conditions that promote TB progression. With about one-fourth of the global population estimated to have LTBI, this large pool serves as a reservoir for TB re-emergence.

See also: https://tbreadingnotes.blogspot.com/2024/07/population-health-impact-and-cost.html

Effective control of M.tb involves T cells, which aid macrophages in granuloma formation, tackling M.tb antigens. CD4+ T cells, in particular, release cytokines and chemokines with macrophage assistance, also supporting CD8+ T cell, DURT, and B cell activities. Both lymphoid and myeloid innate immune cells are crucial for the host’s defense against M.tb. However, diabetes mellitus (DM) significantly impacts the immune response, affecting cytokine levels, immune cell subsets, and increasing apoptosis and tissue fibrosis, suggesting an inflammatory role in DM pathogenesis.

See also: https://tbreadingnotes.blogspot.com/2024/07/clinical-predictors-of-pulmonary-tb.html

Individuals with LTBI and DM display reduced frequencies of myeloid and plasmacytoid dendritic cells (DC), classical and intermediate monocytes, but an elevated frequency of non-classical monocytes compared to those with LTBI alone. Reduced levels of innate lymphoid cells (ILCs), specifically ILC2 and ILC3, have been observed, while ILCs producing IFN-γ increase, and IL-13 decreases. Similarly, LTBI individuals with DM exhibit lower frequencies of γδ T cells, NK, and iNKT cells expressing various cytokines and cytotoxic markers when compared to LTBI-only individuals. Conversely, MAIT cells in LTBIDM individuals maintain or increase cytokine expression, suggesting some innate immune subsets retain TB antigen responsiveness.

See also: https://tbreadingnotes.blogspot.com/2024/07/association-between-long-term-exposure.html

DM-related alterations in innate immune markers appear linked to enhanced mycobacterial pathogenesis in LTBI individuals. Adaptive immunity, largely dependent on CD4+ T cells, particularly Th1 and Th17 cells, shows impairment in DM comorbidities. LTBI with DM individuals exhibit lower frequencies of Th1, Th2, and Th17 CD4+ T cells at baseline and following TB antigen stimulation. Neutralizing IL-10 and TGF-β partially restores these responses, highlighting the influence of these cytokines. Likewise, diminished CD8+ T cell responses to Tc1, Tc2, and Tc17 cytokines occur alongside increased cytotoxic markers (e.g., Granzyme B, perforin) in LTBI with DM cases.

See also: https://tbreadingnotes.blogspot.com/2024/07/modeling-social-environmental-and.html

Additionally, LTBI with DM individuals demonstrate lower effector memory CD4+ T cells, but elevated activated memory and atypical B cells, along with a reduction in naive B cells, signifying adaptive immune modulation in TB-DM. Collectively, DM in LTBI associates with considerable impairments in T cell activation and function, offering insights into how DM may facilitate the progression from LTBI to active TB.

IFN-γ and TNF-α are essential for protective immunity, while IL-17A, a key type 17 cytokine, plays a crucial role in memory immune responses to Mycobacterium tuberculosis (M.tb) in mice. IL-22 supports the human antimycobacterial response, and IL-1 cytokines, particularly IL-1α and IL-1β, are critical for TB resistance. Other cytokines like IL-18 and IL-12 are also vital for M.tb immunity, and IL-6 helps inhibit disease progression.

Individuals with LTBI and diabetes mellitus (DM) show decreased levels of type 1 cytokines (IFN-γ, IL-2, and TNF-α), type 17 cytokines (IL-17A, IL-17F, and IL-22), and other pro-inflammatory cytokines, such as IL-1β and IL-18, compared to those without DM. The presence of DM is associated with reduced protective cytokine production following TB antigen stimulation, potentially explaining the increased risk of active TB in individuals with LTBI and DM.

The IL-20 cytokine subfamily, which plays roles in host defense and glucose metabolism, is implicated in LTBI-DM comorbidity. LTBI-DM individuals exhibit lower plasma levels of IL-10, IL-19, IL-20, and IL-24 but increased IL-22. Additionally, they have reduced plasma adiponectin and adipsin but elevated leptin, visfatin, and PAI-1, suggesting metabolic dysfunction causes an imbalance of pro- and anti-inflammatory adipocytokines, influencing TB pathogenesis.

In newly diagnosed DM (NDM) individuals with LTBI, inflammatory markers like IL-1β, IFN-γ, and adiponectin are elevated, and IL-27 and IL-10 are higher compared to LTBI-only individuals. Meanwhile, IL-38 levels are reduced in LTBI-DM cases, indicating a unique immunological profile in LTBI-DM that may impact TB progression. DM compromises immunity, which can significantly affect the body's response to pathogens like M.tb.

Pre-diabetes (PDM), an intermediate hyperglycemic state, also impacts LTBI. LTBI-PDM individuals show reduced multifunctional Th1 and Th17 CD4+ T cell frequencies and diminished CD8+ Tc1 and Tc17 cell function upon TB antigen stimulation, correlating PDM with altered immune responses in LTBI. Lower systemic levels of IFN-γ, IL-2, TNF-α, and IL-17F suggest a pro- and anti-inflammatory cytokine imbalance in LTBI-PDM.

LTBI-PDM individuals also have reduced TB antigen-specific γδ T cells, NK, and iNKT cell responses, with lower expression of cytokines and cytotoxic markers like perforin and granzyme B. However, MAIT cells in LTBI-PDM show higher expression of type 1 and type 17 cytokines, indicating that while some innate immune cells are compromised, others remain active. These findings underscore that LTBI-PDM is marked by significant changes in immune cell activation and function, which may affect immunity to TB.

Source: Kumar, N.P., & Babu, S. (2023). Impact of diabetes mellitus on immunity to latent tuberculosis infection. Frontiers in Clinical Diabetes and Healthcare, 4, 1095467.

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