Impact of DM on TB prevention, diagnosis, and treatment from an immunologic perspective [TB0093]

One in every ten adults is a diabetic (DM) patient. Long-term hyperglycemia in DM patients leads to decreased immune cell numbers and function, increasing the incidence of tuberculosis (TB). Chronic hyperglycemia severely impairs the function of innate immune cells, affecting processes such as monocyte differentiation into macrophages and dendritic cells. This impairs the recruitment, recognition, phagocytosis, and antigen presentation functions of macrophages and reduces the frequency of dendritic cells and natural killer cells. Additionally, hyperglycemia increases the inflammatory response of neutrophils, which exacerbates bacterial load.

Chronic hyperglycemia may delay the activation of adaptive immune cells, including CD4+ and CD8+ T cells. CD4+ T cells are crucial in anti-tuberculosis immunity, promoting the proliferation of T lymphocytes and macrophage activation via interferon-gamma (IFN-γ) secretion. However, high blood glucose levels can delay CD4+ T cell activation, reducing IFN-γ secretion. Pulmonary tuberculosis (PTB) accounts for nearly 90% of TB cases, and CD4+ T lymphocytes differentiate into Th1, Th2, Th17, and Treg cells, essential for host defense against TB.

CD8+ T lymphocytes, upon recognizing MTB antigen peptides presented by MHC class I molecules, differentiate into cytotoxic T lymphocytes (CTLs). CTLs kill target cells by secreting perforin and granzymes and release IFN-γ and TNF-α, which activate macrophages for MTB clearance. During MTB infection, monocytes migrate to the lungs, differentiate into macrophages and dendritic cells, and present antigens to activate other immune cells. However, high blood glucose levels impair monocyte differentiation into macrophages due to reduced vitamin D levels and increased chemokine receptor CCR2 on monocyte surfaces, hindering effective immune responses.

In some DM patients, cytokine production (e.g., IL-1β, IL-8) decreases, impairing the phagocytic function of monocytes. This reduced cytokine activity can diminish MTB control, while high blood glucose levels alter the complement pathway, affecting monocyte signaling and limiting immune functions. Under hyperglycemic conditions, alveolar macrophage recognition of MTB is compromised, impeding the innate immune response. In the pulmonary microenvironment, macrophages polarize to M2-type, reducing their phagocytic and antimicrobial functions. Medications like glimepiride can exacerbate M2 polarization, impairing macrophage bactericidal abilities and increasing TB susceptibility.

Macrophage activation status changes in DM-TB patients, with decreased HLA-DR, CD80, and CD86 expression and increased PD-L1 expression, which inhibits T cell function. High blood glucose may also cause M1 macrophage polarization through advanced glycation end products (AGEs) via pathways such as HIF-1a, PDK, and MAPK, leading to a pro-inflammatory response that damages lung tissue. Dendritic cells (DCs) in DM-TB patients show delayed activation and decreased frequency, likely due to high blood glucose, and DC frequency tends to improve with controlled TB treatment, emphasizing the impact of hyperglycemia.

High blood glucose levels can reduce IFN-γ production by CD4+ T cells due to decreased MHC-II expression on antigen-presenting cells, impairing the immune response. Elevated glucose also hinders monocyte differentiation into dendritic cells, increasing reactive oxygen species (ROS) production and activating pathways like Wnt/β-catenin, which limits dendritic cell differentiation and maturation. In DM-TB patients, neutrophils often exhibit an excessive inflammatory response, increasing bacterial burden and worsening symptoms. Hyperglycemia can prompt neutrophils to release extracellular traps (NETs), leading to chronic inflammation and tissue damage.

NK cell numbers inversely correlate with fasting blood glucose (FBG) levels in DM-TB patients, indicating an inhibitory effect of hyperglycemia. Additionally, hyperglycemia reduces the expression of CD107a, a marker of NK cell cytotoxic activity. Pro-inflammatory cytokines like TNF-α and IL-17, secreted by NK cells, are significantly elevated, causing excessive inflammation and tissue damage.

DM affects Th1 cell production, leading to reduced IFN-γ secretion, which is crucial for MTB resistance. Poor glycemic control in TB patients correlates with lower IFN-γ levels, while well-controlled blood glucose tends to restore IFN-γ secretion over time. High blood glucose increases Th2 differentiation, potentially suppressing anti-TB immunity and reducing bacterial clearance. Th1 and Th17 cytokine levels (IFN-γ, TNF-α, IL-17) are higher in DM-TB patients, indicating a stronger cytokine response than in non-diabetic TB patients. Elevated HbA1c levels correlate with increased pro-inflammatory cytokines and reduced IL-10, illustrating Th1/Th17 upregulation and Th2 downregulation.

Studies in Asia often report reduced pro-inflammatory and increased anti-inflammatory cytokines in CD4+ T cells of DM-TB patients, while studies from other regions note an increase in pro-inflammatory and a decrease in anti-inflammatory cytokines, suggesting regional differences in immune responses.

Source: Ye, Z., Li, L., Yang, L., Zhuang, L., Aspatwar, A., Wang, L. and Gong, W., 2024. Impact of diabetes mellitus on tuberculosis prevention, diagnosis, and treatment from an immunologic perspective. In Exploration (p. 20230138).