Coexistent Malnutrition Is Associated with Perturbations in Systemic and Antigen-Specific Cytokine Responses in Latent Tuberculosis Infection

Abstract

Malnutrition, as defined by low body mass index (BMI), is a major risk factor for the development of active tuberculosis (TB), although the biological basis underlying this susceptibility remains poorly characterized. To verify whether malnutrition affects the systemic and antigen-specific cytokine levels in individuals with latent TB (LTB), we examined circulating and TB antigen-stimulated levels of cytokines in individuals with LTB and low BMI (LBMI) and compared them with those in individuals with LTB and normal BMI (NBMI). Coexistent LBMI with LTB was characterized by diminished circulating levels of type 1 (gamma interferon [IFN-γ] and tumor necrosis factor alpha [TNF-α]), type 2 (interleukin-4 [IL-4]), type 17 (IL-22), and other proinflammatory (IL-1α, IL-1β, and IL-6) cytokines but elevated levels of other type 2 (IL-5 and IL-13) and regulatory (IL-10 and transforming growth factor beta [TGF-β]) cytokines. In addition, LBMI with LTB was associated with diminished TB antigen-induced IFN-γ, TNF-α, IL-6, IL-1α, and IL-1β levels. Finally, there was a significant positive correlation between BMI values and TNF-α and IL-1β levels and a significant negative correlation between BMI values and IL-2, IL-10, and TGF-β levels in individuals with LTB. Therefore, our data reveal that latent TB with a coexistent low BMI is characterized by diminished protective cytokine responses and heightened regulatory cytokine responses, providing a potential biological mechanism for the increased risk of developing active TB.

FIG 1

Diminished systemic levels of type 1 cytokines and IL-22 in individuals with LBMI. The plasma levels of type 1 (IFN-γ, TNF-α, and IL-2) and type 17 (IL-17A, IL-17F, and IL-22) cytokines in individuals with LBMI (n = 28) or NBMI (n = 28) and LTB were measured by ELISA. The data are presented as scatterplots, with each circle representing a single individual (light gray dots, LBMI; and dark gray dots, NBMI). P values were calculated using the Mann-Whitney test.

FIG 2

Elevated systemic levels of type 2 and regulatory cytokines in individuals with LBMI. The plasma levels of type 2 (IL-4, IL-5, and IL-13) and regulatory (IL-10 and TGF-β) cytokines in individuals with LBMI (n = 28) or NBMI (n = 28) and LTB were measured by ELISA. The data are presented as scatterplots, with each circle representing a single individual (light gray dots, LBMI; and dark gray dots, NBMI). P values were calculated using the Mann-Whitney test.

FIG 3

Diminished systemic levels of proinflammatory cytokines in individuals with LBMI. The plasma levels of IL-1 family (IL-1α, IL-1β, and IL-18) and other proinflammatory (IL-6, IL-12, and GM-CSF) cytokines in individuals with LBMI (n = 28) or NBMI (n = 28) and LTB were measured by ELISA. The data are presented as scatterplots, with each circle representing a single individual (light gray dots, LBMI; and dark gray dots, NBMI). P values were calculated using the Mann-Whitney test.

FIG 4

Diminished TB antigen-stimulated levels of proinflammatory cytokines in individuals with LBMI. The TB antigen-stimulated (A) or mitogen-stimulated (B) levels of IFN-γ, TNF-α, IL-22, IL-6, IL-1α, and IL-1β in whole blood from individuals with LBMI (n = 28) or NBMI (n = 28) and LTB were measured by ELISA. The data are presented as scatterplots, with each circle representing a single individual (light gray dots, LBMI; and dark gray dots, NBMI). P values were calculated using the Mann-Whitney test.

FIG 5

Positive and negative relationships between systemic levels of cytokines and BMI values for individuals with LTB. The relationships between the plasma levels of IFN-γ, TNF-α, IL-2, IL-1β, IL-10, and TGF-β and BMI values were examined for all individuals with LTB (n = 56). The data are presented as scatterplots, with each circle representing a single individual. P values were calculated using Spearman rank correlation.