Influence of type 1 & 2 innate lymphoid cells, and their cytokine production on increasing risk of tuberculosis infection among patients with type 2 diabetes mellitus.
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Absence of or reduced interferon gamma (IFN-γ) production is associated with increased susceptibility to tuberculosis (TB) infection (LTBI), and also with progression from latent to active TB. Immune suppressive diseases such as diabetes mellitus (DM) have adverse effects on the host immune response against TB, accelerating infection and disease, and complicating response to treatment. Several immune cells are dysregulated by chronic immune status in DM including innate lymphoid cells (ILCs). There are three classes of ILCs: ILC1; ILC2; ILC3 that mimic TH1; TH2; TH17 cellular responses in the adaptive arm. The exact mechanisms by which DM increases susceptibility to TB are not well defined, and therefore this study investigated how type 2 DM (T2DM) modulates ILC1s and ILC2s to enhance susceptibility to LTBI. The study also assessed the level of cytokine production by ILC1 and 2, and their association with TB status. Methods: This was a cross-sectional study of 30 participants. Archived Peripheral Blood Mononuclear Cells (PBMCs) were thawed, stimulated and cultured with Phorbolmyristate acetate (PMA)/ionomycin plus Brefeldin A. The cells were stained for both surface and intracellular markers and acquired on an LSR II flow cytometer. Frequencies were exported from FlowJo and statistical tests performed using GraphPad Prism. Data were expressed as median and interquartile range. Kruskal-Wallis and Mann-Whitney U tests were used to show any associations. Results: Eighteen of 30 participants were studied. Of these: 7 had LTBI and T2DM; 7 had LTBI no T2DM; and 4 had no LTBI no T2DM. The ILC1 were lowest among LTBI and T2DM and highest among no LTBI no DM as hypothesized (P = 0.0143). The ILC2 as anticipated were highest in LTBI and T2DM, and lowest in no LTBI no T2DM (P = 0.0146). The IFN-γ and IL-13 expressions by ILC1 and ILC2 respectively were decreased in LTBI and T2DM as compared to LTBI no T2DM supporting the immune suppressive effects of chronic hyperglycaemia. Conclusion: The findings reveal that T2DM profoundly alters the ILC1 response among patients with both LTBI and T2DM by decreasing ILC1 and IFN-γ expression which are vital in protection against Mycobacterium tuberculosis. Type 2 DM also alters the ILC2 response by increasing the ILC2, a subset that restores tissue homeostasis and cross regulates ILC1 responses. It is very plausible that these contribute to the increased susceptibility to TB infection and possibly progression to active disease. This data is contributing to growing evidence that immunodeficiency is an integral part of type 2 DM, that could have serious consequences in the face of intracellular pathogens that require type-1 associated cytokines for resistance.