Coincident Type 2 diabetes mellitus modulates the systemic and antigen – specific induction of Type 1, Type 17, and other cytokines in both active and latent tuberculosis

Abstract

Abstract Type 2 diabetes mellitus (DM) is known to be a major risk factor for the development of active tuberculosis, although its influence on active and latent Mycobacterium tuberculosis infection and disease remains poorly characterized. To identify the influence of coincident DM on cytokine levels in active pulmonary tuberculosis and latent tuberculosis, we examined circulating levels of a panel of cytokines in the plasma of individuals with PTB-DM or PTB alone and LTB-DM or LTB alone. PTB-DM is characterized by elevated circulating levels of type 1 (IFNγ, TNFα, and IL-2), type 2 (IL-5), type 17 (IL-17A) but decreased circulating levels of IL-10 family of cytokines (IL-19, IL-20, IL-22 and IL-24). This was associated with increased systemic levels of other pro-inflammatory cytokines (IL-1β, IL-6, and IL-18) and an anti-inflammatory cytokine (IL-10) but not type 1 IFNs. In contrast, LTB-DM is characterized by diminished circulating levels of type 1 (IFNγ, IL-2, and TNFα), type 17 (IL-17F), IL-10 family (IL-10, IL-19, IL-20 and IL-24) and other pro-inflammatory (IL-1β and IL-18) cytokines. Moreover, PTB-DM showed increased levels of pro-inflammatory cytokines upon tuberculosis antigen stimulation whereas LTB-DM showed diminished pro-inflammatory cytokines upon tuberculosis antigen stimulation. Our data reveal that PTB-DM is characterized by heightened cytokine responsiveness, indicating that chronic inflammation underlying DM potentially contributes to increased immune pathology. On the other hand, LTB-DM is characterized by diminished production of cytokines, implicated in the control of M. tuberculosis, allowing for a potential immunological mechanism that could account for the increased risk of active tuberculosis.