Type 2 Diabetes Mellitus and Latent Tuberculosis Infection Moderately Influence Innate Lymphoid Cell Immune Responses in Uganda.

Phillip Ssekamatte,Mudarshiru Bbuye,Irene Andia Biraro,Matthew R Hepworth,Carol Musubika,Stephen Cose,Marjorie Nakibuule,Moses Egesa,Derek G Doherty,Rose Nabatanzi

doi:10.3389/fimmu.2021.716819

Abstract

BackgroundType 2 diabetes mellitus (T2DM) is a major risk factor for the acquisition of latent tuberculosis (TB) infection (LTBI) and development of active tuberculosis (ATB), although the immunological basis for this susceptibility remains poorly characterised. Innate lymphoid cells (ILCs) immune responses to TB infection in T2DM comorbidity is anticipated to be reduced. We compared ILC responses (frequency and cytokine production) among adult patients with LTBI and T2DM to patients (13) with LTBI only (14), T2DM only (10) and healthy controls (11).MethodsUsing flow cytometry, ILC phenotypes were categorised based on (Lin−CD127+CD161+) markers into three types: ILC1 (Lin−CD127+CD161+CRTH2-CD117−); ILC2 (Lin−CD127+CD161+CRTH2+) and ILC3 (Lin−CD127+CD161+CRTH2−NKp44+/−CD117+). ILC responses were determined using cytokine production by measuring percentage expression of interferon-gamma (IFN-γ) for ILC1, interleukin (IL)-13 for ILC2, and IL-22 for ILC3. Glycaemic control among T2DM patients was measured using glycated haemoglobin (HbA1c) levels. Data were analysed using FlowJo version 10.7.1, and GraphPad Prism version 8.3.ResultsCompared to healthy controls, patients with LTBI and T2DM had reduced frequencies of ILC2 and ILC3 respectively (median (IQR): 0.01 (0.005-0.04) and 0.002 (IQR; 0.002-0.007) and not ILC1 (0.04 (0.02-0.09) as expected. They also had increased production of IFN-γ [median (IQR): 17.1 (5.6-24.9)], but decreased production of IL-13 [19.6 (12.3-35.1)]. We however found that patients with T2DM had lower ILC cytokine responses in general but more marked for IL-22 production (median (IQR): IFN-γ 9.3 (4.8-22.6); IL-13 22.2 (14.7-39.7); IL-22 0.7 (IQR; 0.1-2.1) p-value 0.02), which highlights the immune suppression status of T2DM. We also found that poor glycaemic control altered ILC immune responses.ConclusionThis study demonstrates that LTBI and T2DM, and T2DM were associated with slight alterations of ILC immune responses. Poor T2DM control also slightly altered these ILC immune responses. Further studies are required to assess if these responses recover after treatment of either TB or T2DM.

Highlights

Tuberculosis (TB) still remains the leading cause of death from a single infectious agent globally despite advances in care in the past decade [1]
Latent TB infection and/or Type 2 diabetes mellitus (T2DM) participants were enrolled from October 2017 to March 2018 in the Tuberculosis and Diabetes (TAD) study, a case-control study assessing the frequency of Innate lymphoid cells (ILCs), T and B cells in latent tuberculosis (TB) infection (LTBI) and/or T2DM patients
T2DM was diagnosed using the American Diabetes Association (ADA) criteria based on glycated haemoglobin (HbA1c) levels ≥ 6.5% [39] and latent TB infection based on positive results for the immunological test QuantiFERON TB-Gold-Plus (QFT)

Summary

Introduction

Tuberculosis (TB) still remains the leading cause of death from a single infectious agent globally despite advances in care in the past decade [1]. One-third of the population globally is infected with the bacteria, Mycobacterium tuberculosis (Mtb) that causes the disease, and an estimated 10% of these are likely to develop active tuberculosis in their lifetime [1] Comorbidities such as Type 2 diabetes mellitus (T2DM) are known to influence the outcome of Mtb infection [1]. The susceptibility to Mtb in T2DM patients is attributable to several factors including the direct effects of hyperglycaemia and insulin resistance, and indirectly largely attributable to the immune-compromised state in this population [5]. Both innate and adaptive immune responses are dysregulated in people having T2DM, which delays Mtb clearance [6,7,8,9]. We compared ILC responses (frequency and cytokine production) among adult patients with LTBI and T2DM to patients [13] with LTBI only [14], T2DM only [10] and healthy controls [11]

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