Introduction
One third of the people suffering with type 2 diabetes mellitus (DM)
reside in developing countries many of which are endemic for
Tuberculosis (TB). In Pakistan, the prevalence of diabetes is reported
to be 9.8% and 3% of all national deaths are thought to be associated
with DM and DM-related conditions (1). As Pakistan also ranks
5th amongst high TB burden countries, it is an
additional challenge to manage patients with TB and DM comorbidity (2).
Different risk factors may account for an important proportion of TB
cases in the population. Diabetes (DM) occurs as the individual becomes
resistant to insulin, resulting in poor metabolism of glucose.
Individuals with DM have a threefold increased risk of developing TB (3,
4). DM has also a negative impact on treatment outcomes in patients with
tuberculosis (TB) (5). Latent, asymptomatic infection or immune
reactivity with M. tuberculosis (LTBi) occurs in around one
fourth of the world population (6), and the association between LTBi and
DM-2 has been suggested (7).
Studies on host immunity of individuals with LTBi indicate that CD4 T
cell responses specific to MTB antigens are raised in this group (8).
Which is the premise of the MTB-specific T cell -derived IFNγ assay
testing for LTBi diagnosis (9). Additional cytokines and chemokines such
as IL-10, TNFα, CXCL10, CXCL9 are also found to be raised in LTBi as
compared with healthy endemic controls (EC) (10). Gene expression
studies have identified particular biomarker expression patterns within
LTBi individuals that discriminate them from those who are healthy and
those who have active TB (11) (12). Heterogeneity of LTBI was further
recognised by epidemiological differences in the risk of TB between
those with recent and remote infection (13). It is well understood that
immune regulatory factors such as, IL-12, IFN-γ and TNF-α confer
protective immunity against MTB infection, the understanding of factors
which lead to disease progression from LTBi to TB is very limited (14).
DM is associated with altered cellular and humoral immune responses with
modulation of macrophage and lymphocyte function (15). Delayed
management of DM can lead to diverse complications including
susceptibility to infections (16). Inflammatory mediators including,
proinflammatory cytokines such as IFNγ, TNFα, IL-6, and downregulatory
cytokines IL-10, TGFβ together with adipokines, which affect leptin
regulation and impact metabolism in glycogen stores, are all raised in
DM cases (17). Individuals with LTBi and DM have been shown to
sub-optimal CD4 T cell responses to MTB-specific antigens and increased
production of the Th 2 cytokines IL-10 and TGF-beta (18).
Host innate and adaptive responses are both crucial in protection
against TB. Suppressor of cytokines signaling (SOCS) molecules regulate
key cytokine drivers of activation of both innate and adaptive immunity.
SOCS has eight member molecules including cytokine-inducible regulator
of signaling (CIS), SOCS1-7 (19). SOCS1 and 3 are found to play a role
in the pathogenesis of TB and diabetes (20). SOCS1 suppresses STAT1, the
transcription factor involved in IFN-γ and IFN-α/β signaling, while
SOSC3 has different targets, including STAT3 activation via certain
receptors as the IL6-receptor family (21). SOCS1 and 3 molecules are
modulated by MTB for its own survival, play a pivotal role in
controlling infection outcomes (19, 22, 23).
Separately, SOCS1 and SOCS3 inhibit the insulin receptor substrates 1
and -2 (IRS-1 and IRS-2) protein, hindering insulin responses and
insulin growth factor (IGF)-1 signaling, thereby affecting glucose
metabolism (24). Here we investigated the impact of diabetes on
progression of MTB infection to active disease through the study of
mycobacterial antigen-induced cytokine activation and their association
of regulatory SOCS1 and SOCS3.