Altered levels of innate and adaptive immune markers in type 2 diabetes mellitus

Abstract

Metainflammation provoked by sterile stimulus forms an important component of Type 2 Diabetes Mellitus (T2DM) and gains larger attention in recent days. Both innate and adaptive immune cells play pivotal role in the pathogenesis of T2DM. Toll-like receptors (TLRs) are innate immune receptors which act as sentinels bridging both innate and adaptive arms of immunity. They induce inflammation both at the local and peripheral sites under diabetic conditions. Few studies have previously addressed the involvement of TLRs in diabetes associated inflammation, yielding contradictory results. Further, till date no extensive study has been done to compare the effect of newly diagnosed versus chronic diabetes on TLR signalling. The role of T-cell cytokines in these conditions is also less well studied compared to the proinflammatory cytokines such as TNF-and#945;, IL-6 and IL-1and#946; which are well documented. Towards this end, both T-Helper 1 (Th1) and T-Helper 2 (Th2) cytokines in subjects with Normal Glucose Tolerance (NGT)-control, Newly Diagnosed type 2 Diabetes (NDD) who are not under anti-diabetic medication and Known (also chronic) type 2 Diabetes (KDM) taking anti-diabetic medication have been studied in this thesis. It also analyzes all the major components of TLR signalling: 1. Ligand (Lipopolysaccharide (LPS))/ Coligand (Lipid Binding Protein (LBP) and soluble CD14 (sCD14)) levels, neutralizing antibodies (Endocab) 2. Receptor (TLR2 and 4) and adaptors (MyD88, TRIF, Mal and TRAM) levels and 3. Major effector mechanisms- a) Cytokine secretion (TNF-and#945;, IL-6, IL-1and#946; and IL-10), b) Cellular activation (CD69), c) Activation driven apoptosis (activated caspase-3 expression) and d) Effector enzyme expression (Arg-1, Cox-2, HO-1, IDO and ATF) in NGT, NDD and KDM subjects. TLR induced T-cell activation along with components of antigen processing/presentation in these subjects has also been studied. newline