*The Role of the Receptor for Advanced Glycation Endproducts (RAGE) in Type 1 Diabetes… DOI: http://dx.doi.org/10.5772/intechopen.108528*

Tregs are crucial for the maintenance of the peripheral tolerance where they dampen the effects of any self-reactive cells which have escaped deletion by central tolerance. In T1DM, there is impairment in function of and/or the numbers of Tregs present. This imbalance contributes to greater pathogenic activity of effector T lymphocytes and leads to a loss of peripheral tolerance. Peripheral tolerance is the local backstop to prevent self-antigen production and delete T cells with antigen specificity for self-antigens. Thymic derived Tregs (tTregs) defined as CD4+ CD25+ Foxp3+ Tregs are responsible for suppression of effector T lymphocytes through secretion of anti-inflammatory cytokines and competition for IL-2. Both function and frequencies of this subset of Tregs is impaired in both humans and NOD mice [34]. Therefore, restoring their functionality and numbers appears to be an attractive option for preventing T1DM development and is certainly widely under investigation. Currently, there are a number of T cell-centered therapeutic approaches for treatment and prevention of T1DM under development. These include Treg enhancement and antigen-specific strategies, as well as strategies that dampen activation of T cells using CTLA-4-Ig (Abatacept) or anti-CD3 monoclonal antibody (Teplizumab) (reviewed here [35]). The latter has produced promising results in at risk antibody positive individuals significantly improving β-cell function [36, 37]. If this therapy progresses to clinic in the near future, it will make an excellent candidate for combination therapies.

RAGE expression is elevated on T cells from "at-risk" islet autoantibody positive (IAb+) individuals and is associated with progression to T1DM and increased effector function of T cells [38, 39]. The soluble isoform of RAGE (sRAGE) can competitively bind RAGE ligands and inhibit RAGE signaling. Previous studies have shown that RAGE gene (AGER) polymorphisms result in reduced sRAGE in the circulation which correlates with increased risk of T1DM and seroconversion to islet autoantibodies [9, 40]. Murine studies have demonstrated a role for RAGE in T cell activation, priming and effector function, where RAGE-deficient T cells showed reduced proliferation and production of pro-inflammatory cytokines such as IFN-γ [41]. RAGE also plays a role in DC maturation, migration, and function as well as T cell priming. In children with acute Kawasaki disease and juvenile idiopathic arthritis, RAGE facilitates recruitment and activation of leukocytes and sRAGE is reduced [42].

Another study explored the effects of dietary AGEs in NOD mice. Here, a T cell receptor (TCR) transgenic NOD 8.3 males with CD8+ T cells specific for IGRP206–214, one of the main diabetogenic antigens [43], and NOD/ShiLt females and their NOD8.3 female offspring were fed low or high AGEs containing diets from conception to weaning of the offspring. The low AGEs diet resulted in improvements in insulin, proinsulin, and glucagon secretion by the islets as well as reduction in AGEs and RAGE expression in offspring islets. Furthermore, reduced level of immune cell infiltration was seen in the infants whose parents were fed with low AGEs diet in the perinatal period [16]. This is consistent with another previous intergenerational study of low AGE feeding where decreasing rates of T1DM were seen in subsequent generations during feeding with a low AGE diet [44]. In the NOD model RAGE antagonism using sRAGE, significantly decreases progression to overt diabetes onset in NOD mice and preserves β-cell mass and insulin secretory function and that sRAGE therapy did not work following specific depletion of Tregs. This was evidenced through reduced islet infiltration, preservation of islet integrity and numbers as well as insulin expression. Moreover, an increased proportion of Tregs in pancreata, pancreatic lymph nodes and spleens of treated animals was demonstrated. sRAGE-induced improvements in human Tregs proliferative and suppressive ability *ex vivo* [45],

whilst exposure to RAGE ligands, AGEs impairs Treg suppressive capacity [45]. These observations suggest that RAGE inhibition may offer protection against future T1DM development [46].
