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International Textbook of Diabetes Mellitus, 4th Ed., Excerpt #162: Immunopathogenesis of Type 1 Diabetes in Western Society Part 5

Jan 29, 2019
 

Autoimmunity persists in many patients even many years after diagnosis

Studies in patients with long disease duration suggest that β-cell function may persist long after diagnosis [79,80] in a significant proportion of patients. There is also evidence suggesting the co-existence of some low level of regeneration with chronic autoimmunity [81], as islet autoimmunity may also persist or perhaps be reactivated years after diagnosis. Indeed, significant proportions (30–40%) of islet or pancreas transplant recipients express one or more autoantibodies when evaluated prior to transplantation [82]. Moreover, persisting autoreactive T-cell responses detected prior to transplantation correlate with islet graft failure on follow-up [83]. These cells may be expanded following transplantation, since the lymphopenia induced by chronic immunosuppression may promote homeostatic proliferation of memory T cells, which in patients with an autoimmune disease will include autoreactive T cells [84]. The persistence and/or reactivation of islet autoimmune responses is an obstacle to curing diabetes through transplantation, and autoimmunity may not be completely controlled by the immunosuppression used to prevent transplant rejection [76]. Thus, islet autoimmunity may be active for many years, throughout the diabetes clinical spectrum (Figure 29.2), and not just limited to the time prior to and around diagnosis.

Nonautoimmune factors

Additional factors may play a role in the disease pathogenesis, and may promote β-cell dysfunction and progression of islet autoimmunity. Insulin resistance affects about 20% of young patients with T1DM, especially during puberty. Importantly, insulin resistance precedes T1DM diagnosis and accelerates the progression of islet autoimmunity [85–88]. Obesity and T2DM have become more common in children [89]; children with T1DM are often overweight [89], suggesting that certain pathogenic mechanisms may be shared between T1DM and T2DM [90]. Significant changes in metabolite profiles (amino acids, lipids, fatty acids) precede islet autoimmunity in genetically at-risk children, which could be linked to inflammation and possibly apoptosis occurring in the pancreas [91,92], which has been linked to the PTPN2, a susceptibility gene expressed in islet cells that control apoptosis [93]. Insulin resistance and metabolomic changes may be also be related to inflammation. In the SEARCH study, young patients with T1DM had elevated serum levels of IL-6, fibrinogen, and C-reactive protein [94]; stimulation of patients’ monocytes via toll-like receptors is followed by exaggerated IL-6 responses [95]. Of note, IL-6 has been linked to increased Th17 T-cell responses and impaired regulatory T-cell function [96]. The serum of T1DM patients is characterized by a proinflammatory signature that includes IL-1 and several chemokines [97], many of which were also expressed in the pancreas of T1DM patients [98]. Proinflammatory cytokines have deleterious effects on β-cell function and survival [99], and pancreatic islets from patients with T1DM reportedly express markers of endoplasmic reticulum stress [100]. Inflammation is often associated with obesity, and can be modulated by genetic and environmental factors. In addition to a possible role of enteroviral infections in promoting inflammation in the gut [101], there is growing evidence that dietary habits can influence intestinal permeability and the composition of the gut flora [102]; this in turn can influence production of cytokines, chemokines [98], innate immune responses [95], and the function of gut-associated lymphocytes, including regulatory lymphocytes.

Overall, growing evidence points at inflammation and metabolic changes as significant factors in T1DM pathogenesis. These could even precede the triggering of islet autoimmunity, and may promote chronic immune dysregulation through effects on both innate and adaptive immune responses. Of note, some of the genes linked to T1DM risk include genes that influence the innate immune system [12]. Further genetic studies may provide a genetic underpinning for these and additional disease pathways, considering that not all of the T1DM risk loci map to  immune function genes, that some susceptibility genes are expressed in islet cells, and that additional susceptibility genes remain to be mapped [12].

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