Role of Autoantibodies in Type 1 Diabetes

ArticleinFrontiers in Bioscience 12(1):1889-98 · February 2007with13 Reads
DOI: 10.2741/2195 · Source: PubMed
Abstract
Type 1A, the immune mediated form of diabetes, is a relatively common disorder that develops in genetically susceptible individuals. The disease is associated with a series of anti-islet autoantibodies and the autoantibodies can be present for years prior to the onset of hyperglycemia. In general it is thought that type 1A diabetes is T cell mediated, but there is evidence from studies in the NOD mouse model that antibodies and B-lymphocytes contribute to pathogenesis. In man evidence is lacking that transplacental passage of anti-islet antibodies increases disease risk. Well characterized, high throughput autoantibody assays (tested in a series of international workshops) are now available, and are the mainstays of prediction of type 1A diabetes, diagnosis of the immune mediated form of diabetes, and are important for the design of trials for the prevention of type 1A diabetes. In addition to anti-islet autoantibodies, patients with type 1A diabetes develop a series of associated autoimmune disorders that are usually detected with screening for additional autoantibodies (e.g. anti-thyroid, anti-transglutaminase, anti-21 hydroxylase, anti-parietal cell). At present it is possible to predict the development of type 1A diabetes and prevent the disorder in animal models, but we lack proven therapies for disease prevention in man. The ability to detect specific anti-islet autoantibodies provides the foundation for developing and testing these preventive therapies.
    • "The group of relatives of T1D proband with a high cumulative risk is termed rapid progressors, whereas the second group who lack serological responses against full-length IA-2 including the extracellular domain is termed slow progressors. Recent findings with regards to T1D in animal models [14] show that it is possible to predict the progression of the disease and thus provide an anabolic window of opportunity to hinder the autoimmune disorder, but there is still deficiency in proven therapies for preventive care in humans [33]. The ability to detect specific anti-islet autoantibodies provides the foundation for developing and testing these preventive therapies. "
    [Show abstract] [Hide abstract] ABSTRACT: Defining the role of T-cell avidity and killing efficacy in forming immunological response(s), leading to relapse-remission and autoantibody release in autoimmune type 1 diabetes (T1D), remains incompletely understood. Using competition-based population models of T- and B-cells, we provide a predictive tool to determine how these two parametric quantities, namely, avidity and killing efficacy, affect disease outcomes. We show that, in the presence of T-cell competition, successive waves along with cyclic fluctuations in the number of T-cells are exhibited by the model, with the former induced by transient bistability and the latter by transient periodic orbits. We hypothesize that these two immunological processes are responsible for making T1D a relapsing-remitting disease within prolonged but limited durations. The period and the number of peaks of these two processes differ, making them potential candidates to determine how plausible waves and cyclic fluctuations are in producing such effects. By assuming that T-cell and B-cell avidities are correlated, we demonstrate that autoantibodies associated with the higher avidity T-cell clones are first to be detected, and they reach their detectability level faster than those associated with the low avidity clones, independent of what T-cell killing efficacies are. Such outcomes are consistent with experimental observations in humans and they provide a rationale for observing rapid and slow progressors of T1D in high risk subjects. Our analysis of the models also reveals that it is possible to improve disease outcomes by unexpectedly increasing the avidity of certain subclones of T-cells. The decline in the number of [Formula: see text]-cells in these cases still occurs, but it terminates early, leaving sufficient number of functioning [Formula: see text]-cells in operation and the affected individual asymptomatic. These results indicate that the models presented here are of clinical relevance because of their potential use in developing predictive algorithms of rapid and slow progression to clinical T1D.
    Full-text · Article · Apr 2014
    • "Such information can have significant benefit for developing improved metrics for identifying/stratifying of at-risk subjects, developing potential therapeutic targets, and advancing understanding of the pathophysiology of the disease [27]. Currently, three major molecular targets (insulin, GAD 65 and IA-2) have been reported, with approximately 94% of all subjects with a clinical diagnosis of T1D expressing autoantibodies to at least one of these molecules at clinical onset [2,3,91011. However, the precise interrelation of these markers autoantibodies with the extent of T1D progress is largely unknown. "
    [Show abstract] [Hide abstract] ABSTRACT: Abstract Background: Type 1 diabetes mellitus (T1D) is a chronic autoimmune disease with autoantibodies against glutamic-aciddecarboxylase (GAD)65, insulin and tyrosine phosphatase (TP) as a feature of disease. The correlations of these autoantibodies with disease severity remain to be explored. Here we investigate the status and contribution of autoantibodies against GAD65, insulin and TP in T1D patients and to explore whether these antibodies have a role in T1D progression and in T1D associated neuropathy. Methods: Sera from 57 T1D patients with varying levels of disease activities and 42 age- and sex-matched healthy controls were evaluated for anti-GAD65-antibodies, anti-insulin-antibodies and anti-TP-antibodies. Results: Serum analysis showed T1D patients contain 42% of anti-GAD65-antibodies, 76% of anti-insulin-antibodies and 34% of anti-TP-antibodies. Interestingly, not only was there an increased number of subjects positive for these antibodies, but also levels of these antibodies were significantly higher among T1D patients whose ages were >35 years as compared with younger T1D patients (age ≤35 years). In addition, significant correlation was observed between the levels of these antibodies and glycosylated haemoglobin (HbA1c). Furthermore, T1D neuropathic patients had higher levels of these antibodies compared with T1D patients without neuropathy. Conclusions: Our data support an association between these markers autoantibodies and severity of T1D. The stronger response observed in patients with uncontrolled T1D suggests that these antibodies may be useful biomarkers in evaluating the progress of T1D and in elucidating the mechanisms of disease pathogenesis. Keywords: Diabetes type 1, autoimmunity, anti-GAD65-autoantibodies, anti-insulin-autoantibodies, anti-TP-autoantibodies, T1D progress, T1D associated neuropathy
    Full-text · Article · Feb 2013
    • "For example, in the large, NIH-funded Diabetes Prevention Trial – Type 1 (DPT-1), the 5-yr risk of T1D was 20% – 25% for subjects with one autoantibody, 50% –60% for subjects with two autoantibodies, nearly 70% for those with three autoantibodies, and almost 80% for those with four autoantibodies (Winter 2011) (note: this study did include ICAs as part of its performance , in addition to biochemical autoantibodies ). This ability to use autoantibodies for predicting future cases of T1D has also been supported by several large natural history trials including the NIH TrialNet and TEDDYefforts, as well as in a number of general populationbased efforts (Miao et al. 2007; Orban et al. 2009; Knip et al. 2010b). Although one would consider T1D-associ- ated autoantibodies a relatively easy biomarker for studies of the disease, the reality for such a notion in everyday practice has often proved otherwise. "
    [Show abstract] [Hide abstract] ABSTRACT: The purpose of this article is to provide an overview that summarizes much in the way of our current state of knowledge regarding the pathogenesis and natural history of type 1 diabetes in humans. This information is presented to the reader as a series of seminal historical discoveries that, when advanced through research, transformed our understanding of the roles for the immune system, genes, and environment in the formation of this disease. In addition, where longitudinal investigations of these three facets occurred, their roles within the development of type 1 diabetes, from birth to symptomatic onset and beyond, are discussed, including their most controversial elements. Having an understanding of this disorder's pathogenesis and natural history is key for attempts seeking to understand the issues of what causes type 1 diabetes, as well as to develop a means to prevent and cure the disorder.
    Article · Nov 2012
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