Development of a novel autoantibody assay for autoimmune gastritis in type 1 diabetic individuals
Barbara Davis Center for Childhood Diabetes, University of Colorado Denver, Aurora, CO 80045, USA. Diabetes/Metabolism Research and Reviews
(Impact Factor: 3.55).
11/2011; 27(8):887-90. DOI: 10.1002/dmrr.1267
Autoimmune atrophic body gastritis (ABG) and pernicious anaemia are prototypical, organ-specific autoimmune diseases whose prevalence in the general population is 2.0 vs 2 and 0.15-1%, respectively. The incidence of disease increases with age and is frequently associated with other autoimmune disorders such as type 1 diabetes mellitus (T1DM). Early diagnosis of ABG/pernicious anaemia is essential for the prevention and/or treatment before manifestations of chronic disease become irreversible. Parietal cell autoantibody detection via enzyme-linked immunosorbent assay is currently the most widely used biomarker of disease with diagnosis confirmed by subsequent immunohistochemistry via biopsy.
To improve the assay we designed a specific, molecularly defined radioimmunoprecipitation assay for early detection of ABG, targeting its major antigen, the gastric H+/K+ ATPase 4A subunit ATP4A.
The major antigenic domain in ATP4A was tested against a panel of sera from new onset patients with T1DM which tested positive for the gold standard T1DM autoantibodies (IAA, IA2A, GAD65A, and ZnT8A). Significant immunoreactivity to ATP4A was measured (25%) while 6% of first-degree relatives of subjects with T1DM who were sero-negative for T1DM autoantigens were positive for ATP4A autoantibodies. ATP4A antibody prevalence increased with age of onset of T1DM, which is atypical of other T1DM autoantibodies. Immunoreactivity to ATP4A, unlike that of T1DM antigens, demonstrates a significant gender bias in newly diagnosed individuals with T1DM.
Although the utility of the assay as a biomarker for T1DM is likely limited, it may serve as an improved indicator of ABG.
Available from: Michael Iadarola
- "The overall higher incidence of organ-specific autoimmunity of approximately 50% detected in our study was mainly due to the inclusion of gastric ATPase autoantibodies which were not previously tested in parallel with other organ-specific autoantibodies. The prevalence of anti-gastric ATPase autoantibodies in approximately 16–24% of T1D subjects in the two different DASP cohorts is also consistent with other published findings that used immunofluorescence ,  and recently developed radioimmunoprecipitation assay . In contrast to previous studies , , no significant association of anti-gastric autoantibodies was detected with autoantibodies against GAD65 or TPO in our cohort, but this lack of correlation in our study may be due to our small sample size. "
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ABSTRACT: Type I diabetes (T1D) is an autoimmune disease characterized by destruction of insulin-producing β-cells in the pancreas. Although several islet cell autoantigens are known, the breadth and spectrum of autoantibody targets has not been fully explored. Here the luciferase immunoprecipitation systems (LIPS) antibody profiling technology was used to study islet and other organ-specific autoantibody responses in parallel. Examination of an initial cohort of 93 controls and 50 T1D subjects revealed that 16% of the diabetic subjects showed anti-gastric ATPase autoantibodies which did not correlate with autoantibodies against GAD65, IA2, or IA2-β. A more detailed study of a second cohort with 18 potential autoantibody targets revealed marked heterogeneity in autoantibody responses against islet cell autoantigens including two polymorphic variants of ZnT8. A subset of T1D subjects exhibited autoantibodies against several organ-specific targets including gastric ATPase (11%), thyroid peroxidase (14%), and anti-IgA autoantibodies against tissue transglutaminase (12%). Although a few T1D subjects showed autoantibodies against a lung-associated protein KCNRG (6%) and S100-β (8%), no statistically significant autoantibodies were detected against several cytokines. Analysis of the overall autoantibody profiles using a heatmap revealed two major subgroups of approximately similar numbers, consisting of T1D subjects with and without organ-specific autoantibodies. Within the organ-specific subgroup, there was minimal overlap among anti-gastric ATPase, anti-thyroid peroxidase, and anti-transglutaminase seropositivity, and these autoantibodies did not correlate with islet cell autoantibodies. Examination of a third cohort, comprising prospectively collected longitudinal samples from high-risk individuals, revealed that anti-gastric ATPase autoantibodies were present in several individuals prior to detection of islet autoantibodies and before clinical onset of T1D. Taken together, these results suggest that autoantibody portraits derived from islet and organ-specific targets will likely be useful for enhancing the clinical management of T1D.
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ABSTRACT: The prevalence of diabetes mellitus (DM) continues to increase because of sedentary life style and inappropriate diet. DM is one of the most common metabolic diseases, affecting more than 240 million people worldwide. It is projected that the number of people with DM will continue to increase in the next decade. Alzheimer disease (AD) is the most common cause of dementia, and affects over 24 million people globally, mostly senior citizens. The worldwide prevalence of AD is estimated to double in the next 20 years. How are these two chronic and debilitating diseases similar? Do they have common denominators? AD is similar to DM in many ways, in that both are associated with defective insulin release and/or signalling, impaired glucose uptake, amyloidosis, increased oxidative stress, stimulation of the apoptotic pathway, angiopathy, abnormal lipid peroxidation, ageing (in type 2 DM), brain atrophy, increased formation of advanced glycation end products and tau phosphorylation, impaired lipid metabolism and mitochondrial pathology. The pathogenesis of both AD and DM has genetic as well as environmental components. Both can also cause impaired cognition and dementia. All of these common denominators indicate that AD and DM share a lot of factors in terms of pathophysiology, histopathology and clinical outcome. These similarities can be used in the search for and design of effective pharmacotherapy for AD, since potent therapeutic agents such as insulin, incretins, oral hypoglycaemic agents and antioxidants used in the management of DM may play a key role in the treatment of patients with AD.
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ABSTRACT: Autoantibodies are currently the most robust biomarkers of type 1 diabetes and are frequently used to establish entry criteria for the participation of genetically at-risk individuals in secondary prevention/intervention clinical trials. Since their original description almost 40 years ago, considerable efforts have been devoted toward identifying the precise molecular targets that are recognized. 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. Currently, four major molecular targets ([pro]insulin, GAD65, IA-2, and ZnT8) have been confirmed, with approximately 94% of all subjects with a clinical diagnosis of type 1 diabetes expressing autoantibodies to at least one of these molecules at clinical onset. In this review, we summarize some of the salient properties of these targets that might contribute to their autoantigenicity and methods that have been used in attempts to identify new components of the humoral autoresponse.
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