Role of autoantibodies in type 1 diabetes

University of Colorado, Denver, Colorado, United States
Frontiers in Bioscience (Impact Factor: 4.25). 02/2007; 12:1889-98. 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.

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    ABSTRACT: Type 1 diabetes (T1D) is an autoimmune disease resulting from self-destruction of insulin-producing β cells. Reduced neutrophil counts have been observed in patients with T1D. However, the pathological roles of neutrophils in the development of T1D remain unknown. Here we show that circulating protein levels and enzymatic activities of neutrophil elastase (NE) and proteinase 3 (PR3), both of which are neutrophil serine proteases (NSPs) stored in neutrophil primary granules, were markedly elevated in patients with T1D, especially those with disease duration of less than one year. Furthermore, circulating NE and PR3 levels increased progressively with the increase of the positive numbers and titers of the autoantibodies against β-cell antigens. An obvious elevation of NE and PR3 was detected even in those autoantibody-negative patients. Increased NE and PR3 in T1D patients are closely associated with elevated formation of neutrophil extracellular traps. By contrast, the circulating levels of α1-antitrypsin (A1AT), an endogenous inhibitor of NSPs, are decreased in T1D patients. These findings support an early role of neutrophil activation and augmented NSPs activities in the pathogenesis of β-cell autoimmunity, and also suggest that circulating NE and PR3 may serve as sensitive biomarkers for diagnosis of T1D.
    Diabetes 08/2014; 63(12). DOI:10.2337/db14-0480 · 7.90 Impact Factor
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    PLoS ONE 04/2014; 9(4):e93326. DOI:10.1371/journal.pone.0093326 · 3.53 Impact Factor
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    ABSTRACT: Dendritic cells (DCs) play an important role in pathogenesis of autoimmunity, including type 1 diabetes (T1D). In this study, we investigated DC subpopulations and their responses to TLR stimulation in T1D patients and their relatives. We analyzed the frequency of myeloid (mDCs) and plasmacytoid DCs (pDCs) in 97 T1D patients (69onset, 28 long-term), 67 first-degree relatives, and 64controls. We additionally tested the IFN-alpha production by pDCs upon stimulation with TLR 7,8 and 9 agonists. A lower number of mDCs and pDCs were found in T1D patients and their relatives. Of all tested TLR ligands, only stimulation with CpG 2216 induced IFN-alpha production that was highest in T1D relatives, except of autoantibody-negative relatives bearing the protective haplotypes. Our data demonstrate disturbances in DC number and function expressed most significantly in T1D relatives and point to a potential role of TLR9-induced IFN-alpha production in T1D development.
    Clinical Immunology 04/2014; 153(1). DOI:10.1016/j.clim.2014.03.018 · 3.77 Impact Factor


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