Role of Autoantibodies in Type 1 Diabetes

University of Colorado, Denver, Colorado, United States
Frontiers in Bioscience (Impact Factor: 3.52). 02/2007; 12(1):1889-98. DOI: 10.2741/2195
Source: PubMed


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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    • "Previous work has implicated B cells in initiation of T1D and as precursors for relevant autoantibody-producing cells (Bouaziz et al., 2007; Miao et al., 2007; Silveira and Grey, 2006; Skyler, 2007; Xiu et al., 2008), However, little is known regarding defects in peripheral B cell tolerance that may favor development of T1D. Our observations with respect to the B cell compartment in control subjects who carry PTPN22 1858T led us to hypothesize that analogous alterations might be present in individuals with T1D. "
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    ABSTRACT: The PTPN22 genetic variant 1858T, encoding Lyp620W, is associated with multiple autoimmune disorders for which the production of autoantibodies is a common feature, suggesting a loss of B cell tolerance. Lyp620W results in blunted BCR signaling in memory B cells. Because BCR signal strength is tightly coupled to central and peripheral tolerance, we examined whether Lyp620W impacts peripheral B cell homeostasis in healthy individuals heterozygous for the PTPN221858T variant. We found that these subjects display alterations in the composition of the B cell pool that include specific expansion of the transitional and anergic IgD(+)IgM(-)CD27(-) B cell subsets. The PTPN22 1858T variant was further associated with significantly diminished BCR signaling and a resistance to apoptosis in both transitional and naive B cells. Strikingly, parallel changes in both BCR signaling and composition of B cell compartment were observed in type 1 diabetic subjects, irrespective of PTPN22 genotype, revealing a novel immune phenotype and likely shared mechanisms leading to a loss of B cell tolerance. Our combined findings suggest that Lyp620W-mediated effects, due in part to the altered BCR signaling threshold, contribute to breakdown of peripheral tolerance and the entry of autoreactive B cells into the naive B cell compartment.
    Full-text · Article · Nov 2011 · The Journal of Immunology
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    • "A single clinical case of type 1 diabetes in a person with X-linked agammaglobulinemia indicates that type 1 diabetes can develop in the absence of antibodies and B cells (4). However, antibodies to insulin and other islet antigens are predictive of subsequent type 1 diabetes (5), and B cells are required for diabetes development in the nonobese diabetic (NOD) mouse model of type 1 diabetes (6–8). A recent clinical trial of B-cell depletion with anti-CD20 in humans with newly diagnosed type 1 diabetes demonstrated a significant delay in further loss of insulin synthesis and established a role for B cells (9), but how B cells contribute to type 1 diabetes pathology remains unclear. "
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    ABSTRACT: To define cellular mechanisms by which B cells promote type 1 diabetes. The study measured islet-specific CD4 T cell regulation in T-cell receptor transgenic mice with elevated frequencies of CD4 T cells recognizing hen egg lysozyme (HEL) autoantigen expressed in islet β-cells and thymic epithelium under control of the insulin-gene promoter. The effects of a mutation in Roquin that dysregulates T follicular helper (Tfh) cells to promote B-cell activation and anti-islet autoantibodies were studied, as were the effects of HEL antigen-presenting B cells and passively transferred or maternally transmitted anti-islet HEL antibodies. Mouse anti-islet IgG antibodies-either formed as a consequence of excessive Tfh activity, maternally transmitted, or passively transferred-caused a breakdown of tolerance in islet-reactive CD4(+) cells and fast progression to diabetes. Progression to diabetes was ameliorated in the absence of B cells or when the B cells could not secrete islet-specific IgG. Anti-islet antibodies increased the survival of proliferating islet-reactive CD4(+) T cells. FcγR blockade delayed and reduced the incidence of autoimmune diabetes. B cells can promote type 1 diabetes by secreting anti-islet autoantibodies that act in an FcγR-mediated manner to enhance the expansion of islet-reactive CD4 T cells and cooperate with inherited defects in thymic and peripheral CD4 T-cell tolerance. Cooperation between inherited variants affecting CD4 T-cell tolerance and anti-islet autoantibodies should be examined in epidemiological studies and in studies examining the efficacy of B-cell depletion.
    Full-text · Article · Aug 2011 · Diabetes
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    • "Type 1 diabetes results from the immune destruction of insulin-producing β-cells in the pancreas. In humans, the breakdown in immune tolerance is evident years before disease onset with detectable autoantibodies to a number of β-cell antigens in first-degree relatives of subjects with diabetes (1,2). However, the immune changes that trigger progression to overt diabetes are not known. "
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    ABSTRACT: The mechanistic basis for the breakdown of T-cell tolerance in type 1 diabetes is unclear and could result from a gain of effector function and/or loss of regulatory function. In humans, the CD4+CD25+Foxp3+ T-cell compartment contains both effector and regulatory T cells, and it is not known how their relative proportions vary in disease states. We performed a longitudinal study of CD4+CD25+ T-cell function in children with type 1 diabetes at onset and throughout the 1st year of disease. Function was assessed using single-cell assays of proliferation, cytokine production, and suppression. Type 1 diabetic individuals were compared with age-matched control subjects, and suppression was directly assessed by coculture with control T-cell targets. We identify novel functional changes within the type 1 diabetes CD4+CD25+ compartment. Type 1 diabetic CD4+CD25+ cells exhibited a striking increase in proliferative capacity in coculture with CD4 T cells that was present at onset and stable 9-12 months from diagnosis. Elevated type 1 diabetes CD4+CD25+ cell proliferation correlated with increased inflammatory cytokines interleukin 17 and tumor necrosis factor-α but not γ-interferon. Type 1 diabetes CD4+CD25+ cytokine production occurred coincident with suppression of the same cytokines in the control targets. Indeed, enhanced proliferation/cytokines by CD4+CD25+ cells was uncoupled from their suppressive ability. Longitudinally, we observed a transient defect in type 1 diabetes CD4+CD25+ suppression that unexpectedly correlated with measures of improved metabolic function. Type 1 diabetes onset, and its subsequent remission period, is associated with two independent functional changes within the CD4+CD25+ T-cell compartment: a stable increase in effector function and a transient decrease in regulatory T-cell suppression.
    Full-text · Article · Jun 2011 · Diabetes
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