Elimination of maternally transmitted autoantibodies prevents diabetes in nonobese diabetic mice.
ABSTRACT The influence of maternally transmitted immunoglobulins on the development of autoimmune diabetes mellitus in genetically susceptible human progeny remains unknown. Given the presence of islet beta cell-reactive autoantibodies in prediabetic nonobese diabetic (NOD) mice, we abrogated the maternal transmission of such antibodies in order to assess their influence on the susceptibility of progeny to diabetes. First, we used B cell-deficient NOD mothers to eliminate the transmission of maternal immunoglobulins. In a complementary approach, we used immunoglobulin transgenic NOD mothers to exclude autoreactive specificities from the maternal B-cell repertoire. Finally, we implanted NOD embryos in pseudopregnant mothers of a non-autoimmune strain. The NOD progeny in all three groups were protected from spontaneous diabetes. These findings demonstrate that the maternal transmission of antibodies is a critical environmental parameter influencing the ontogeny of T cell-mediated destruction of islet beta cells in NOD mice. It will be important to definitively determine whether the transmission of maternal autoantibodies in humans affects diabetes progression in susceptible offspring.
Article: Enhanced anti-serpin antibody activity inhibits autoimmune inflammation in type 1 diabetes.[show abstract] [hide abstract]
ABSTRACT: Intracellular (clade B) OVA-serpin protease inhibitors play an important role in tissue homeostasis by protecting cells from death in response to hypo-osmotic stress, heat shock, and other stimuli. It is not known whether these serpins influence immunological tolerance and the risk for autoimmune diseases. We found that a fraction of young autoimmune diabetes-prone NOD mice had elevated levels of autoantibodies against a member of clade B family known as serpinB13. High levels of anti-serpinB13 Abs were accompanied by low levels of anti-insulin autoantibodies, reduced numbers of islet-associated T cells, and delayed onset of diabetes. Exposure to anti-serpinB13 mAb alone also decreased islet inflammation, and coadministration of this reagent and a suboptimal dose of anti-CD3 mAb accelerated recovery from diabetes. In a fashion similar to that discovered in the NOD model, a deficiency in humoral activity against serpinB13 was associated with early onset of human type 1 diabetes. These findings suggest that, in addition to limiting exposure to proteases within the cell, clade B serpins help to maintain homeostasis by inducing protective humoral immunity.The Journal of Immunology 05/2012; 188(12):6319-27. · 5.79 Impact Factor
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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.Frontiers in Bioscience 02/2007; 12:1889-98. · 3.52 Impact Factor
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ABSTRACT: Type 1 Diabetes (T1D) is an autoimmune disease requiring contributions from effectors in both CD4+ and CD8+ T cell compartments in order to destroy insulin producing pancreatic beta cells. Autoantibodies specific for islet cell proteins are also often generated during the prodromal stages of T1D development. While providing excellent prognostic markers of future disease risk, it has generally been believed that the induction of autoantibody secretion by B cells was a secondary consequence of the ongoing autoreactive T cell response. However, studies in the NOD mouse model of disease have demonstrated that B cells play a key function during T1D development by serving as a subpopulation of antigen presenting cell (APC) which can most efficiently support the expansion of diabetogenic CD4+ T cells. Furthermore, studies utilizing this model have indicated that autoantibodies may play an important role in initiating an early phase of pancreatic beta cell destruction ultimately leading to overt T1D. This review will focus on the under appreciated role B cells play in T1D development not only in NOD mice, but also potentially in humans.Frontiers in Bioscience 02/2007; 12:2183-93. · 3.52 Impact Factor