Insulin-Dependent Diabetes in the Nod Mouse Model I. Detection and Characterization of Autoantibody Bound to the Surface of Pancreatic Beta Cells Prior to Development of the insulitis Lesion in Prediabetic Nod Mice

Abstract

Type I, insulin-dependent diabetes (IDD) results from an autoimmune response against the insulin producing pancreatic beta cells. This autoimmune reaction involves both humoral and cell-mediated factors; nevertheless, the relative role of each remains unresolved. Furthermore, while adoptive transfer experiments have provided evidence for the role of T cells in beta cell destruction, the specific events which initiate leukocyte migration into the islets (insulitis) are unknown. Earlier studies indicated that NOD pancreatic beta cells may bind small amounts of autoantibody. Because of the possible importance of an early humoral response to the initiation of insulitis and subsequent disease, we have investigated a number of aspects of this phenomenon to determine the nature and specificity of the early autoantibodies as well as the time at which autoantibody binds to beta cells. Results of this study demonstrate that NOD/Uf mice are sensitized to islet-cell associated antigens, including GAD, prior to the first appearance of insulitis; that a small percentage of the beta cells of NOD/Uf mice have autoantibody bound to their surface prior to insulitis; that sera collected from preinsulitis NOD/Uf mice contain autoantibodies which will bind to beta cells of both IDD-prone and IDD-resistant mice; and that the autoantibodies which bind pancreatic beta cells are predominantly IgM with lesser amounts of IgG and IgA. These findings suggest that, in the natural course of IDD, insulitis may develop in response to an initial autoantibody-mediated injury of beta cells.

Innate stimulation of B1a cells enhances the autoreactive IgM repertoire in the NOD mouse: implications for type 1 diabetes

“…Accordingly, binding of IgM to beta cells has been described in vivo in very young NOD mice [10]. We showed here that NOD B1a-derived IgM binds to beta cells in vitro and that the expression of Nos2 is upregulated in islet cells in contact with NOD B1a-derived supernatant fraction, suggesting that IgM binding is involved in triggering the beta cell oxidative stress response.…”

“…It has previously been shown that NOD mice, but not C57BL/6 nondiabetic control mice, have antibodies bound to beta cells before the development of insulitis. Interestingly, these antibodies are mainly of the IgM isotype [10] and thus are unlikely to originate in germinal centre reactions. Consistently, young NOD mice have a pronounced repertoire of IgM AAbs [11].…”

Development of Improved Animal Models for the Study of Diabetes

“…Also, knowing that NOD mouse develop cell immune mediated diabetes, many of the experiments aim to picture the immunological status which is responsible for the onset of diabetes [37,38]. It is important to bear in mind that diabetes in NOD mice is not only the result of cell mediated immunity but also of humoral factors as GAD and IgM [39].…”

Autoimmunity Triggers in the NOD Mouse

“…Additionally, sera collected from these animals contain auto‐antibodies that bind to β‐cells of both T1D‐prone and T1D‐resistant mice. Auto‐antibodies binding to pancreatic β‐cells in this strain are predominantly of the IgM isotype, 24 therefore an early humoral response may be involved in β‐cell targeting, the initiation of insulitis, and subsequent disease development. Natural auto‐antibodies bound to pancreatic islet antigens can trigger complement system–mediated inflammation, 25 which may contribute to the observed deregulation in the NOD mouse immune system and modulate T1D development.…”