Islet cell antigens in the prediction and prevention of insulin-dependent diabetes mellitus

Insulin-dependent diabetes mellitus (IDDM) is associated with both antibody and T-cell autoimmunity to pancreatic islet cell components. In recent years, considerable progress has been made in the identification of the molecular components of the pancreatic islets to which these immune responses are directed. These advances have led to the development of a number of immune markers for use in screening for individuals at risk for disease, and there is promise of antigen-specific immune intervention therapies to prevent diabetes in those identified as at risk. In this article, we review our current knowledge of autoantigens associated with IDDM and the implications this has on the prediction and prevention of the disease.</p

Tyrosine phosphatase-like proteins as autoantigens in insulin-dependent diabetes mellitus: the targets for 37/40k antibodies

No abstract</p

Novel considerations on the antibody/autoantigen system in type I (insulin-dependent) diabetes mellitus

Insulin dependent diabetes (IDDM) has an autoimmune pathogenesis. Included is the presence of antibodies to pancreatic islet cells. The first identified were islet cell antibodies (ICA), detected by indirect immunofluorescence, and which react with all cells within islets. Importantly, the autoantibodies are found several years prior to disease and although a pathogenic role for the autoantibodies is unclear, they have become useful markers of prediabetes. A number of studies of twins discordant for IDDM and of first degree relatives of IDDM patients have established that there is an increased risk for disease in individuals who have ICA, especially when ICA levels are high. This high predictive value of ICA decreases in the general population where the incidence of IDDM is lower than in first degree relatives, and both ICA and the disease risk associated with ICA, appear to be influenced by a genetic susceptibility. This has been substantiated in a study of patients with endocrine autoimmunity and ICA (Polyendocrine Study) where the predictive value of very high levels of ICA is less than 50 in patients without a first degree relative with IDDM. Hence, there remain a substantial number of patients with ICA who do not develop disease. From these patients, it was demonstrated that ICA include at least two distinct specificities, one of which is beta cell specific and is not associated with a high risk for IDDM. These data, and an increasing list of new autoantibodies in IDDM, have increased the search for the relevant autoantigens. That of classic ICA is suggested to be a sialoganglioside, and a number of protein autoantigens have been suggested as other potential autoantigens. Of particular importance has been the identification of glutamic acid decarboxylase (GAD), the biosynthesizing enzyme of the neurotransmitter gamma amino butyric acid, as the autoantigen corresponding to the 64K autoantibodies found in the majority of newly diagnosed IDDM patients. Despite the identification of GAD, specific assays developed so far have not detected anti GAD antibodies at high frequencies in newly diagnosed patients. Like ICA, it appears that there may be distinct specificities of autoantibodies to GAD and associated products. Enzyme digestion of the autoantigen yields 50K, 40K and 37K fragments which appear to be derived from distinct polypeptide chains. Patients may have autoantibodies to either the 50K fragment or the 40/37K fragment or all fragments. Importantly, studies in twins and in the polyendocrine patients indicate that autoantibodies to the 37K fragment are more strongly associated with the progression to disease. In addition to these autoantigens, autoantibodies are detected against the hormone insulin and its precursor proinsulin in up to 40 of newly diagnosed patients. Heat shock protein 65, carboxypeptidase H and glucose transporter have also been reported as autoantigens relevant to IDDM. It is now clear that the autoimmune response associated with IDDM is heterogeneous and against several islet antigens. The search will continue to determine which of these is important in the pathogenesis and which will provide effective markers for prediction which will eventually allow safe intervention therapy for the prevention of IDDM. © 1991 Informa UK Ltd All rights reserved: reproduction in whole or part not permitted.</p

Antibodies to islet 37k antigen, but not to glutamate decarboxylase, discriminate rapid progression to IDDM in endocrine autoimmunity

Apart from islet cell antibodies (ICAs), antibodies to glutamate decarboxylase (GAD), insulin autoantibodies (IAAs), and a novel islet antigen (37k antigen) are potential markers for insulin-dependent diabetes mellitus (IDDM). GAD is also an antigen in stiff-man syndrome (SMS), and both SMS and IDDM are associated with ICAs and autoimmunity to other endocrine organs. We investigated possible links between antibody responses to islet antigens with autoimmunity to other endocrine organs and determined which specific antibodies can identify individuals who progress to IDDM. Antibodies to GAD were detected in â?¥90 of both diabetic and nondiabetic patients with ICAs and other endocrine autoimmunity, in 59 of ICA-positive IDDM patients without endocrine autoimmunity, in all patients with SMS, but in only 1-3 of healthy (nondiabetic) and autoimmune disease control subjects. GAD antibody levels were increased in ICA-positive IDDM patients with polyendocrine autoimmunity compared with those without. In contrast, antibodies to 37k antigen were only detected in patients who developed acute-onset IDDM. IAAs were also associated with IDDM. Thus, certain factors enhance antibody responses to GAD in polyendocrine autoimmunity, but this does not necessarily lead to development of IDDM or SMS. Antibodies to 37k antigen are strongly associated with acute-onset IDDM and are useful serological markers for disease.</p

Combined analysis of autoantibodies improves prediction of IDDM in islet cell antibody-positive relatives

Prediction of insulin-dependent diabetes mellitus (IDDM) is still largely based on islet cell antibodies (ICAs), but it may be improved by combined analysis with other humoral markers. We examined autoantibodies to insulin (IAAs), glutamic acid decarboxylase (GAD), and M(r) 37,000 and M(r) 40,000 fragments of islet antigens (37 and 40 kDa) together with ICA subtypes in 101 family members with ICAs â?¥10 Juvenile Diabetes Foundation units (JDF U) followed for up to 14 years, of whom 18 have developed IDDM. Life-table analysis showed a 43 risk of IDDM within 10 years for those with ICAs â?¥10 JDF U, rising to 53 for those with ICAs â?¥20 JDF U. The risk for ICAs â?¥10 JDF U was 62 in the family members in the youngest age quartile (40.7 years of age (P = 0.03). ICAs â?¥10 JDF U combined with IAAs gave a risk of 84 (P = 0.03 compared with IAA-), and ICAs â?¥10 JDF U combined with GAD antibodies gave a risk of 61 (P = 0.018). The risk for ICAs â?¥10 JDF U with antibodies to 37- kDa antigen was 76 (P < 0.0001). Risk increased with the number of autoantibodies, from 8 for ICAs alone to 88 with â?¥3 autoantibodies (14 cases detected) (P < 0.0001). The increased risk associated with multiple antibodies was observed independent of age. The median time to diagnosis in those with antibodies to 37- and/or 40-kDa antigen was 1.5 years, compared with 7.2 years in those with IAAs and GAD antibodies in the absence of antibodies to 37/40 kDa. The intensity and range of the autoantibody response offers better overall prediction of diabetes than any single autoantibody specificity, although antibodies to 37-/40-kDa antigens may prove to be useful markers of early clinical onset. We found that 78 of future cases of IDDM in ICA+ relatives came from the 27 with multiple autoantibodies and estimate that 88 of individuals within this category will need insulin treatment within 10 years. We propose a simple predictive strategy based on these observations.</p

Lack of immunohistological changes in the islets of nondiabetic, autoimmune, polyendocrine patients with ?-Selective GAD-specific islet cell antibodies

We examined the pancreases from three nondiabetic, autoimmune, polyendocrine patients with islet cell antibodies (ICAs) and glutamic acid decarboxylase (GAD) antibodies who died without developing insulin-dependent diabetes mellitus (IDDM). All three patients had the β-selective GAD- specific ICA subtype and antibodies to the GAD-derived 50 kD tryptic fragment. None had whole islet ICA or antibodies to the non-GAD-derived 37k islet antigen, which appear to be more closely associated with IDDM than antibodies to GAD. The three patients also were negative for insulin autoantibodies. Islets within pancreas from patients 1 and 2 appeared well preserved as assessed by hematoxylin and eosin staining. In these two patients, insulin content, as assessed by indirect immunofluorescence on cryostat sections, was normal. Patient 3 had a prolonged postmortem time, and the islet insulin content was reduced slightly. In all three pancreases, no evidence was found of increased human leukocyte antigen class I or de novo class II molecule expression on islet cells, and islet infiltration by T- or B-cells or macrophages was not detected. Islet capillary endothelial cells did not show signs of hypertrophy. No immunoglobulin or complement deposition within or around islets was found. These data indicate that humoral GAD autoimmunity does not necessarily associate with visible β-cell damage.</p