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

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

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

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

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

Slow metabolic deterioration towards diabetes in islet cell antibody positive patients with autoimmune polyendocrine disease

We studied metabolic progression to IDDM in a cohort of adults who are ICA-positive and have associated autoimmune endocrine disease or circulating organ-specific autoantibodies (the Polyendocrine Study). Of the 186 individuals recruited 27 developed overt diabetes after a median follow-up of 4.5 years (range 0.4-12). Of these, eight patients did not require insulin treatment until at least 6 months after clinical diagnosis, with an interval of 1.8 years (1.2-5.7). An IVGTT was performed in 38 subjects and 23 had sequential studies. Of the initial 38 subjects six developed diabetes and only three showed a loss of FPIR to glucose (below the first percentile of a normal control group) before clinical onset of the disease. An additional three subjects showed a loss of the FPIR, and all still have normal glucose tolerance after median follow-up of 28 months (22-95). A whole or mixed pattern of islet cell staining was found in five of the six patients who developed diabetes and antibodies against an islet 37 k-antigen were detectable in four patients, all of whom required insulin soon after diagnosis. A beta-cell selective ICA staining pattern was seen in 14 of 17 subjects who did not develop diabetes and the mixed pattern in only three. None of this group had detectable 37k-antibodies. We conclude that metabolic deterioration is slow in polyendocrine patients, and that the IVGTT has less prognostic significance in this group than in first degree relatives of patients with IDDM. In contrast, the presence of the whole or mixed ICA staining pattern or of 37k-antibodies can identify a high risk of progression to IDDM within this polyendocrine population and may indicate the rate of metabolic deterioration. © 1994 Springer-Verlag.</p

Slow metabolic deterioration towards diabetes in islet cell antibody positive patients with autoimmune polyendocrine disease

We studied metabolic progression to IDDM in a cohort of adults who are ICA-positive and have associated autoimmune endocrine disease or circulating organ-specific autoantibodies (the Polyendocrine Study). Of the 186 individuals recruited 27 developed overt diabetes after a median follow-up of 4.5 years (range 0.4-12). Of these, eight patients did not require insulin treatment until at least 6 months after clinical diagnosis, with an interval of 1.8 years (1.2-5.7). An IVGTT was performed in 38 subjects and 23 had sequential studies. Of the initial 38 subjects six developed diabetes and only three showed a loss of FPIR to glucose (below the first percentile of a normal control group) before clinical onset of the disease. An additional three subjects showed a loss of the FPIR, and all still have normal glucose tolerance after median follow-up of 28 months (22-95). A whole or mixed pattern of islet cell staining was found in five of the six patients who developed diabetes and antibodies against an islet 37 k-antigen were detectable in four patients, all of whom required insulin soon after diagnosis. A beta-cell selective ICA staining pattern was seen in 14 of 17 subjects who did not develop diabetes and the mixed pattern in only three. None of this group had detectable 37k-antibodies. We conclude that metabolic deterioration is slow in polyendocrine patients, and that the IVGTT has less prognostic significance in this group than in first degree relatives of patients with IDDM. In contrast, the presence of the whole or mixed ICA staining pattern or of 37k-antibodies can identify a high risk of progression to IDDM within this polyendocrine population and may indicate the rate of metabolic deterioration. © 1994 Springer-Verlag.</p

Identification of novel genetic loci associated with thyroid peroxidase antibodies and clinical thyroid disease

Autoimmune thyroid diseases (AITD) are common, affecting 2-5% of the general population. Individuals with positive thyroid peroxidase antibodies (TPOAbs) have an increased risk of autoimmune hypothyroidism (Hashimoto's thyroiditis), as well as autoimmune hyperthyroidism (Graves' disease). As the possible causative genes of TPOAbs and AITD remain largely unknown, we performed GWAS meta-analyses in 18,297 individuals for TPOAb-positivity (1769 TPOAb-positives and 16,528 TPOAb-negatives) and in 12,353 individuals for TPOAb serum levels, with replication in 8,990 individuals. Significant associations (P<5×10?8) were detected at TPO-rs11675434, ATXN2-rs653178, and BACH2-rs10944479 for TPOAb-positivity, and at TPO-rs11675434, MAGI3-rs1230666, and KALRN-rs2010099 for TPOAb levels. Individual and combined effects (genetic risk scores) of these variants on (subclinical) hypo- and hyperthyroidism, goiter and thyroid cancer were studied. Individuals with a high genetic risk score had, besides an increased risk of TPOAb-positivity (OR: 2.18, 95% CI 1.68–2.81, P?=?8.1×10?8), a higher risk of increased thyroid-stimulating hormone levels (OR: 1.51, 95% CI 1.26–1.82, P?=?2.9×10?6), as well as a decreased risk of goiter (OR: 0.77, 95% CI 0.66–0.89, P?=?6.5×10?4). The MAGI3 and BACH2 variants were associated with an increased risk of hyperthyroidism, which was replicated in an independent cohort of patients with Graves' disease (OR: 1.37, 95% CI 1.22–1.54, P?=?1.2×10?7 and OR: 1.25, 95% CI 1.12–1.39, P?=?6.2×10?5). The MAGI3 variant was also associated with an increased risk of hypothyroidism (OR: 1.57, 95% CI 1.18–2.10, P?=?1.9×10?3). This first GWAS meta-analysis for TPOAbs identified five newly associated loci, three of which were also associated with clinical thyroid disease. With these markers we identified a large subgroup in the general population with a substantially increased risk of TPOAbs. The results provide insight into why individuals with thyroid autoimmunity do or do not eventually develop thyroid disease, and these markers may therefore predict which TPOAb-positives are particularly at risk of developing clinical thyroid dysfunction.</p

Identification of novel genetic loci associated with thyroid peroxidase antibodies and clinical thyroid disease

Autoimmune thyroid diseases (AITD) are common, affecting 2-5% of the general population. Individuals with positive thyroid peroxidase antibodies (TPOAbs) have an increased risk of autoimmune hypothyroidism (Hashimoto's thyroiditis), as well as autoimmune hyperthyroidism (Graves' disease). As the possible causative genes of TPOAbs and AITD remain largely unknown, we performed GWAS meta-analyses in 18,297 individuals for TPOAb-positivity (1769 TPOAb-positives and 16,528 TPOAb-negatives) and in 12,353 individuals for TPOAb serum levels, with replication in 8,990 individuals. Significant associations (P<5×10?8) were detected at TPO-rs11675434, ATXN2-rs653178, and BACH2-rs10944479 for TPOAb-positivity, and at TPO-rs11675434, MAGI3-rs1230666, and KALRN-rs2010099 for TPOAb levels. Individual and combined effects (genetic risk scores) of these variants on (subclinical) hypo- and hyperthyroidism, goiter and thyroid cancer were studied. Individuals with a high genetic risk score had, besides an increased risk of TPOAb-positivity (OR: 2.18, 95% CI 1.68–2.81, P?=?8.1×10?8), a higher risk of increased thyroid-stimulating hormone levels (OR: 1.51, 95% CI 1.26–1.82, P?=?2.9×10?6), as well as a decreased risk of goiter (OR: 0.77, 95% CI 0.66–0.89, P?=?6.5×10?4). The MAGI3 and BACH2 variants were associated with an increased risk of hyperthyroidism, which was replicated in an independent cohort of patients with Graves' disease (OR: 1.37, 95% CI 1.22–1.54, P?=?1.2×10?7 and OR: 1.25, 95% CI 1.12–1.39, P?=?6.2×10?5). The MAGI3 variant was also associated with an increased risk of hypothyroidism (OR: 1.57, 95% CI 1.18–2.10, P?=?1.9×10?3). This first GWAS meta-analysis for TPOAbs identified five newly associated loci, three of which were also associated with clinical thyroid disease. With these markers we identified a large subgroup in the general population with a substantially increased risk of TPOAbs. The results provide insight into why individuals with thyroid autoimmunity do or do not eventually develop thyroid disease, and these markers may therefore predict which TPOAb-positives are particularly at risk of developing clinical thyroid dysfunction.</p