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  • 1
    Electronic Resource
    Electronic Resource
    A multiplicity of protein antigens in subcellular fractions of rat insulinoma tissue are able to stimulate T cells obtained from non-obese diabetic mice (1993)
    Springer
    Diabetologia 36 (1993), S. 385-390 
    Details
    ISSN: 1432-0428
    Keywords: Type 1 (insulin-dependent) diabetes mellitus ; autoimmunity ; T cells ; rat insulinoma (RIN) tissue
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Type 1 (insulin-dependent) diabetes mellitus is a T-cell mediated autoimmune disease with a number of different proteins being implicated as target autoantigens. A 38 kDa protein residing in the insulin secretory granule of insulinoma tissue is recognized by T-cell clones from a newly-diagnosed Type 1 diabetic patient. We have investigated the capacity of normal rat pancreatic beta-cell extracts and various subcellular fractions of transplantable RIN tissue to induce proliferation of T cells from non-obese diabetic (NOD) mice and H-2 identical NON · NOD-H-2g7 control mice. Normal rat islet beta-cell protein fractions induced intense, dose-dependent proliferation of NOD splenic T cells, but only marginal proliferative responses of NON · NOD-H-2g7 splenic T cells. To further localize the target antigens, four different subcellular fractions from RIN tissue were used as a source of antigen; here in particular the cytosolic proteins showed dose-dependent activation capacity with splenic T cells in NOD animals. These activities were absent in control mice. There was no proliferation after incubation with microsome preparations from other rat endocrine tissues. Purified carboxypeptidase H did not have any stimulatory activity on NOD T cells. Fractionation of the RIN cytosolic proteins showed a large number of different fractions eliciting proliferative activity. These results demonstrate that NOD T cells respond to a large number of potential islet beta-cell target antigens and it will be necessary to utilize NOD T-cell clones to identify the number and nature of these antigens.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00402272
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  • 2
    Electronic Resource
    Electronic Resource
    Two amino acids in glutamic acid decarboxylase act in concert for maintainance of conformational determinants recognised by Type I diabetic autoantibodies (2000)
    Springer
    Diabetologia 43 (2000), S. 881-889 
    Details
    ISSN: 1432-0428
    Keywords: Keywords Glutamic acid decarboxylase 65, autoimmune polyendocrine syndrome, stiff-man syndrome, human monoclonal antibodies, mutants.
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Aims/hypothesis. Glutamic acid decarboxylase 65 is a major autoantigen in Type I (insulin-dependent) diabetes mellitus, autoimmune polyendocrine syndrome and stiff-man syndrome. These disorders are characterised by the presence of multiple autoantibodies to the autoantigen which can be distinguished in a variety of different ways. We have investigated the role of single amino-acid mutations in glutamic acid decarboxylase 65 in distinguishing the binding of serum antibodies and a variety of patient-derived human IgG monoclonal antibodies directed to different determinants of the autoantigen.¶Methods. We identified a mutant of glutamic acid decarboxylase 65 that contained four single amino-acid mutations from the wild-type molecule. The role of these mutations was investigated by site-directed mutagenesis. We investigated the binding of patient-derived serum antibodies to glutamic acid decarboxylase 65 to a number of single and double amino-acid mutants using immunoprecipitation with labelled, recombinant antigen. To overcome the heterogeneity of different anti-glutamic acid decarboxylase 65 antibodies present in a patient's serum, the binding of a panel of eleven patient-derived human monoclonal antibodies recognising different determinants on the autoantigen was also studied.¶Results. Two replacements in glutamic acid decarboxylase 65 at Asn247Ser and Leu574Pro were identified that preferentially influence the anti-glutamic acid decarboxylase 65 serum antibodies of Type I diabetic patients, without statistically significantly effecting those recognised in other disorders. Single or double amino-acid replacements Asn247Ser and Leu574Pro in the autoantigen showed differential affects on expression of epitopes recognised by the human monoclonals. The double replacement of Asn247Ser and Leu574Pro in glutamic acid decarboxylase 65 resulted in the loss of binding of all eleven human monoclonal antibodies, irrespective of their epitope recognition. In contrast, single replacement of Leu574Pro statistically significantly reduced the binding of some carboxyl terminal-directed antibodies such as MICA 1, MICA 3 and DP-A without influencing the binding of other monoclonals. Replacement of Asn247Ser did not, however, influence the binding of any patients serum or human monoclonal antibodies.¶Conclusion/interpretation. Two distantly spaced amino acids, Asn247 and Leu574 in glutamic acid decarboxylase 65 were identified that act in concert to greatly influence the conformational structure of the autoantigen and statistically significantly influence the binding of antibodies present in Type I diabetic sera. The single or double amino-acid mutants can be used to distinguish some anti-glutamic acid decarboxylase-65 autoantibodies and could prove useful in distinguishing Type I diabetic from autoimmune polyendocrine syndrome and stiff-man syndrome patients' sera as well as to study changes in antibody patterns during disease progression. [Diabetologia (2000) 43: 881–889]
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s001250051465
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  • 3
    Electronic Resource
    Electronic Resource
    No association between islet cell antibodies and coxsackie B, mumps, rubella and cytomegalovirus antibodies in non-diabetic individuals aged 7–19 years (1991)
    Springer
    Diabetologia 34 (1991), S. 835-838 
    Details
    ISSN: 1432-0428
    Keywords: Viral antibodies ; Beta-cell function ; population study
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Viral antibodies were tested in a cohort of 44 isletcell antibody-positive individuals age 7–19 years, and 44 of their islet cell antibody-negative age and sex-matched classmates selected from a population study of 4208 pupils who had been screened for islet cell antibodies. Anti-coxsackie B1-5 IgM responses were detected in 14 of 44 (32%) of the islet cell antibody-positive subjects and in 7 of 44 (16%) control subjects. This difference did not reach the level of statistical significance. None of the islet cell antibody-positive subjects had specific IgM antibodies to mumps, rubella, or cytomegalovirus. There was also no increase in the prevalence or the mean titres of anti-mumps-IgG or IgA and anti-cytomegalovirus-IgG in islet cell antibody-positive subjects compared to control subjects. These results do not suggest any association between islet cell antibodies, and possibly insulitis, with recent mumps, rubella or cytomegalo virus infection. Further studies are required to clarify the relationship between islet cell antibodies and coxsackie B virus infections.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00408360
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  • 4
    Electronic Resource
    Electronic Resource
    Human monoclonal islet specific autoantibodies share features of islet cell and 64 kDa antibodies (1993)
    Springer
    Diabetologia 36 (1993), S. 785-790 
    Details
    ISSN: 1432-0428
    Keywords: Islet cell antibodies ; 64 kDa antibodies ; human monoclonal antibodies ; glutamate decarboxylase ; gangliosides ; Type 1 (insulin-dependent) diabetes mellitus ; islet cell antigens
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The first human monoclonal islet cell antibodies of the IgG class (MICA 1-6) obtained from an individual with Type 1 (insulin-dependent) diabetes mellitus were cytoplasmic islet cell antibodies selected by the indirect immunofluorescence test on pancreas sections. Surprisingly, they all recognized the 64 kDa autoantigen glutamate decarboxylase. In this study we investigated which typical features of cytoplasmic islet cell antibodies are represented by these monoclonals. We show by double immunofluorescence testing that MICA 1-6 stain pancreatic beta cells which is in agreement with the beta-cell specific expression of glutamate decarboxylase. In contrast an islet-reactive IgM monoclonal antibody obtained from a pre-diabetic individual stained all islet cells but lacked the tissue specificity of MICA 1-6 and must therefore be considered as a polyreactive IgM-antibody. We further demonstrate that MICA 1-6 revealed typical features of epitope sensitivity to biochemical treatment of the target tissue which has been demonstrated for islet cell antibodies, and which has been used to argue for a lipid rather than a protein nature of target antigens. Our results provide direct evidence that the epitopes recognized by the MICA are destroyed by methanol/chloroform treatment but reveal a high stability to Pronase digestion compared to proinsulin epitopes. Conformational protein epitopes in glutamate decarboxylase therefore show a sensitivity to biochemical treatment of sections such as ganglioside epitopes. MICA 1-6 share typical features of islet cell and 64 kDa antibodies and reveal that glutamate decarboxylase-reactive islet cell antibodies represent a subgroup of islet cell antibodies present in islet cell antibody-positive sera.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00401152
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  • 5
    Electronic Resource
    Electronic Resource
    Relation of fibre intake to HbA1c and the prevalence of severe ketoacidosis and severe hypoglycaemia (1998)
    Springer
    Diabetologia 41 (1998), S. 882-890 
    Details
    ISSN: 1432-0428
    Keywords: Keywords Fibre intake ; soluble fibre ; insoluble fibre ; HbA1 c ; severe ketoacidosis ; severe hypoglycaemia ; Type I diabetes mellitus ; Europe.
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The effect of dietary fibre intake on glycaemic control is still controversial. This study analysed the intake of natural dietary fibre in patients with Type I diabetes mellitus enrolled in the EURODIAB IDDM Complications Study to determine any associations with HbA1c levels and with the prevalence of severe ketoacidosis or severe hypoglycaemia. Dietary intake was assessed by a 3-day dietary record. The relation between intake of fibre (total, soluble and insoluble) and HbA1c was examined in 2065 people with Type I diabetes. Associations with severe ketoacidosis (requiring admission to hospital) and severe hypoglycaemia (requiring the help of another person) were analysed in 2687 people with Type I diabetes. Total fibre intake (g/day) was inversely related to HbA1c (p = 0.02), independently of carbohydrate intake, total energy intake and other factors regarding lifestyle and diabetes management. Severe ketoacidosis risk fell significantly with higher fibre intake (p = 0.002), with an adjusted odds ratio of 0.48 (95 % confidence interval 0.27 to 0.84) in the highest quartile ( ≥ 23.0 g fibre/day) compared with the lowest quartile ( ≤ 13.7 g fibre/day). The occurence of severe hypoglycaemia was not related to fibre intake. Beneficial effects of fibre on HbA1c and the risk of severe ketoacidosis were particularly pronounced in patients from southern European centres. This study shows that higher fibre intake is independently related to a reduction in HbA1c levels in European people with Type I diabetes. Furthermore, increased fibre intake may reduce the risk of severe ketoacidosis. These beneficial effects were already observed for fibre intake within the range commonly consumed by people with Type I diabetes. [Diabetologia (1998) 41: 882–890]
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s001250051003
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  • 6
    Electronic Resource
    Electronic Resource
    Combined screening for autoantibodies to IA-2 and antibodies to glutamic acid decarboxylase in first degree relatives of patients with IDDM (1996)
    Springer
    Diabetologia 39 (1996), S. 1351-1356 
    Details
    ISSN: 1432-0428
    Keywords: Keywords Insulin-dependent diabetes mellitus ; antibodies to tyrosine phosphatase IA-2 ; GAD antibodies ; islet cell antibodies ; prediction.
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary To determine the value of antibodies to the intracytoplasmic domain of the tyrosine phosphatase IA-2 (anti-IA-2 ic) and glutamic acid decarboxylase (GADA) for identification of subjects at risk for insulin-dependent diabetes mellitus (IDDM) we investigated 1238 first degree relatives of patients with IDDM for the presence of anti-IA-2 ic and GADA and compared the results with cytoplasmic islet cell antibodies (ICA). Anti-IA-2 ic were observed in 54 (4.4 %) first degree relatives, in 51 of 86 (59.3 %) ICA positive relatives and in 3 of 4 individuals who developed overt IDDM within a follow-up period of 1 to 28 months. GADA were found in 78 of 1238 (6.3 %) first degree relatives. They were detected in 22 of 35 (62.9 %) sera with ICA alone and in 1 of 3 subjects with anti-IA-2 ic in the absence of ICA. Of the 1238 subjects 37 (3.0 %) sera were positive for all three antibodies. Both anti-IA-2 ic and GADA were positively correlated with high levels of ICA. Anti-IA-2 ic and GADA were detected in 39.1 and 47.8 % of subjects with ICA of less than 20 Juvenile Diabetes Foundation units (JDF-U) but in 66.7 and 76.2 % of individuals with ICA of 20 JDF-U or more, respectively (p 〈 0.05). The levels of ICA and GADA in first degree relatives with at least one additional marker were significantly higher than in subjects with ICA alone (p 〈 0.005) or GADA alone (p 〈 0.03). The combination of anti-IA-2 ic and GADA identified 84.9 % of all ICA positive subjects and 93.7 % of individuals with high level ICA (≥ 20 IDF-U). All 4 individuals who progressed to IDDM had either IA-2 ic or GADA. Our data indicate that primary screening for anti-IA-2 ic and GADA provides a powerful approach with which to identify subjects at risk for IDDM in large-scale population studies which may represent the basis for the design of new intervention strategies. [Diabetologia (1996) 39: 1351–1356]
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s001250050582
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  • 7
    Electronic Resource
    Electronic Resource
    Immunological heterogeneity in Type I diabetes: presence of distinct autoantibody patterns in patients with acute onset and slowly progressive disease (1998)
    Springer
    Diabetologia 41 (1998), S. 891-897 
    Details
    ISSN: 1432-0428
    Keywords: Keywords Type I diabetes ; slowly progressive Type I diabetes ; autoantibodies ; protein tyrosine phosphatase ; glutamic acid decarboxylase ; islet cell antibodies.
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Type I diabetes mellitus may represent a heterogeneous disorder with a distinct pathogenesis in patients with young and adult onset of the disease. To investigate whether serological markers directed to different autoantigens have the potential to distinguish acute onset from slowly progressive Type I diabetes we analysed antibodies to tyrosine phosphatases IA-2/ICA512 (IA-2A) and IA-2β/phogrin (IA2βA), antibodies to GAD65 (GADA) and cytoplasmic islet cell antibodies (ICA) in a non-selected group of diabetic patients clinically classified as having Type I or Type II diabetes at diagnosis. Both IA-2A and IA-2βA were found to be positively associated with onset before the age of 20 years and the presentation of classical features of Type I diabetes. In Type I diabetes 56 % (112/200) of patients were positive for IA-2A and 38 % (76/200) for IA-2βA. In contrast, only 1 of 785 (0.1 %) patients with Type II diabetes had IA-2A and all of them were negative for IA-2βA (p 〈 0.001). Among the patients with Type II diabetes 7.6 % (n = 60) were ICA positive and 2.8 % (n = 22) had GADA suggesting the presence of slowly progressive Type I diabetes. GADA were found in 8 of 60 (13.3 %) ICA positive subjects which was lower than the percentage detected in patients with acute onset of diabetes (115/157 73.2 %) (p 〈 0.001). Blocking of double antibody positive sera showed that only 3 of 8 (37.5 %) patients with slowly progressive diabetes had ICA restricted to GAD or IA-2 whereas ICA were completely inhibited in 12 of 20 (60.0 %) patients with Type I diabetes. Among 193 patients with Type II diabetes available for follow-up, 35 % of ICA positives, 58 % of GADA positives and 60 % of those positive for both markers required insulin by 3 years. However, using strict criteria for the switch to insulin treatment the corresponding sensitivity of each marker was only low (9 %, 10 % and 5 %). We show that clinical subtypes of Type I diabetes are associated with distinct humoral autoimmunity. IA-2A and GADA were associated with classical features of Type I diabetes whereas GADA and an uncharacterized ICA subspecificity indicate slowly progressive disease. [Diabetologia (1998) 41: 891–897]
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s001250051004
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  • 8
    Electronic Resource
    Electronic Resource
    Antibodies to the Mr 64,000 (64K) protein in islet cell antibody positive non-diabetic individuals indicate high risk for impaired Beta-cell function (1992)
    Springer
    Diabetologia 35 (1992), S. 550-554 
    Details
    ISSN: 1432-0428
    Keywords: Population study ; 64K antibodies ; islet cell antibodies ; complement-fixing islet cell antibodies ; insulin autoantibodies ; HLA
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary A prospective study of a normal childhood population identified 44 islet cell antibody positive individuals. These subjects were typed for HLA DR and DQ alleles and investigated for the presence of antibodies to the Mr 64,000 (64K) islet cell antigen, complement-fixing islet cell antibodies and radiobinding insulin autoantibodies to determine their potency in detecting subjects with impaired Beta-cell function. At initial testing 64K antibodies were found in six of 44 islet cell antibody positive subjects (13.6%). The same sera were also positive for complement-fixing islet cell antibodies and five of them had insulin autoantibodies. During the follow-up at 18 months, islet cell antibodies remained detectable in 50% of the subjects studied. In all six cases who were originally positive, 64K antibodies were persistently detectable, whereas complement-fixing islet cell antibodies became negative in two of six and insulin autoantibodies in one of five individuals. HLA DR4 (p 〈 0.005) and absence of asparic acid (Asp) at position 57 of the HLA DQ β chain (p 〈 0.05) were significantly increased in subjects with 64K antibodies compared with control subjects. Of 40 individuals tested in the intravenous glucose tolerance test, three had a first phase insulin response below the first percentile of normal control subjects. Two children developed Type 1 (insulin-dependent) diabetes mellitus after 18 and 26 months, respectively. Each of these subjects was non-Asp homozygous and had persistent islet cell and 64K antibodies. We conclude that 64K antibodies, complement-fixing islet cell antibodies and insulin autoantibodies represent sensitive serological markers in assessing high risk for a progression to Type 1 diabetes in islet cell antibody positive non-diabetic individuals.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00400483
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  • 9
    Electronic Resource
    Electronic Resource
    Autoantibodies to ICA12 (SOX-13) are not specific for Type I diabetes (2000)
    Springer
    Diabetologia 43 (2000), S. 1381-1384 
    Details
    ISSN: 1432-0428
    Keywords: Keywords Autoantibodies, autoantigen, ICA12, SOX-13, Type I diabetes.
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Aims/hypothesis. The majority of patients with Type I (insulin-dependent) diabetes mellitus has autoantibodies to insulin, glutamic acid decarboxylase and the tyrosine phosphatase-like protein IA-2. Some patients with Type I diabetes, in particular with adult onset diabetes, have, however, only cytoplasmic islet cell antibodies that could be directed to as yet unknown beta cell autoantigens. Recently, one potential antigen, ICA12, was identified as the high mobility group (HMG) box transcription factor SOX-13. Our aim was to evaluate the diagnostic sensitivity and specificity of autoantibodies to SOX-13 for autoimmune diabetes.¶Methods. Full-length SOX-13 was cloned from human brain mRNA, expressed by vitro transcription/translation and used to detect autoantibodies by immunoprecipitation and radioligand assay in patients suffering from autoimmune diabetes or non-organ-specific autoimmune diseases.¶Results. We found SOX-13 antibodies to be present in 11 of 125 (8.8 %) patients with newly diagnosed Type I diabetes and in 3 of 43 (7.0 %) patients with latent autoimmune diabetes in adults. There was no association with age, sex and a particular pattern of diabetes-specific autoantibodies. Similar frequencies of SOX-13 antibodies were found in 84 patients with rheumatic diseases (4.0–11.4 %) and 211 healthy control subjects (5.2 %).¶Conclusions/interpretation. Our data indicate that SOX-13 represents a minor target of autoantibodies in patients with autoimmune diabetes. Because SOX-13 antibodies were found not to be disease-specific, we assume they are not helpful in improving the diagnosis and prediction of Type I diabetes. [Diabetologia (2000) 43: 1381–1384]
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s001250051542
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  • 10
    Electronic Resource
    Electronic Resource
    Myasthenia gravis: Overlap with ‘polyendocrine’ autoimmunity (1983)
    Springer
    Journal of molecular medicine 61 (1983), S. 509-515 
    Details
    ISSN: 1432-1440
    Keywords: Myastenia gravis ; Autoimmune diseases ; Autoantibodies ; HLA
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary 81 patients with spontaneously acquired myasthenia gravis (MG) were investigated for the presence of autoimmune (AI) diseases and their sera were tested for a range of organ-specific autoantibodies. 77 of the patients were HLA-phenotyped. Antibody titres to acetylcholine receptors (AChR) were higher in non-thymomatous patients who possessed HLA-B8 (p〈0.05) and/or -DR3 (p〈0.05) as compared to patients lacking these HLA antigens. 3 out of 20 (15%) patients with ocular MG, 7/23 (30%) with generalized MG of early onset, 11/23 (48%) generalized MG of late onset and 5/14 (35%) patients with thymoma had either overt AI diseases or significant titres of organ-specific autoantibodies suggesting subclinical AI disease. In ocular MG, low titres and an infrequent finding of antibodies to AChR (32%) as well as the low prevalence of associated autoantibodies and AI diseases indicate that this subgroup of MG consists of patients with restricted AI reactivity. HLA-B8and -DR3 were present in all the patients with associated AI disorders in the young onset group but in none of the patients with old age of onset. In the young group, 6 out of 7 patients with associated AI conditions were women whereas the sex ratio was about equal in the older cases in both, patients with and without associated AI diseases or autoantibodies. We conclude from these observations that ageing provides conditions that allow the breakdown of self tolerance. The simultaneous presence of HLA B8, DR3 and female sex provide important additional factors for early expression of MG.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01488718
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