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Biomedical subjects

A G Ziegler

Publications and source records attributed to A G Ziegler.

At least 73 records · Page 4Linked to original sources
PubMed1996

Perinatal autoimmunity in offspring of diabetic parents. The German Multicenter BABY-DIAB study: detection of humoral immune responses to islet antigens in early childhood.

IDDM results from immune-mediated destruction of insulin-producing pancreatic beta-cells in individuals genetically susceptible for the disease. There is evidence that the 65-kDa isoform of GAD plays a critical role in the induction of autoimmune diabetes in NOD mice. In humans, it is still unclear when and to what beta-cell antigens autoreactive lymphocytes become activated during early disease. We conducted a prospective study from birth, BABY-DIAB, among children of mothers with IDDM or gestational diabetes or fathers with IDDM, and we investigated the temporal sequence of antibody responses to islet cells (ICA), insulin (IAA), GAD (GADA), and the protein tyrosine phosphatase IA-2/ICA512 (IA-2A). Of 1,019 children included at birth, we have currently followed 513 to the age of 9 months, 214 to the age of 2 years, and 37 to the age of 5 years. At birth, all antibody specificities were frequent in newborns of diabetic mothers but not fathers and are suggested to be transplacentally acquired because they are strongly correlated with antibody levels in their diabetic mothers. In early childhood, antibody levels were <99th percentile of control subjects in the majority of children. However, 37 children exhibited elevated antibody levels; these were most frequently detected at the age of 2 years. The antibody prevalence at age 2 years was 2.3% for ICA, 7% for IAA, 4.2% for GADA, and 2.8% for IA-2A (8.9% positive for at least one antibody). Children of diabetic fathers were positive for at least one antibody more frequently than were children of diabetic mothers (9 months of age: 8.5 vs. 3.6%; 2 years of age: 16.7 vs. 7.9%). There was no specific sequence in the appearance of positive autoantibodies, but 13 (35%) antibody-positive cases already had more than one ICA before the age of 2 years and 7 (19%) showed reactivity to three islet cell antigens before age 5 years. The presence of multiple antibodies confers high risk for the future development of diabetes; three of six children who exhibited positive antibody responses to all four antibodies tested and another child with two positive antibodies developed clinical diabetes at the ages of 13, 21, and 27 months and 5 years. We conclude that loss of tolerance to beta-cell autoantigens and appearance of autoimmune phenomena occur very early in life in individuals with genetic susceptibility for IDDM. Screening programs to identify candidates for disease-prevention therapies can therefore be focused on this young age-group, in whom the disease process may be less advanced and who may therefore be best suited to such therapies.

Animals↗
PubMed1995

[Prediction of type I diabetes by antibody screening].

For the prediction of type I diabetes in first degree relatives of type I diabetics, a variety of laboratory methods are now available. Thus, screening for serum antibodies against the body's own insulin, islet cells and the enzyme glutamate decarboxylase, represents a simple and well-established routine examination used for early diagnosis. The combination of various parameters such as e.g. the age of the person at risk, antibody status (nature, number, combination or titer of the antibodies) and capacity for early insulin secretion following i.v. glucose loading, permits us to predict, with quite good accuracy, the risk years before there are any clinical manifestations. These successes of early diagnosis have led to new concepts of immunoprophylaxis for the prevention of type I diabetes. Thus, at the present time two highly promising studies involving the prophylactic administration of insulin or nicotinamide in persons at risk are underway in Germany, the results of which to date suggest that a new epoch of immunotherapeutic treatment of this disease may be in the offering.

Adolescent↗
PubMed1995

No association of antibodies to glutamic acid decarboxylase and diabetic complications in patients with IDDM.

OBJECTIVE: To evaluate the association of antibodies to glutamic acid decarboxylase (GAD-ab) and diabetic complications (neuropathy, retinopathy, and nephropathy) in patients with insulin-dependent diabetes mellitus (IDDM). RESEARCH DESIGN AND METHODS: We examined the prevalence of GAD-ab (immunoprecipitation assay) and islet cell antibodies (ICAs) (indirect immunofluorescence) in a representative sample of IDDM patients (n = 146) with different disease duration (2-52 years, median 13.2 years). Of all patients characterized for the existence of diabetic complications, 56 of 146 had peripheral neuropathy, 24 of 142 had autonomic neuropathy, 67 of 141 had retinopathy, and 39 of 146 had nephropathy. RESULTS: GAD-ab (> 2 SD) were detected more frequently than ICA (> 5 Juvenile Diabetes Foundation units) in IDDM patients of different disease duration (GAD-ab+ 37% [54 of 146] vs. ICA+ 22% [32 of 146], P = 0.011; diabetes duration less than median: GAD-ab+ 47% vs. ICA+ 23%, P = 0.0046; diabetes duration greater than median: GAD-ab+ 27% vs. ICA+ 22%, P > 0.05). For GAD-ab and for ICA, respectively, no difference was observed in frequency of positivity or titers between patients with or without diabetic complications. CONCLUSIONS: Both GAD-ab and, to a lesser extent, ICA persist for a long time in several individuals. This persistence is not related to diabetic neuropathy or any other diabetic complication.

Adolescent↗
PubMed1994

Alterations of lymphocyte subsets in children of diabetic mothers.

To investigate the impact of diabetic mothers on the maturation of the immune system in their offspring, immunophenotypic markers of major lymphocyte subpopulations were evaluated by two-colour flow cytometric analysis in 160 healthy children of diabetic mothers (100 with insulin-dependent diabetes mellitus (IDDM): 48 with gestational diabetes), including 22 neonates, 45 infants aged 8-12 months, 46 children aged 1-2 years, 29 children aged 3-6 years and 18 children aged 7-17 years. Results were compared with 21 neonates of healthy mothers from our hospital and with 110 paediatric subjects of a reference population. In neonates of diabetic mothers, percentages of total lymphocytes (p = 0.044), T and B lymphocytes (p = 0.004, respectively) were significantly decreased compared to our neonates of healthy mothers. By subdividing the group of neonates in offspring of mothers with IDDM (n = 15) or gestational diabetes (n = 7), differences compared to normal neonates were mainly observed in neonates of mothers with IDDM (T lymphocytes: p = 0.006; B lymphocytes: p = 0.008). In cord blood, 45.5% of neonates had antibodies to islet cells, insulin or glutamic acid decarboxylase, most likely transmitted through the placenta of the diabetic mother. No association was found between alterations of lymphocyte subsets and antibody-positivity in cord blood, nor was there any correlation of lymphocyte counts and mean HbA1 during pregnancy, maternal age at delivery, diabetes duration, or neonatal birth weight, respectively. Comparisons among age groups from newborn infants through adolescents revealed higher percentages of total lymphocytes and lower percentages of activated T cells in children of diabetic mothers compared to children of the reference population between the age of 1 to 6 years (67-73% of the cases above and 62-77% below the interquartiles of the reference range, respectively). No significant differences in lymphocyte subpopulations between children of mothers with IDDM diabetes and gestational diabetes have been detected. In addition, there were no abnormalities of lymphocyte subsets in children who are at high risk for the development of IDDM. In summary, we suggest that the observed changes in children of diabetic mothers may reflect a cellular immune reaction to the particular maternal environment, characterized by both an abnormal metabolic state and persisting autoimmunity in the affected mother.

Adolescent↗
PubMed1994

Associations of anti-GAD antibodies with islet cell antibodies and insulin autoantibodies in first-degree relatives of type I diabetic patients.

Sera from 114 first-degree relatives of insulin-dependent diabetes mellitus (type I diabetes) patients and 81 healthy individuals living in Germany were analyzed for antibodies to rat brain glutamic acid decarboxylase (GAD-ab) using an immunoprecipitation assay. The determination of GAD-ab in the 81 islet cell antibody (ICA) and insulin autoantibody (IAA) negative healthy individuals established a normal range (mean +/- 2 SD); 2 healthy individuals (2.5%) possessed GAD-ab levels above this range, but became negative on follow-up. None of 86 ICA-/IAA- first-degree relatives had GAD-ab; whereas, 42.9% of 28 ICA+ and/or IAA+ relatives were positive for GAD-ab. Presence of GAD-ab was negatively correlated with IAA (P = 0.02) and positively with ICA (P = 0.0006). Follow-up samples were obtained from 25 of 28 ICA+ and/or IAA+ relatives with a mean (+/- SD) follow-up period of 20.6 +/- 12.1 months. In these 25 relatives, GAD-ab were positive in 70% ICA+/IAA-, 0% ICA-/IAA+, and 57.1% ICA+/IAA+ relatives in the first sample and in 57.1% ICA+/IAA-, 0% ICA-/IAA+, and 70% ICA+/IAA+ relatives in the last sample. GAD-ab, once detected, persisted in 9 of 11 GAD-ab+ relatives. Of the relatives, 2 converted to GAD-positivity, concomitant with the appearance of ICA, and 2 others lost GAD-ab during follow-up. Of the 28 ICA+ and/or IAA+ relatives, 6 progressed to overt type I diabetes on follow-up, and GAD-ab were detectable in 4 of these relatives.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1994

HLA-DQ-restricted, islet-specific T-cell clones of a type I diabetic patient. T-cell receptor sequence similarities to insulitis-inducing T-cells of nonobese diabetic mice.

We established a T-cell line and 20 CD4+ T-cell clones from the peripheral blood lymphocytes of a type I diabetic patient using a membrane preparation of a rat insulinoma cell line (beta membrane antigen [BMA]) as a source of antigen. The T-cell line and three selected clones proliferated specifically to stimulation with BMA and to membranes prepared from human islets, rat pancreas, and NOD pancreas, but not to control antigens. Proliferation-inhibition studies using human leukocyte antigen (HLA)-specific monoclonal antibodies revealed HLA-DQw1-restricted recognition of BMA. An analysis of the T-cell receptor (TCR) repertoire of the T-cell line after 8 and 40 days of culture showed a prominent usage of the V alpha 1 and V alpha 12 gene families. Although sequencing of the TCR V alpha and V beta chains of the three clones demonstrated that each used different V alpha and V beta gene segments, structural similarities were found in complementary-determining region 3 (CDR3), the region that is postulated to interact with the peptide component of the TCR ligand. When we compared these TCR sequences with published sequences of disease-inducing T-cells of NOD mice, highly related TCR V beta families were detected. Furthermore, stretches of identical amino acids within the CDR3 region were found between two pairs of human and mouse T-cells. If one considers the species differences in TCR genes and sequence differences in the restriction elements for these cells (HLA-DQ vs. H-2 I-A nod), these sequence similarities are striking and may be useful for pinpointing T-cells of primary importance in the development of disease.

Amino Acid Sequence↗
PubMed1993

On the appearance of islet associated autoimmunity in offspring of diabetic mothers: a prospective study from birth.

For the first time the incidence of insulin autoantibodies and islet cell antibodies were evaluated in a prospective study from birth. Consecutive neonates (168) from mothers with Type 1 (insulin-dependent) diabetes mellitus (n = 113) and gestational diabetes (n = 55) were included at birth. To date, follow-up sera were obtained from 90 of 168 mother-child-pairs 9 months postpartum and from 39 of 168, 2 years postpartum. At birth, there was a strong correlation between the presence of antibodies in the cord blood of neonates and in maternal circulation [Type 1 diabetic mothers: 20% islet cell antibodies > or = 20 JDF-U (detection threshold of our islet cell antibody assay), 74% insulin antibodies > 49 nU/ml (upper limit of normal range in sera of healthy control subjects aged 0.5 to 46 years); neonates: 21% islet cell antibodies > or = 20 JDF-U, 76% insulin antibodies > 49 nU/ml; gestational diabetic mothers: 11% islet cell antibodies > or = 20 JDF-U, 18% insulin antibodies > 49 nU/ml; neonates: 13% islet cell antibodies > or = 20 JDF-U, 55% insulin antibodies > 49 nU/ml]. This supports transplacental passage of insulin antibodies and islet cell antibodies from diabetic mothers to their offspring. During follow-up, the majority of children lost antibody-positivity after birth. A few offspring, however, exhibited or developed antibodies consistently, whereby insulin autoantibodies preceded islet cell antibodies in each case (antibody-positivity: 9 months: 0% islet cell antibody positive, 3.3% insulin autoantibody positive; 2 years: 2.6% islet cell antibody positive, 7.7% insulin autoantibody positive).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1993

Dermatoglyphics in type 1 diabetes mellitus.

Although fingerprints and handprints are widely used in criminology, it is only recently that this approach has been applied to the field of medical and genetic diagnoses. In order to investigate dermatoglyphics in Type 1 diabetes mellitus, quantitative characteristics of fingers and palms (ridge count and main line indices) as well as qualitative parameters such as digital and interdigital patterns, the position of the palmar axial triradii and main line courses were analysed in 88 male and 108 female Type 1 diabetic patients and compared with data from 100 male and 99 female normal controls. Type 1 diabetic patients show a lower third finger ridge count (p < 0.05) and a-b ridge count (p < 0.001) and higher transversality of the main lines as indicated by the main line index value (p < 0.001) or the ending of the main line A in a specific sector 5, 5', and 5" (p < 0.001) compared with controls. In addition, diabetic patients show higher frequency of palmar axial t' and t" triradii (p < 0.001) and a lower frequency of 'true' patterns in the fourth interdigital and thenar area (p < 0.001) than controls. By multivariate analysis of quantitative and qualitative variables a predictive value of 78.6% and 77.3%, respectively, for male, and 81.4% and 82.2%, respectively, for female Type 1 diabetic patients was found. In conclusion, dermatoglyphics seem to be an interesting tool for genetic studies related to Type 1 diabetes.

Dermatoglyphics↗
PubMed1993

Characterization of insulin autoantibodies in relatives of patients with type I diabetes.

We studied in detail the anti-insulin autoantibodies in 29 nondiabetic relatives of patients with type I diabetes. The affinity of the autoantibodies for [125I]human insulin was high (1.34 x 10(9)-20.71 x 10(9) L/mol), and the capacity was low (0.84 x 10(-12)-37.80 x 10(-12) M). The product of affinity x capacity of each relative's antibodies directly correlated (r = 0.99) with the level of antibodies determined in our standard radioassay. The autoantibodies from each of the subjects studied had the same rank order of affinities for insulin from different species. Guinea pig, fish insulin, and insulin containing Trp rather than Leu in position 13 of the A-chain inhibited minimally the human insulin binding. Human proinsulin, insulin containing Gln rather than Glu in position 17 of the A-chain, and desoctapeptide insulin (des B23-30) all inhibited binding effectively. Insulin autoantibodies in relatives of patients with type I diabetes share common epitope(s), which suggests a common pathogenic mechanism for production of such antibodies. The epitopes from this initial analysis appear to include amino acids B1-B3 and A8-A13. The region recognized can be distinguished from the insulin receptor binding domain.

Adolescent↗
PubMed1993

[Etiology and pathogenesis of type I diabetes].

A large body of evidence supports the hypothesis that type I diabetes is an autoimmune disease. The development of type I diabetes can conceptually be divided in three stages: 1. genetic susceptibility, 2. pretype I diabetes with beginning beta-cell destruction and insulitis, and 3. clinical overt type I diabetes. During stage 2, an unknown "triggering event" leads to inflammation and active autoimmunity towards beta cells. In this chapter, recent developments concerning genetics and environmental factors, pathogenic mechanisms, prediction, and immunotherapy of type I diabetes will be reviewed.

Autoantibodies↗
PubMed1992

Involvement of dendritic cells in early insulitis of BB rats.

In this study, subsets of mononuclear infiltrates in pancreatic islets of BB rats at different stages of insulitis were determined by various monoclonal antibodies against rat lymphoid cells, including a mouse monoclonal IgM antibody that distinguishes between macrophages and dendritic cells (mAb 1F119). 1F119+ dendritic cells were absent in and around islets of Wistar control rats. In BB rats, the first alteration of islets detectable by immunohistochemistry when compared with normal islets was the enhanced expression of 1F119 antigen around and in the islets (17% 1F119+ islets). At disease stage 1 (i.e. no leukocyte infiltration after HE staining), lymphocytes and macrophages were almost absent. At disease stage 2 (leukocyte infiltration < 20 cells), a more intense form of dendritic cell infiltration was seen (stage 1 versus stage 2, P < 0.0001). In addition, ED2+ and ED3+ cells were present around the islets (50% of islets were infiltrated with 1F119+ cells versus 16% with ED2+, 19% with ED3+, 11% with W3/25+ cells, and 11% with OX8+ cells, P < 0.0001). At disease stage 3 (> 20 cells), a clear increase of ED2+ and ED3+ macrophages and of W3/25+ and OX8+ T-lymphocytes in the infiltrates was observed. These observations suggest a role for antigen presenting dendritic cells in the initiation of immune reaction in type 1 diabetes of BB rats.

Animals↗
PubMed1992

Natural course of remission in IDDM during 1st yr after diagnosis.

OBJECTIVE: To describe the natural course of clinical remission in insulin-dependent diabetes mellitus (IDDM) when insulin dose is minimized without loss of target glycemia and to identify factors that predict clinical remission. RESEARCH DESIGN AND METHODS: Ninety-five patients, who were placebo-treated control subjects in the Canadian-European multicenter randomized trial of cyclosporin A in recent-onset IDDM, were studied. RESULTS: The mean insulin dose decreased during the first months after diagnosis, with a nadir at 3 mo, when 27% of the patients did not require insulin to maintain target glycemia. At 1 yr, 10% of patients still did not need insulin. Patients not receiving insulin who had glycosylated hemoglobin within the normal range were called remitters. Mean basal and glucagon-stimulated C-peptide values were significantly (P less than 0.025) higher in remitters than nonremitters at the start of the study. Therefore, all patients were divided into those with values above the mean stimulated C-peptide (0.4 nM) and those with values below the mean at entry. The probability of entering a remission with a stimulated C-peptide greater than 0.4 nM was 10 times as high (P less than 0.05) as for those with a stimulated C-peptide below this level. Surprisingly, the beginning and end of the remission were associated with neither major changes in C-peptide levels nor islet cell antibody and insulin-antibody titer. A more rapid loss of stimulated C-peptide occurred in patients who lacked HLA-DR3 and -DR4 (P less than 0.05 at mo 9). CONCLUSIONS: This study shows a higher spontaneous clinical remission rate than expected during the 1st yr after diagnosis. Preserved beta-cell function at entry predicts a greater chance of entering a remission, and a more rapid loss of beta-cell function was seen in patients without HLA-DR3 and -DR4.

Adult↗
PubMed1991

[Insulin autoantibodies and islet cell antibodies in recently appearing diabetes mellitus type I. Association with age of manifestation and HLA phenotype].

Insulin autoantibody (IAA) and islet cell antibody (ICA) titres were measured in 108 newly diagnosed type I diabetics (49 male, 59 female, mean age 20 [1-38] years) and 103 non-diabetic controls (41 male, 62 female, mean age 23 [16-46] years). IAA titres in the controls were normally distributed, with a mean of 5 +/- 11 nU/ml. The upper limit of normal was established as 49 nU/ml (mean + 4 standard deviations). Raised IAA and ICA titres were present in 45% and 44% of type I diabetics, respectively, with 59% positive for either IAA or ICA or both. IAA were markedly age-dependent, being positive in 70% (26 out of 37) of diabetics under the age of 15 years, and in 32% (23 out of 71) at the age of 15 years or more (P = 0.0004). There was a less marked difference for ICA titres (positive in 62% of patients less than 15 years, and in 35% of those of 15 years of older; P less than 0.01). IAA were significantly more common in HLA DR4 positive patients than in HLA DR4 negative patients (56% vs 11%; Pc less than 0.00015). With regard to age a significant association between IAA and HLA DR phenotype was present only in homozygous (Pc less than 0.03) and heterozygous (P less than 0.0003) patients aged 15 years or older. By contrast, ICA was not significantly correlated with HLA phenotype. These data suggest a genetic predisposition for the development of IAA.

Adolescent↗