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A G Ziegler

Publications and source records attributed to A G Ziegler.

At least 55 records · Page 3Linked to original sources
PubMed1998

Humoral and cellular immune parameters before and during immunosuppressive therapy of a patient with stiff-man syndrome and insulin dependent diabetes mellitus.

OBJECTIVES: Humoral and cellular immune reactivity are reported for two neuroendocrine autoantigens-glutamic acid decarboxylase (GAD) and the protein tyrosine phosphatase IA-2-in a patient with the autoimmune type of stiff-man syndrome and insulin dependent diabetes (IDDM). METHODS: Antibodies and T cell proliferation against GAD and IA-2 and cytokine release of antigen stimulated T cells (IFN-gamma) were determined before and several times during immunosuppressive therapy with prednisolone. RESULTS: Raised GAD antibodies against full length GAD65 or chimeric constructs were detected before therapy and they remained at a high concentration despite a marked clinical improvement during cortisone treatment. Antibodies to IA-2 were undetectable, but weak T cell responses to both GAD and IA-2 were seen before therapy and once on reduction of high cortisone dosages when the patient showed signs of clinical deterioration. Cytokine profiles showed increased IFN-gamma production after stimulation with GAD or IA-2 suggesting increased activation of TH1 cells. CONCLUSION: Immunosuppressive therapy --even with extremely high doses of 500 mg a day--does not lead to the reduction of antibody concentrations in the periphery nor to a switch in epitope recognition of such antibodies despite clinical improvement. The amount of T cell reactivity to various antigens, however, may be a useful marker to monitor the effectiveness of immunotherapy.

Autoantibodies↗
PubMed1998

GADIA2-combi determination as first-line screening for improved prediction of type 1 diabetes in relatives.

A new radiobinding assay for the simultaneous detection of antibodies to GAD and the tyrosine phosphatase IA2 has been recently described in patients with newly diagnosed type 1 diabetes. Here we assessed sensitivity and predictive value of this GADIA2-combi test in first-degree relatives of type 1 diabetic patients compared with islet cell antibody (ICA) and insulin autoantibody (IAA) screening. Of 1,606 relatives, 77 (4.8%) had elevated GADIA2-combi titers above the 99th percentile of 105 nondiabetic control subjects, and results were confirmed by testing these samples for GAD antibody (GADA) and tyrosine phosphatase IA2 antibody (IA2A) in the single antibody test (29 GADA+/IA2A+, 44 GADA+/IA2A-, and 4 IA2A+/GADA-). A further 9 of 1,606 relatives had detectable ICA (1) or IAA (8), but they were negative in the GADIA2-combi assay as well as in the single test for GADA or IA2A. Twenty-four relatives progressed to IDDM within a median follow-up time of 5.6 years (range 0.5-8.2). The sensitivity of antibody determination in relatives with progression to IDDM was 92% for the GADIA2-combi assay, 96% for the combined testing of IAA and GADIA2-combi antibodies, and 83, 67, 67, and 79%, respectively, for GADA, IA2A, IAA, or ICA testing alone. The cumulative life-table risk of antibody-positive relatives was related to GADIA2-combi titers (5-year risk: >50 U, 51% [95% CI 30-73]; >10 to 50 U, 12% [1-24]; <10 U, 0.17% [0-0.5]; P=0.0001) and on the presence of IA2A in addition to GADA (5-year risk: GADA+/IA2A+, 47% [25-68]; GADA+/IA2A-, 15% [2-28]; P=0.006). In those with detectable antibodies, risk was not associated with age (<15 vs. >15 years) or relation to proband (offspring, sibling, parent). Relatives with GADIA2-combi antibodies >10 U and the additional presence of IAA had a slightly higher diabetes risk than relatives without IAA (5-year: IAA+, 46% [23-68]; IAA-, 19% [6-32]; P=0.07). Furthermore, low first-phase insulin release after intravenous glucose tolerance test was associated with risk in relatives with GADIA2-combi antibodies (P=0.01). These results indicate that the GADIA2-combi test is a valuable marker for first-line screening and risk assessment of type 1 diabetes in relatives. It can be used for venous as well as capillary blood samples.

Adolescent↗
PubMed1997

Identification of naturally processed T cell epitopes from glutamic acid decarboxylase presented in the context of HLA-DR alleles by T lymphocytes of recent onset IDDM patients.

Glutamic acid decarboxylase (GAD) has been defined as a major target antigen in insulin-dependent diabetes mellitus (IDDM). To identify the molecular ligands triggering a T cell response to GAD, a panel of human GAD65-specific T lymphocyte lines was generated from peripheral blood of three recent onset IDDM patients. All lines derived from a patient expressing the high-risk-conferring HLA-DR*0301/ *0401 haplotypes recognized a single epitope localized between amino acid positions 270 and 283 of GAD65, a stretch that is located in close proximity to the homology region shared with Coxsackie virus P2-C protein. All lines with this specificity were restricted to the DRA, B1*0401 product of the DR4 haplotype. Analysis of the GAD-specific T cell response in a second patient homozygous for DR4 haplotypes demonstrated that the same DRA, B1*0401 allele selected T cells specific for a different determinant. The T cell response profile in a third patient showed that DR*1501/ *1601-encoding haplotypes could present at least three different epitopes to GAD65-specific T lymphocytes. One of these epitopes was presented by a DR allele associated with the resistance-conferring DRB1*1501 haplotype. GAD-specific T cell lines could not be isolated from HLA class II-matched normal individuals. Our data reveal that (a) the T cell response to GAD65 is quite heterogenous in recent onset IDDM patients; (b) HLA-DR, not DQ, seems to be the principal restriction element used by T cells present at the onset of the disease; and (c) T cells responding to epitopes containing identical sequences to Coxsackie virus P2-C protein were not detected.

Alleles↗
PubMed1997

[Alström syndrome--a rare disease of diabetic association].

BACKGROUND: Alström's disease is a rare hereditary multiple-system illness, whereas a second-messenger defect can be assumed. CASE REPORT: We describe a case-the first in Germany of 15 known cases in the world literature-, who suffers from all clinical features, such as non-insulin-dependent diabetes mellitus, retinitis pigmentosa, pancochlear damage of the ears, hypogonadism, obesity and chronic nephropathy, with the exception of acanthosis nigricans. CONCLUSION: Because of the multiplicity of affected organs the diagnosis of Alström's disease is difficult.

Adult↗
PubMed1997

Antibodies to bovine serum albumin (BSA) in type 1 diabetes and other autoimmune disorders.

Clinical and experimental studies have delineated a link between dietary cow milk protein and the development of insulin-dependent diabetes mellitus (IDDM), and bovine serum albumin (BSA) was proposed as one candidate mediator of this effect. The demonstration of anti-BSA antibodies in new onset type 1-diabetic children from Finland initiated a controversial debate on the utility of BSA antibodies as a disease marker and on the role of BSA in IDDM. Here we analyzed BSA antibodies in newly diagnosed type 1-diabetic patients and their first degree relatives, patients with other autoimmune diseases, and children with Down's syndrome from Germany. Blinded serum samples (n = 308) were screened for IgG anti-BSA antibodies by particle concentration fluoroimmunoassay (PCFIA). The prevalence of elevated BSA antibodies in newly diagnosed type 1-diabetic patients was low (11%), although mean BSA antibody levels were significantly increased in diabetic patients as compared to controls (1.94 +/- 1.51 vs. 0.97 +/- 0.93 kFU, p < 0.0007). Mean BSA antibody levels were also increased in ICA+ and/or IAA+ first degree relatives (1.32 +/- 0.43, p < 0.002) and in children with Down's syndrome (3.01 +/- 1.93, p < 0.0007), but not in the other autoimmune disorders tested. The low prevalence of elevated anti-BSA levels in IDDM patients limits the clinical usefulness of this immune marker. We conclude that current anti-BSA assays do not substantially contribute to the prediction and diagnosis of IDDM.

Adolescent↗
PubMed1997

Prediction of type 1 diabetes postpartum in patients with gestational diabetes mellitus by combined islet cell autoantibody screening: a prospective multicenter study.

Women with gestational diabetes mellitus (GDM) have a considerable risk of developing diabetes later in life. To determine the predictive value of autoantibody markers in gestational diabetic pregnancy for the development of type 1 diabetes postpartum, we tested 437 patients with GDM (289 women treated with diet only [GDM-A] and 148 requiring insulin treatment during pregnancy [GDM-B]) for antibodies to islet cells (ICAs), GAD (GADAs), and tyrosine phosphatase ICA512/IA-2 (IA2As). We prospectively followed them with repeated oral glucose tolerance tests and antibody determinations for up to 7 years postpartum (mean, 1.6 years; range, 0-7.2 years). The cumulative risk of diabetes up to 5 years postpartum was 17% (95% CI 12-22%). The risk of type 1 diabetes was 3% (2-5%) by 9 months and 7% (4-9%) 2 years after delivery. At delivery, 8.5% of all patients were ICA+, 9.5% were GADA+, 6.2% were IA2A+, and 18.1% were positive for at least one antibody (12.6% for GDM-A vs. 30.4% for GDM-B, P < 0.0001). During follow-up, GADAs persisted in 75%, ICAs in 35%, and IA2As in 30% of the subjects positive for the respective marker at delivery. By 2 years postpartum, 29% (19-39%) of patients positive for at least one antibody developed type 1 diabetes, compared with 2% (1-4%) of antibody-negative patients (P < 0.0001). Thereby, the risk for type 1 diabetes 2 years postpartum increased with the number of antibodies present at delivery from 17% (6-28%) for one antibody, to 61% (30-91%) for two antibodies, and to 84% (55-100%) for 3 antibodies. Risk of progression to type 1 diabetes postpartum was also associated with the status of parity. Women with one or more pregnancies before the index pregnancy had a higher risk for type 1 diabetes 2 years after delivery (14.7% [4.9.-24.5%]) than women having their first (i.e., index) pregnancy (5% [2.9-7.1%]) (P < 0.006). A comparison of different prediction strategies showed that single antibody screening with GADA yielded the highest sensitivity of 63% (45-75%), compared with ICA (48% [31-65%]) and IA2A (34% [13-47%]). Combined screening with two autoantibodies increased sensitivity to 74% (58-90%) and 75% (60-92%) when using GADA plus ICA or GADA plus IA2A, respectively. Screening with all three markers improved sensitivity further to 82% (67-100%). Beta-cell autoantibodies determined at delivery in women with GDM are highly predictive for the development of type 1 diabetes postpartum. Autoantibody screening in pregnant women with GDM from populations at high risk for type 1 diabetes should therefore be considered to allow early diagnosis and appropriate therapy.

Adolescent↗
PubMed1997

Autoantibodies to sympathetic ganglia, GAD, or tyrosine phosphatase in long-term IDDM with and without ECG-based cardiac autonomic neuropathy.

OBJECTIVE: To evaluate the association of autoantibodies to complement-fixing sympathetic ganglia (CF-SG), and tyrosine phosphatase (IA-2) with electrocardiogram (ECG)-based cardiac autonomic neuropathy (CAN) in long-term IDDM. RESEARCH DESIGN AND METHODS: We examined the prevalence of autoantibodies to CF-SG (by complement-fixing indirect immunoflourescence), GAD, and IA-2 (by radioligand assay) and islet cells (by indirect immunofluorescence) in 96 long-term IDDM patients (41 with ECG-based CAN, > or = 2 of 5 cardiac reflex tests abnormal; 55 without ECG-based CAN). As a control group, 89 healthy nondiabetic subjects were investigated. RESULTS: CF-SG autoantibodies were observed more frequently in long-term IDDM patients than in the control group (25 vs. 4%, P = 0.0001). Of the IDDM patients, 14 (34%) with CAN and 10 (18%) without CAN presented with CF-SG autoantibodies (P = 0.06). GAD or IA-2 autoantibodies were detected in 14 (34%) and 17 (41%) IDDM patients with CAN, compared with 24 (44%) and 29 (53%) IDDM patients without CAN (P = 0.2, P = 0.2). Islet cell antibodies were observed in 6 (15%) IDDM patients with and in 9 (16%) IDDM patients without CAN (P = 0.5). CONCLUSIONS: In long-term IDDM, the role of CF-SG autoantibodies, which tend to be more frequent in patients with ECG-based CAN, requires further investigations. The persistence of GAD and IA-2 autoantibodies is not related to ECG-based CAN.

Adult↗
PubMed1997

Validity of screening for individuals at risk for type I diabetes by combined analysis of antibodies to recombinant proteins.

OBJECTIVE: To determine whether screening for the presence of multiple antibody markers for IDDM is effective at identifying individuals with high risk for disease development. RESEARCH DESIGN AND METHODS: Antibodies to GAD and the tyrosine phosphatase-like protein 1A-2 were determined in sequential serum samples from 44 first-degree relatives of IDDM patients, identified as possessing islet cell antibody (ICA) and/or insulin autoantibody (IAA), who were followed prospectively for IDDM development, ICA, IAA, and antibodies to GAD and 1A-2 were also determined in 93 cases of new-onset nonfamilial IDDM. RESULTS: The presence of two or more antibodies in addition to ICA or IAA conferred high risk (61%) for development of IDDM within 5 years of entry into the study and identified 89% of those who have developed IDDM on current follow-up. None of the relatives positive for ICA or IAA alone, in the absence of other antibody markers, have developed IDDM. Antibodies to islet antigens could both appear and disappear in follow-up samples obtained after entry into the study. The majority (60%) of young (< 16 years), sporadic cases of IDDM had multiple antibodies to islet antigens, but this proportion was lower in older patients (37%). CONCLUSIONS: A screening strategy based on the analysis of antibodies to multiple islet antigens can predict IDDM at high sensitivity and specificity in families, and such a strategy may also be applicable to identify young individuals in the general population with high disease risk. Since appearance of antibodies to different antigens occurs sequentially rather than simultaneously, accurate assessment of diabetes risk based on the presence of multiple antibodies will require follow-up over a number of years after the first evidence of islet autoimmunity.

Adolescent↗
PubMed1997

High-dose intravenous insulin infusion versus intensive insulin treatment in newly diagnosed IDDM.

High-dose intravenous insulin infusion at the onset of IDDM has been suggested to improve beta-cell function during the 1st year of insulin treatment. To test this hypothesis, we randomly assigned newly diagnosed IDDM patients to receive either an experimental 2-week high-dose intravenous insulin infusion (n = 9; age, 25 +/- 7 years; HbA1e, 10.5 +/- 2.0%) or an intensive insulin therapy of four injections per day (n = 10; age, 28 +/- 7 years; HbA1c, 12.3 +/- 3.0%). The experimental-therapy group received three times more insulin (1.2 +/- 0.4 U.kg-1.day-1) than the intensive-therapy group (0.4 +/- 0.1 U.kg-1. day-1, P < 0.0005). By week 3, both groups were treated similarly with intensive insulin therapy and were followed for 1 year. beta-cell function was evaluated with fasting plasma C-peptide and glucagon-stimulated and mixed meal-stimulated C-peptide concentrations. In both groups, insulin doses were comparable, and HbA1c levels were near normal during follow-up. At diagnosis of IDDM, fasting C-peptide was 0.40 +/- 0.13 nmol/l in the experimental-therapy group and 0.39 +/- 0.23 nmol/l in the intensive-therapy group. Irrespective of treatment, a slight decline of fasting C-peptide was observed in sequential measurements up to 12 months in both groups (delta, -0.13 and -0.08 nmol/l, respectively; NS). Glucagon-stimulated C-peptide concentrations decreased from 0.54 +/- 0.18 and 0.70 +/- 0.39 nmol/l at month 0 to 0.41 +/- 0.20 and 0.61 +/- 0.52 nmol/l, respectively, at month 12. In the experimental-therapy group, mixed meal-stimulated C-peptide concentrations (area under the curve over 2 h) increased from 82.10 +/- 43.72 to 101.20 +/- 32.53 nmol/l and in the intensive-therapy group, from 75.05 +/- 46.01 to 107.20 +/- 102.51 nmol/l. Changes in stimulated C-peptide concentrations between month 0 and 12 were not significant in both groups. During follow-up, fasting and stimulated C-peptide concentrations were not significantly different between the experimental-therapy group and the intensive-therapy group. We conclude that as initial treatments of newly diagnosed IDDM, high-dose intravenous insulin infusion and intensive insulin therapy equally preserve beta-cell function during the 1st year of insulin therapy.

Adolescent↗
PubMed1996

Relation between cellular and humoral immunity to islet cell antigens in type 1 diabetes.

The autoimmune disease insulin-dependent diabetes is thought to result from T-cell mediated destruction of pancreatic beta cells. We analysed the relation between humoral and cellular immunity to multiple islet cell antigens, including human insulin, glutamate decarboxylase GAD65, tyrosine phosphatase (ICA512/IA2), human pancreas and RIN cells in 28 patients with newly diagnosed type 1 diabetes and 9 antibody-positive (Ab+) relatives at high risk for type 1 diabetes. Of newly diagnosed patients, all showed reactivity to at least one recombinant islet cell antigen, by elevated cellular or humoral (or both) immune responses. Fifty-seven percent of patients and relatives showed T-cell reactivity to more than one islet cell antigen and 68% revealed humoral immunity to more than one islet cell antigen. Increased T-cell response to one single islet cell antigen was observed in 32% and positive antibody response in 25% of diabetic patients and relatives. Further-more, we found that T-cell reactivity to GAD was associated with T-cell reactivity to RIN cells, whereas reactivity to ICA512 and insulin was not associated with any other T-cell response. Likewise, antibody response to ICA512/IA2 correlated with antibodies to human pancreas (ICA), whereas antibody response to GAD or insulin was not related to any other antibody response. No positive or inverse correlation, however, was detected between T cell and humoral immunity, except for a positive association of antibodies and T-cell reactivity to insulin. Our data suggest that both humoral and cellular immune reactivity to multiple islet cell antigens are present in patients with newly diagnosed type 1 diabetes and in high risk relatives, but the two immune responses are individually activated.

Adolescent↗
PubMed1996

Autoantibodies against sympathetic ganglia and evidence of cardiac sympathetic dysinnervation in newly diagnosed and long-term IDDM patients.

To investigate the presence of autoantibodies against sympathetic nervous tissue and their correlation with cardiac sympathetic dysinnervation in insulin-dependent diabetes mellitus (IDDM), 20 newly diagnosed (age 26 +/- 6 years) and 48 long-term IDDM patients (age 40 +/- 13 years, duration of diabetes 22 +/- 12 years) without myocardial perfusion abnormalities (normal 99mTC-methoxyisobutylisonitrile uptake) were assessed for myocardial 123I-metaiodo benzylguanidine (123I-MIBG) uptake and complement-fixing sympathetic ganglia (CF-SG) autoantibodies. Both groups of patients were also studied for islet cell antibodies (ICA) and ECG-based cardiac autonomic neuropathy. Eighty control subjects (age 18-49 years) were investigated for CF-SG autoantibodies. Eight newly diagnosed (40%) and 12 long-term (25%) IDDM patients exhibited CF-SG autoantibodies, compared to 4 control subjects (5%; p < 0.01, p < 0.05). In long-term diabetic patients, the reduction of global but not of regional myocardial 123I-MIBG uptake correlated with CF-SG autoantibodies (r = 0.34, p = 0.02). Newly diagnosed diabetic patients did not show an association between CF-SG autoantibodies and global or regional myocardial 123I-MIBG uptake. ECG-based cardiac autonomic neuropathy (> or = two of five cardiac reflex tests abnormal) was present in 22 and absent in 26 long-term IDDM patients, of whom 9 (41%) and 3 (12%), respectively were positive for CF-SG autoantibodies (p = 0.02). Only 1 newly diagnosed IDDM patient demonstrated ECG-based cardiac autonomic neuropathy and was also positive for CF-SG autoantibodies. Although they are somewhat suggestive, results concerning autoantibodies against sympathetic nervous tissue and cardiac sympathetic dysinnervation do not strongly support the view that autoimmune mechanisms play a major role in the pathogenesis of cardiac sympathetic neuropathy in IDDM.

3-Iodobenzylguanidine↗
PubMed1996

The T-cell receptor beta chain CDR3 region of BV8S1/BJ1S5 transcripts in type 1 diabetes.

We recently described the T-cell receptor (TCR) beta chain CDR3 motif S-SDRLG-NQPQH (BV8S1-BJ1S5) in an islet-specific T-cell clone (K2.12) from a type 1 diabetic patient (AS). A similar motif (RLGNQ) was also reported in a T-cell clone of non-obese diabetic (NOD) mice by others. In order to determine the frequency of our motif in selected and unselected T-cell populations, we cloned and sequenced the CDR3 region of BV8S1-BJ1S5 transcripts. These transcripts were derived from unstimulated peripheral blood T lymphocytes from two type 1 diabetic patients (AS and FS) and their non-diabetic sibling (WS), as well as from an islet-specific T-cell line of one of the patients. In addition, we compared the structure and composition of the CDR3 region in BV8S1-BJ1S5 transcripts from peripheral blood T cells between the patients and their non-diabetic sibling (>50 sequences each). We found that 30% of the islet-specific T-cell line cDNA clones expressed the entire sequence-motif, whereas it was absent in the clones of unstimulated peripheral blood T cells from both patients and their non-diabetic sibling. The average length of the CDR3 region was shorter in the patients (mean AS 9.9, FS 9.9, versus WS 10.7, p = 0.0037) and the number of inserted nucleotides in N nucleotide addition at the DJ-junction lower (mean AS 3.5, FS 3. 2, versus WS 5.2, P = <10(-4)) as compared with their non-diabetic sibling. Moreover, the pattern of amino acid usage in the CDR3 region was dissimilar at positions 5 and 6, where polar amino acids predominated in both diabetic siblings. In contrast, basic amino acids are preferentially used at position 5 in the clones of the non-diabetic sibling. These data provide information on the general structure of the TCR(BV8S1-BJ1S5) CDR3 region in type 1 diabetes and may indicate differences in the amino and nucleic acid composition of the TCR beta chain CDR3 region between two type 1 diabetic patients and their non-diabetic sibling.

Adult↗
PubMed1996

Value of ICA512 antibodies for prediction and diagnosis of type 1 diabetes.

ICA512 was isolated from an islet cDNA expression library and was identified as transmembrane protein closely related to the T-cell tyrosine phosphatase CD45. In order to determine the frequency of antibodies (ab) to ICA512, we tested sera of 124 newly diagnosed type 1 diabetic patients (IDDM) and 30 patients with long standing IDDM, 44 non-diabetic first degree relatives (FDR) with positive ICA or IAA, and 76 healthy control subjects using an ELISA. The mean +/- SD that we obtained in our control population was 4.1 +/- 3.9 U and a cut-off of 16 U was defined as normal range (mean + 3 SD). Of newly diagnosed diabetic patients and patients with long standing IDDM, 32% and 23% respectively had positive ICA512-ab with a mean of 22 +/- 33 U (vs controls p < 0.001) and 14 +/- 14 U (p < 0.01). Of antibody-positive first degree relatives, 36% were found to have elevated ICA512-ab with a mean of 24 +/- 41 U (p < 0.01). In relatives with multiple follow-up samples, ICA512-ab were found to be constantly positive or negative in 86% of cases, whereas fluctuation of ICA512-ab positivity occurred in five relatives in which three developed positive ICA512-ab and two lost ICA512-ab positivity during follow-up. Of ICA512-ab + relatives, 76% progressed to clinical type 1 diabetes within 5 years of follow-up, whereas only 24% developed diabetes in the ICA512-ab negative group (p < 0.01). ICA512-ab were more frequent in newly diagnosed diabetic children below age 15 years (p < 0.02) and in patients with positive ICA (p < 0.001) or positive IAA (p < 0.02). There was, in contrast, no correlation of ICA512-ab with GADA. One patient with newly diagnosed type 1 diabetes exclusively exhibited ICA512-ab. In conclusion, these results suggest that ICA512-ab are related to autoimmune type 1 diabetes and useful as an additional screening marker for the prediction of type 1 diabetes.

Adolescent↗
PubMed1996

Prediction of type 1 diabetes.

Prediction of type 1 diabetes is largely based on islet cell antibodies, but may be improved by combined analysis with other markers. We conducted a screening of first-degree relatives of type 1 diabetic patients in Germany using islet cell antibodies (ICA, indirect immunofluorescence on human pancreas) and insulin autoantibodies (IAA, radioimmunoassay) as screening markers. Of 1460 relatives tested, 2.3% (n = 33) were identified to be ICA+ (> or = 10 JDFu) and 1.9% (n = 27) to be IAA+ (> or = 50 nU/ml) in at least two subsequent serum samples. Of 44 antibody-positive relatives, 17 (39%) progressed to clinical insulin-dependent diabetes mellitus (IDDM) within 5 years. Life-table analysis showed a 58% risk of IDDM for ICA+ and 46% risk for IAA+ individuals. ICA combined with IAA gave a risk of 67% (p < 0.02 compared with ICA-, n.s. compared with IAA-). Of all relatives who progressed to clinical IDDM, only one was negative for ICA, but 6 were negative for IAA, resulting in a sensitivity of 94% for ICA and 65% for IAA. All antibody-positive relatives were characterized for HLA DR and DQ markers by genotyping. Relatives with 2 non DR3/ non-DR4 (DRx/x) alleles had no risk of IDDM, although they were consistently positive for one or more antibody specificities. We conclude that IAA screening is less sensitive than screening with ICA and relatives who lack ICA rarely progress to clinical disease. HLA analysis may be useful among antibody-positive relatives to define subgroups with a low risk of progression to exclude those from future intervention trials.

Autoantibodies↗
PubMed1996

Cellular immune response to diverse islet cell antigens in IDDM.

In IDDM, T-cells are postulated to mediate the destruction of pancreatic beta-cells. We analyzed peripheral blood mononuclear cell (PBMC) responses to human insulin, glutamate decarboxylase GAD65, tyrosine phosphatase ICA512, glucagon, membrane preparations of RIN cells and human pancreas, and three control antigens (La = nuclear cell antigen, tetanus toxoid, and phytohemagglutinin). A total of 28 patients with newly diagnosed IDDM, 9 antibody-positive (Ab+) first-degree relatives, and 16 healthy control subjects were included. Increased proliferative responses to pancreatic islet cell antigens were observed in diabetic patients and in Ab+ relatives compared with control subjects, whereas T-cell reactivity to nonpancreatic control antigens was similar between the study groups. The highest differences in the magnitude of proliferative responses were seen for ICA512, followed by membrane preparations of RIN cells, GAD65, and human pancreas. Few subjects reacted with insulin or glucagon. Interestingly, Ab+ relatives showed higher T-cell reactivity with respect to stimulation indexes and prevalences than newly diagnosed diabetic patients, and as many as 89% of Ab+ relatives showed proliferation to more than one islet cell antigen preparation in comparison to 43% of newly diagnosed diabetic patients and none of the control subjects. Statistical analysis revealed significant positive correlation of insulin autoantibody levels with the levels of insulin-specific T-cells in Ab+ relatives, but no relation of PBMC responses to age, sex, or HLA-DR haplotypes. Our results demonstrate the simultaneous existence of various autoreactive T-cells specific for islet cell antigens in the prediabetic period. These T-cells may play a significant role in the pathogenesis of the disease.

Adolescent↗