Ag Ziegler

Development of celiac disease-associated antibodies in offspring of parents with Type I diabetes

Aims/hypothesis. The aim of this study was to determine the frequency and temporal development of antibodies related to celiac disease in offspring of parents with Type I (insulin-dependent) diabetes mellitus. Methods. Sera from 913 offspring of parents with Type I diabetes prospectively followed from birth to the age of 8 years were tested for IgG-transglutaminase antibodies (IgG-tTGCAs), endomysial IgA antibodies (EMA) and gliadin antibodies. Results. We found tTGCAs in 32 (3.5 %) of the 913 relatives. Prevalence was related to age and reached 6.5 % at age 8 years. Endomysial IgA antibodies were detected in 44 % of the relatives with tTGCAs and 0.6 % of tTGCA negative relatives and were also most prevalent (5 %) in those aged 8 years. Both tTGCAs and EMAs were more frequent in relatives with the HLA DRB1*03 DQA1*0501 DQB1*02 haplotype (7.1 % and 7.2 %, respectively; p < 0.005). Anti-gliadin antibodies were common in both tTGCA positive (42 %) and negative (23 %) relatives, did not show a relation with age and were less prevalent in relatives with HLA DR3 (p < 0.05). There was no association between the presence of antibodies associated with celiac disease and islet autoantibodies in these relatives. Of the relatives 15 (1.6 %) had tTGCAs plus EMAs. In two of these, anti-gliadin antibodies were detected before the detection of tTGCAs and EMAs at the age of 9 months whereas none of the remainder had any antibodies associated with celiac disease before age 2 years. In three there were no detectable anti-gliadin antibodies in any of the samples tested. Celiac disease without clinical symptoms was diagnosed in 9 of 12 by intestinal biopsy. Conclusion/interpretation. A statistically significant proportion of relatives of patients with Type I diabetes have celiac disease-associated autoimmunity and the silent form of celiac disease early in life. These relatives should, therefore, be considered for celiac antibody screening. [Diabetologia (2000) 43: 1005–1011]

Breastfeeding habits in families with Type 1 diabetes

Aims  Breastfeeding is acknowledged to be beneficial for child development. Women with diabetes may be more likely not to breastfeed their children because of neonatal morbidity and instability in diabetes control. The aim of this study was to assess the effect of maternal Type 1 diabetes on breastfeeding habits.

A strategy for combining minor genetic susceptibility genes to improve prediction of disease in type 1 diabetes.

Genome-wide association studies have identified gene regions associated with type 1 diabetes. The aim of this study was to determine how the combined allele frequency of multiple susceptibility genes can stratify islet autoimmunity and/or type 1 diabetes risk. Children of parents with type 1 diabetes and prospectively followed from birth for the development of islet autoantibodies and diabetes were genotyped for single-nucleotide polymorphisms at 12 type 1 diabetes susceptibility genes (ERBB3, PTPN2, IFIH1, PTPN22, KIAA0350, CD25, CTLA4, SH2B3, IL2, IL18RAP, IL10 and COBL). Non-human leukocyte antigen (HLA) risk score was defined by the total number of risk alleles at these genes. Receiver operator curve analysis showed that the non-HLA gene combinations were highly effective in discriminating diabetes and most effective in children with a high-risk HLA genotype. The greatest diabetes discrimination was obtained by the sum of risk alleles for eight genes (IFIH1, CTLA4, PTPN22, IL18RAP, SH2B3, KIAA0350, COBL and ERBB3) in the HLA-risk children. Non-HLA-risk allele scores stratified risk for developing islet autoantibodies and diabetes, and progression from islet autoimmunity to diabetes. Genotyping at multiple susceptibility loci in children from affected families can identify neonates with sufficient genetic risk of type 1 diabetes to be considered for early intervention.

Human Monoclonal Antibodies Isolated from Type I Diabetes Patients Define Multiple Epitopes in the Protein Tyrosine Phosphatase-Like IA-2 Antigen

Protein tyrosine phosphatase-like IA-2 autoantigen is one of the major targets of humoral autoimmunity in patients with insulin-dependant diabetes mellitus (IDDM). In an effort to define the epitopes recognized by autoantibodies against IA-2, we generated five human mAbs (hAbs) from peripheral B lymphocytes isolated from patients most of whom had been recently diagnosed for IDDM. Determination and fine mapping of the critical regions for autoantibody binding was performed by RIA using mutant and chimeric constructs of IA-2- and IA-2β-regions. Four of the five IgG autoantibodies recognized distinct epitopes within the protein tyrosine phosphatase (PTP)-like domain of IA-2. The minimal region required for binding by three of the PTP-like domain-specific hAbs could be located to aa 777–979. Two of these hAbs cross-reacted with the related IA-2β PTP-like domain (IA-2β aa 741-1033). A further PTP-like domain specific hAb required the entire PTP-like domain (aa 687–979) for binding, but critical amino acids clustered in the N-terminal region 687–777. An additional epitope could be localized within the juxtamembrane domain (aa 603–779). In competition experiments, the epitope recognized by one of the hAbs was shown to be targeted by 10 of 14 anti-IA-2-positive sera. Nucleotide sequence analysis of this hAb revealed that it used a VH germline gene (DP-71) preferably expressed in autoantibodies associated with IDDM. The presence of somatic mutations in both heavy and light chain genes and the high affinity or this Ab suggest that the immune response to IA-2 is Ag driven.

Breastfeeding in women with gestational diabetes

BACKGROUND AND OBJECTIVE Children born to mothers with gestational diabetes are at an increased risk of developing obesity. Breastfeeding is acknowledged as beneficial for child development and it is suggested that breastfeeding protects against becoming obese. The aim of this study was to document breastfeeding habits of women with gestational diabetes and to identify factors that affect breastfeeding habits. METHODS Breastfeeding habits (breastfeeding of any duration) were recorded of 257 mothers with gestational diabetes (mean age 31.4 +/- 4.8 years) who participated in a prospective post-partum study between 1989 and 1999 and compared to breastfeeding habits of 527 healthy mothers (mean age 30.3 +/- 4.2 years), all enrolled in the prospective BABYDIAB study between the years 1989 and 2000. Breastfeeding data were prospectively obtained by questionnaire and interview. RESULTS Compared to children of healthy mothers, fewer children of mothers with gestational diabetes were breastfed (75% vs 86%; P<0.0001). Among breastfed children the duration of full or any breastfeeding was shorter in children of mothers with gestational diabetes (median for full breastfeeding 9 weeks. [mothers with gestational diabetes] vs. 17 weeks. [healthy mothers]; p<0.0001; median duration of any breastfeeding 16 weeks. vs. 26 weeks.; p<0.0001). After stratification for other risk factors the duration of breastfeeding significantly differed between mothers with gestational DM and those who were healthy (hazard ratio [HR] 1.4; p<0.05 for full breastfeeding; HR 1.5; p<0.0001 for any breastfeeding). Full and any breastfeeding was shorter in women with insulin-dependent gestational diabetes than in those with diet-controlled gestational diabetes (full breast-feeding 4 weeks. vs. 12 weeks.; p<0.01 and any breastfeeding 10 weeks. vs. 20 weeks,; p<0.0001). Fewer women with gestational diabetes and a body weight index (BMI) >30 kg/m2 breastfed (65% vs 80%; p=0.01) and for a shorter duration than women with a BMI <30 kg/m2 (any breastfeeding 12 weeks. vs. 17 weeks; p=0.02). The type of DM therapy independently correlated with reduced breastfeeding duration (HR 1.7; p=0<0.01). CONCLUSIONS Mothers with gestational diabetes, especially mothers with insulin-dependent gestational diabetes, and obese mothers breastfed their children significantly less and for a shorter duration than healthy mothers. These findings could explain the higher risk of their children developing obesity later in life and should be considered when counselling women with gestational diabetes.

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-γ) 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-γ 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.

Übersicht über aktuelle Studien zur Prävention und Immunintervention des Diabetes mellitus Typ 1

Immunomodulatory strategies in the management of type 1 diabetes mellitus (T1DM) have as their primary target the prevention of initiating islet autoimmunity (primary-), the secondary one is the progression to diabetes (secondary-) in non-diabetic persons at risk, and the decline of beta-cell function in new-onset patients (tertiary-prevention). This article reviews four recent immunointervention trials in patients with T1DM. (1) The Pre-POINT study is a primary prevention trial that will test whether vaccination with oral or nasal insulin can prevent the progression of islet autoimmunity and of T1DM in autoantibody-negative children who are genetically at high diabetes risk. (2) The Cord Blood study is a tertiary immunointervention trial that will test whether administration of autologous umbilical cord blood to children with T1DM can lead to regeneration of pancreatic islet insulin-producing beta-cells and improved blood glucose control. (3) The GAD Vaccination study will test whether vaccination with alum-formulated rhGAD65 (recombinant human glutamic acid decarboxylate) can preserve beta-cell function in 320 children with newly diagnosed T1DM, as has been suggested in a recent phase II study. (4) The AIDA study will test the beta-cell protective effect of interleukin-1-receptor antagonist Anakinra in 80 patients with T1DM, which has recently been shown to improve beta-cell function in patients with type 2 diabetes.