[Show abstract][Hide abstract] ABSTRACT: The humoral Idiotypic Network consisting of antibodies and their anti-idiotypic antibodies (anti-Id) can be temporarily upset by antigen exposure. In the healthy immune response the original equilibrium is eventually restored through counter-regulatory mechanisms. In certain autoimmune diseases however, autoantibody levels exceed those of their respective anti-Id, indicating a permanent disturbance in the respective humoral Idiotypic Network. We investigated anti-Id directed to a major Type 1 diabetes (T1D)-associated autoantibody (GAD65Ab) in two independent cohorts during progression to disease. Samples taken from participants of the Natural History Study showed significantly lower anti-Id levels in individuals that later progressed to T1D compared to non-progressors (anti-Id antibody index of 0.06 vs. 0.08, respectively, p = 0.02). We also observed a significant inverse correlation between anti-Id levels and age at sampling, but only in progressors (p = 0.014). Finally, anti-Id levels in progressors showed a significant decline during progression as compared to longitudinal anti-Id levels in non-progressors (median rate of change: -0.0004 vs. +0.0004, respectively, p = 0.003), suggesting a loss of anti-Id during progression. Our analysis of the Diabetes Prediction in Skåne cohort showed that early in life (age 2) individuals at risk have anti-Id levels indistinguishable from those in healthy controls, indicating that low anti-Id levels are not an innate characteristic of the immune response in individuals at risk. Notably, anti-Id levels declined significantly in individuals that later developed GAD65Ab suggesting that the decline in anti-Id levels precedes the emergence of GAD65Ab (median rate of change: -0.005) compared to matched controls (median rate of change: +0.001) (p = 0.0016). We conclude that while anti-Id are present early in life, their levels decrease prior to the appearance of GAD65Ab and to the development of T1D.
PLoS ONE 06/2013; 8(6):E65173. · 3.53 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Aims/hypothesis
The aim of this work was to investigate, in children newly diagnosed with type 1 diabetes: (1) the prevalence of autoantibodies against thyroid peroxidase (TPOAb) and thyroglobulin (TGAb); and (2) the association between TPOAb, TGAb or both, with either islet autoantibodies or HLA-DQ genes.
Blood samples from 2,433 children newly diagnosed with type 1 diabetes were analysed for TPOAb and TGAb in addition to autoantibodies against arginine zinc transporter 8 (ZnT8RA), tryptophan zinc transporter 8 (ZnT8WA), glutamine zinc transporter 8 (ZnT8QA), glutamic acid decarboxylase (GADA), insulin (IAA), insulinoma-associated protein-2 (IA-2A), HLA-DQA-B1 genotypes, thyroid-stimulating hormone (TSH) and free thyroxine (T4).
At type 1 diabetes diagnosis, 12% of the children had thyroid autoantibodies (60% were girls; p < 0.0001). GADA was positively associated with TPOAb (p < 0.001) and with TGAb (p < 0.001). In addition, ZnT8A was associated with both TPOAb (p = 0.039) and TGAb (p = 0.015). DQB1*05:01 in any genotype was negatively associated with TPOAb (OR 0.55, 95% CI 0.37, 0.83, p value corrected for multiple comparisons (p
c) = 0.012) and possibly with TGAb (OR 0.55, 95% CI 0.35, 0.87, p
c = 0.07). Thyroid autoimmunity in children newly diagnosed with type 1 diabetes was rarely (0.45%) associated with onset of clinical thyroid disease based on TSH and free T4.
GADA and ZnT8A increased the risk for thyroid autoimmunity at the time of clinical diagnosis of type 1 diabetes, while HLA-DQB1*05:01 reduced the risk. However, the associations between thyroid autoimmunity and HLA-DQ genotype were weak and did not fully explain the co-occurrence of islet and thyroid autoimmunity.
[Show abstract][Hide abstract] ABSTRACT: The major histocompatibility complex class II transactivator (CIITA) gene (16p13) has been reported to associate with susceptibility to multiple sclerosis, rheumatoid arthritis and myocardial infarction, recently also to celiac disease at genome-wide level. However, attempts to replicate association have been inconclusive. Previously, we have observed linkage to the CIITA region in Scandinavian type 1 diabetes (T1D) families. Here we analyze five Swedish T1D cohorts and a combined control material from previous studies of CIITA. We investigate how the genotype distribution within the CIITA gene varies depending on age, and the association to T1D. Unexpectedly, we find a significant difference in the genotype distribution for markers in CIITA (rs11074932, P=4 × 10(-5) and rs3087456, P=0.05) with respect to age, in the collected control material. This observation is replicated in an independent cohort material of about 2000 individuals (P=0.006, P=0.007). We also detect association to T1D for both markers, rs11074932 (P=0.004) and rs3087456 (P=0.001), after adjusting for age at sampling. The association remains independent of the adjacent T1D risk gene CLEC16A. Our results indicate an age-dependent variation in CIITA allele frequencies, a finding of relevance for the contrasting outcomes of previously published association studies.Genes and Immunity advance online publication, 11 October 2012; doi:10.1038/gene.2012.44.
Genes and immunity 10/2012; 13(8):632-40. · 4.22 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To test whether the TCF7L2 gene was associated with gestational diabetes, whether the association between TCF7L2 and gestational diabetes was independent of HLA-DQB1*0602 and islet cell autoantibodies, as well as maternal age, number of pregnancies, family history of diabetes and the HLA-DQB1 genotypes, and to test whether the distribution of HLA-DQB1 alleles was affected by country of birth.
We genotyped the rs7903146, rs12255372 and rs7901695 single nucleotide polymorphisms of the TCF7L2 gene in 826 mothers with gestational diabetes and in 1185 healthy control subjects in the Diabetes Prediction in Skåne Study. The mothers were also typed for HLA-DQB1 genotypes and tested for islet cell autoantibodies against GAD65, insulinoma-associated antigen-2 and insulin.
The heterozygous genotypes CT, GT and TC of the rs7903146 (T is risk for Type 2 diabetes), rs12255372 (T is risk for Type 2 diabetes) and rs7901695 (C is risk for Type 2 diabetes), respectively, as well as the homozygous genotypes TT, TT and CC of the rs7903146, rs12255372 and rs7901695, respectively, were strongly associated with gestational diabetes (P < 0.0001). These associations remained statistically significant after adjusting for maternal age, number of pregnancies, family history of diabetes and HLA-DQ genotypes and were independent of the presence of islet cell autoantibodies. No interaction was observed between TCF7L2 and HLA-DQB1*0602, which was shown to be negatively associated with gestational diabetes in mothers born in Sweden (P = 0.010).
The TCF7L2 was associated with susceptibility for gestational diabetes independently of the presence of HLA-DQB1*0602 and islet cell autoantibodies and other factors such as maternal age, number of pregnancies, family history of diabetes and other HLA-DQ genotypes. The HLA-DQB1*0602 was negatively associated with gestational diabetes in mothers born in Sweden.
Diabetic Medicine 06/2011; 28(9):1018-27. · 3.24 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The 65-kD isoform of glutamic acid decarboxylase (GAD) is a major autoantigen in patients with type 1 diabetes mellitus. This trial assessed the ability of alum-formulated GAD (GAD-alum) to reverse recent-onset type 1 diabetes in patients 10 to 18 years of age.
We randomly assigned 70 patients with type 1 diabetes who had fasting C-peptide levels above 0.1 nmol per liter (0.3 ng per milliliter) and GAD autoantibodies, recruited within 18 months after receiving the diagnosis of diabetes, to receive subcutaneous injections of 20 microg of GAD-alum (35 patients) or placebo (alum alone, 35 patients) on study days 1 and 30. At day 1 and months 3, 9, 15, 21, and 30, patients underwent a mixed-meal tolerance test to stimulate residual insulin secretion (measured as the C-peptide level). The effect of GAD-alum on the immune system was also studied.
Insulin secretion gradually decreased in both study groups. The study treatment had no significant effect on change in fasting C-peptide level after 15 months (the primary end point). Fasting C-peptide levels declined from baseline levels significantly less over 30 months in the GAD-alum group than in the placebo group (-0.21 vs. -0.27 nmol per liter [-0.62 vs. -0.81 ng per milliliter], P=0.045), as did stimulated secretion measured as the area under the curve (-0.72 vs. -1.02 nmol per liter per 2 hours [-2.20 vs. -3.08 ng per milliliter per 2 hours], P=0.04). No protective effect was seen in patients treated 6 months or more after receiving the diagnosis. Adverse events appeared to be mild and similar in frequency between the two groups. The GAD-alum treatment induced a GAD-specific immune response.
GAD-alum may contribute to the preservation of residual insulin secretion in patients with recent-onset type 1 diabetes, although it did not change the insulin requirement. (ClinicalTrials.gov number, NCT00435981.)
New England Journal of Medicine 11/2008; 359(18):1909-20. · 51.66 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Achondroplasia is a skeletal dysplasia with extreme, disproportionate, short stature.
In a 5-y growth hormone (GH) treatment study including 1 y without treatment, we investigated growth and body proportion response in 35 children with achondroplasia.
Patients were randomized to either 0.1 IU/kg (n = 18) or 0.2 IU/kg (n = 17) per day. GH treatment was interrupted for 12 mo after 2 y of treatment in prepubertal patients to study catch-down growth. Mean height SDS (HSDS) at start was -5.6 and -5.2 for the low- and high-dose groups, respectively, and mean age 7.3 and 6.6 y.
Mean growth velocity (baseline 4.5/4.6 cm/y for the groups) increased significantly by 1.9/3.6 cm/y during the first year and by 0.5/1.5 cm/y during the second year. During the third year, a decrease of growth velocity was observed at 1.9/1.3 cm/y below baseline values. HSDS increased significantly by 0.6/0.8 during the first year of treatment and in total by 1.3/1.6 during the 5 y of study. Sitting height SDS improved significantly from -2.1/-1.7 to -0.8/0.2 during the study. Body proportion (sitting height/total height) or arm span did not show any significant change.
GH treatment of children with achondroplasia improves height during 4 y of therapy without adverse effect on trunk-leg disproportion. The short-term effect is comparable to that reported in Turner and Noonan syndrome and in idiopathic short stature.
[Show abstract][Hide abstract] ABSTRACT: To measure autoantibodies against tissue transglutaminase (tTG) in young children prospectively screened for coeliac disease (CD).
In total, 652 children aged 2.9 (2.5-4.2) y were analysed for IgA-tTG and IgG-tTG with radioligand-binding assays and IgA endomysial antibodies (EMA) by indirect immunofluorescence. Antibody-positive children were retested after 1.2 (range 0.2-1.9) y. Intestinal biopsy was performed on children with persistently high antibody levels.
In total, 3.2% (95% CI: 1.9-4.6%) of the 652 children were positive for at least one antibody at baseline: 2.5% (95% CI: 1.3-3.7%) for IgA-tTG, 1.7% (95% CI: 0.7-2.7%) for IgG-tTG and 2.9% (95% CI: 1.6-4.2%) for IgA-EMA, respectively. Ten children were positive for all three antibodies, five for both IgA-tTG and EMA, four for EMA only, one for IgA-tTG and another for IgG-tTG. IgA-EMA titres correlated with IgA-tTG levels (r = 0.73, p = 0.0003). At follow-up, seven of 20 children remained positive for all three antibodies, three for IgA-tTG only, one for both IgA-tTG and EMA, one for IgA-tTG and IgG-tTG, and the remaining child refused further participation. Three biopsies showed villous atrophy, two increased intraepithelial lymphocytes and two normal findings. Biopsy was not performed in four children with low or declining tTG antibody levels at follow-up and in one child who declined. CD was evident in 0.5% (95% CI: 0.0-1.0%) (3/652).
This study revealed a high number of young children positive for tTG antibodies as well as EMA, but the majority showed declining levels in both antibodies over time. We suggest using radioligand-binding assays for quantitative measurement of tTG antibodies when change in antibody levels is studied in young children.
[Show abstract][Hide abstract] ABSTRACT: The association between autoantibodies against tissue transglutaminase (tTG) and human leucocyte antigen (HLA)-DQB1 alleles was tested in Down's syndrome (DS) patients with and without coeliac disease (CD). Immunoglobulin A (IgA) and G (IgG) anti-tTG were measured in radioligand binding assays and compared with conventionally analysed IgA antibodies against gliadin (AGA) and IgA autoantibodies against endomysium (EMA) in 48 DS patients. HLA-DQB1 typing was carried out by polymerase chain reaction and hybridization with allele-specific probes in 41/48 patients. Both IgA-tTG and IgG-tTG, as well as EMA, were detected in 7/48 and AGA in 15/48 patients. Intestinal biopsy showed histopathological changes consistent with CD in 9/16 patients. HLA-DQB1 typing, available for 8/9 patients with and for 33/39 without CD, demonstrated that 5/8 with CD had DQB1*02 compared with 7/33 of those without (p = 0.0345). In patients with anti-tTG, 5/6 had the DQB1*02 allele compared with 7/35 of those without (p = 0.0053). Conclusions: Anti-tTG are HLA-DQB1*02-associated autoantibodies which together could be useful screening tests for silent CD in DS patients. In patients with gastrointestinal symptoms or clinical signs of malabsorption, anti-tTG should be combined with AGA to detect other forms of enteropathies and CD.
[Show abstract][Hide abstract] ABSTRACT: To estimate the burden of disease due to congenital toxoplasmosis in Sweden the incidence of primary infections during pregnancy and birth prevalence of congenital toxoplasmosis in 40,978 children born in two regions in Sweden was determined. Women possibly infected during pregnancy were identified based on: 1, detection of specific IgG based on neonatal screening of the phenylketonuria (PKU) card blood spot followed by retrospective testing of stored prenatal samples to detect women who acquired infection during pregnancy and follow up of their children to 12 months: 2, detection of specific IgM on the PKU blood spot. The birth prevalence of congenital toxoplasmosis was 0.73/10,000 (95 % CI 0.15-2.14) (3/40,978). The incidence of primary infection during pregnancy was 5.1/10,000 (95% CI 2.6-8.9) susceptible pregnant women. The seroprevalence in the southern part was 25.7% and in the Stockholm area 14.0%. The incidence of infection during pregnancy was low, as the birth prevalence of congenital toxoplasmosis. Neonatal screening warrants consideration in view of the low cost and feasibility.
Epidemiology and Infection 09/2001; 127(1):121-7. · 2.87 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Blood samples from 141 children and adolescents were used to evaluate differences between commercial kits and radioimmunoassay (RIA) methods for detecting thyroid autoantibodies. Thyroglobulin autoantibodies (Tg-Ab) were analyzed with a hemagglutination kit and a RIA; thyroid peroxidase autoantibodies (TPO-Ab) were measured with a gelagglutination assay and a RIA. The results of the antibody tests were compared with thyroid function tests (triiodothyronine [T3], thyroxine [T4], thyrotropin [TSH]) and with the results of ultrasound of the thyroid in antibody-positive patients. The correlation of antibody levels between the two methods was higher for TPO-Ab than for Tg-Ab. Moderate to high levels of TPO-Ab correlated to elevated TSH levels. Autoimmune thyroiditis (AIT) was found in 6 of the 141 children. The RIA-based thyroglobulin assay was the only test that identified autoantibodies in all 6 cases. In contrast, the hemagglutination kit thyroglobulin assay failed to identify 4 of the 6 AIT cases.
[Show abstract][Hide abstract] ABSTRACT: The aim of this study was to examine the putative role of mutations in the insulin promoter 1 (IPF1) gene in early-onset diabetes.
We carried out mutation screening of the IPF1 gene in 115 Scandinavian families with at least two members with onset of diabetes younger than 40 years. The allele frequencies were also tested in 183 unrelated patients with late-onset Type II (non-insulin-dependent) diabetes mellitus and in 92 non-diabetic control subjects.
Two novel IPF1 variants (G212R and P239Q) and one previously reported (D76N) IPF1 variant were identified in the 115 families (3.5%). The D76N variant was found in one MODY3 family (S315fsinsA of HNF1alpha) and also in two families with late-onset Type II diabetes. The P239Q variant was identified in two families with early-onset diabetes including one with MODY3 (R272C of HNF1alpha) and in three families with late-onset Type II diabetes. Despite the fact that the variants did not segregate completely with diabetes, the non-diabetic carriers of the IPF1 variants had increased blood glucose concentrations (p < 0.05) and reduced insulin:glucose ratios (p < 0.05) during an oral glucose tolerance test compared with non-diabetic family members without these variants. In addition, when the G212R and P239Q variants were expressed in cells without IPF1 i.e.. Nes2y cells, both variants showed about a 50% reduction in their ability to activate insulin gene transcription compared to wild-type IPF1, as measured by reporter gene assay.
Although mutations in the IPF-1 gene are rare in early- (3.5 %) and late-onset (2.7 % ) Type II diabetes, they are functionally important and occur also in families with other MODY mutations.
[Show abstract][Hide abstract] ABSTRACT: The study was designed to investigate the prevalence of celiac disease (CD) among 2.5-year-old children in a Swedish urban population with a high incidence of CD.
Six hundred ninety apparently healthy children, born in the 12-month period of July 1992 through June 1993, were screened for immunoglobulin A (IgA) antigliadin antibodies and IgA antiendomysium antibodies, and those antibody-positive at repeated testing were further investigated with intestinal biopsy.
Of the 690 children, 6 were both IgA antigliadin antibody- and IgA antiendomysium antibody-positive, and 7 were antiendomysium antibody-positive but antigliadin antibody-negative. Jejunal biopsy, performed in 12 cases, manifested partial or total villous atrophy in 8 cases. Thus, together with an additional child whose parents declined the offered biopsy, but whose response to a gluten-free diet confirmed the presence of CD, the prevalence of CD in the study series was 1.3% (9/690; 95% confidence interval:.4-2.2). However, independent of the study, an additional 22 cases of symptomatic, biopsy-verified CD have already been detected in the birth cohort of 3004 children.
The prevalence of CD in our study series was high, at least 1.0%, but may be as high as 2.0% if the frequency of silent CD is as high as we have found in the remaining unscreened cohort. These findings confirm that CD is one of the most common chronic disorders.
[Show abstract][Hide abstract] ABSTRACT: Dyschondrosteosis (DCO) and hypochondroplasia (HCH) are common skeletal dysplasias characterized by disproportionate short stature. The diagnosis of these conditions might be difficult to establish especially in early childhood. Point mutations and deletions of the short stature homeobox containing gene (SHOX) are detected in DCO and idiopathic short stature with some rhizomelic body disproportion, whereas mutations in the fibroblast growth factor receptor 3 (FGFR3) gene are found in 40-70% of HCH cases. In this study, we performed mutational analysis of the coding region of the SHOX gene in five DCO and 18 HCH patients, all of whom tested negative for the known HCH-associated FGFR3 mutations. The polymorphic CA-repeat analysis, direct sequencing and Southern blotting were used for detection of deletions and point mutations. The auxological and radiological phenotype of these patients was carefully determined. Three novel mutations in DCO patients were found: (1) a deletion of one base (de1272G) (according to GenBank accession nos. Y11536, Y11535), resulting in a premature stop codon at position 75 of the amino acid sequence; (2) the transversion C485G resulting in the substitution Leu132Val; and (3) the transversion G549T causing an Arg153Leu substitution. These substitutions segregate with the DCO phenotype and affect evolutionarily conserved homeodomain residues, based on a comparison of homeobox containing proteins in 13 species. Moreover, these changes were not found in 80 unrelated, unaffected individuals. This strongly suggests that these mutations are pathogenic. The phenotype of our patients with DCO and HCH varied from mild to severe shortness and body disproportion. These results further support clinical and genetic heterogeneity of dyschondrosteosis and hypochondroplasia.
Human Genetics 09/2000; 107(2):145-9. · 4.63 Impact Factor