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  • 1
    Electronic Resource
    Electronic Resource
    Antibodies to GAD65 Epitopes at Diagnosis and Over the First 10 years of Clinical Type 1 Diabetes Mellitus (2004)
    Oxford, UK; Malden , USA : Blackwell Science Ltd
    Scandinavian journal of immunology 59 (2004), S. 0 
    Details
    ISSN: 1365-3083
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Antibodies to glutamate decarboxylase (GAD65Ab) may persist, and their titres even increase after the clinical onset of type 1 diabetes. To characterize this phenomenon in detail, we analysed sequentially antibodies to GAD65 epitope clusters in a radio-binding assay in patients with type 1 diabetes. Serum samples were taken at diagnosis and 2, 5 and 10 years later from 50 young patients who had tested positive for GAD65Ab at least once during observation. The levels of GAD65Ab peaked in 21 patients after diagnosis. Antibodies to the middle region of GAD65 (GAD65-M-Ab, 88%) were more common at diagnosis than antibodies to the C-terminal (GAD65-C-Ab, 68%, P 〈 0.05) or N-terminal region (4%, P 〈 0.001). Antibodies to middle and especially to C-terminal epitopes decreased in those with decreasing levels of GAD65Ab (P 〈 0.001), whereas the frequencies of GAD65-M-Ab and GAD65-C-Ab remained quite stable among the subjects with increasing levels. Lower exogenous insulin dose and HbA1 levels and stronger humoral immune response to islet cells were observed in those with increasing levels of GAD65-M-Ab than in those with decreasing levels (P 〈 0.05). The present observation supports the view that the middle region of GAD65 comprises immunodominant epitopes. An enhanced humoral immune response to GAD65 after diagnosis is related to persistent immune reactivity to the middle and C-terminal regions.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1111/j.0300-9475.2004.01402.x
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  • 2
    Electronic Resource
    Electronic Resource
    Cytokine Expression in Unstimulated PBMC of Children with Type 1 Diabetes and Subjects Positive for Diabetes-Associated Autoantibodies (2001)
    Oxford, UK : Blackwell Science Ltd
    Scandinavian journal of immunology 53 (2001), S. 0 
    Details
    ISSN: 1365-3083
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: The aim of this study was to evaluate possible changes in the circulating levels of interferon (IFN)-γ, interleukin (IL)-4 and transforming growth factor (TGF)-β in association with the autoimmune process leading to type 1 diabetes. Expression levels of mRNAs specific for each cytokine were determined in peripheral blood mononuclear cells (PBMC) by a multiplex reverse transcription–polymerase chain reaction (RT–PCR) followed by hybridization reactions with lanthanide-labelled probes and detection by time-resolved fluorometry. Newly diagnosed diabetic children had lower levels of IFN-γ, IL-4 and TGF-β1 signals compared to their age- and sex-matched controls (P 〈 0.02, P 〈 0.005 and P 〈 0.005, respectively) and also the autoantibody-positive subjects had significantly lower levels of IL-4 and TGF-β1 in comparison with their matched controls (P = 0.0013 and P = 0.012). No significant differences were observed when comparing matched pairs of diabetic children and autoantibody-positive subjects. Our results suggest a systemic bias towards reduced production of T-helper cell type 2 cytokines (IL-4 and TGF-β1) during the autoimmune process, but there was also a reduced level of IFN-γ expression in the periphery at the onset of clinical diabetes.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1046/j.1365-3083.2001.00904.x
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  • 3
    Electronic Resource
    Electronic Resource
    The occurrence of type 1 diabetes in patients with dermatitis herpetiformis and their first-degree relatives (2004)
    Oxford, UK : Blackwell Science Ltd
    British journal of dermatology 150 (2004), S. 0 
    Details
    ISSN: 1365-2133
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Background  The increased prevalence of type 1 diabetes (T1D) is well documented in patients with coeliac disease, whereas evidence is scanty in patients with dermatitis herpetiformis (DH).Objectives  To assess the prevalence of T1D in patients with DH and their first-degree relatives, and to study how DH patients with associated T1D respond to a gluten-free diet (GFD) treatment.Methods  A series of 1104 consecutive patients with DH was recorded and a specific questionnaire sent to 341 of these for familial disease surveillance. Sex- and age-matched patients with isolated DH served as controls in the diet treatment analysis.Results  Twenty-five (2·3%) patients with DH were affected by T1D and three (3·0%) of their first-degree relatives also were affected by T1D, the frequencies being significantly higher than in the general population. Most DH patients with T1D and with isolated DH could adhere strictly to the GFD. The response was good or moderate in 84% of the DH patients with T1D and in 94% of the patients with isolated DH.Conclusions  The prevalence of T1D is increased in patients with DH and their first-degree relatives. The rash in DH patients with T1D responds to a GFD in a way similar to that seen in patients with isolated DH.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1111/j.1365-2133.2004.05642.x
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  • 4
    Electronic Resource
    Electronic Resource
    Tumour Necrosis Factor-β Gene RFLP Alleles in Finnish IDDM Hapiotypes (1992)
    Oxford, UK : Blackwell Publishing Ltd
    Scandinavian journal of immunology 36 (1992), S. 0 
    Details
    ISSN: 1365-3083
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: The genes located between class II and class I HLA genes including polymorphic tumour necrosis factor (TNF) genes may contribute to the disease susceptibility in IDDM. Restriction fragment polymorphisms of the TNF-β gene have been found to be fixed in the major IDDM susceptibility haplotypes, the B62,DR4 haplotype being associated with the 10.5-kb fragment and the B8,DR3 haplotype with a 5.5-kb fragment. We studied this TNF polymorphism in a sample of diabetic families. In all IDDM-associated haplotypes (n= 129) the 5.5-kb allele was more frequent than in haplotypes found only in healthy family members (n=112) (58.1% versus 40.2%, P〈0.01). Among IDDM haplotypes the B62,DR4 haplotype was characterized by the 10.5-kb TNF fragment, whereas two other common Finnish IDDM-associated DR4 haplotypes-A24,B39,DR4 and A2,B56,DR4-had the 5.5-kb TNF fragment. Both IDDM-associated and non-associated DR3 positive haplotypes were linked to the 5.5-kb fragment. The distribution of various combinations of TNF alleles in IDDM probands (n= 63) did not differ from that expected according to the Hardy-Weinberg distribution. Our results indicate that the 10.5-kb allele of TNF-β gene as such is not a risk factor contributing to DR4/DQ8-associated susceptibility. Alternatively, there may be heterogeneity in pathogenetic effector mechanisms.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1111/j.1365-3083.1992.tb03139.x
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  • 5
    Electronic Resource
    Electronic Resource
    Evidence of delayed β-cell destruction in Type 1 (insulin-dependent) diabetic patients with persisting complement-fixing cytoplasmic islet cell antibodies (1984)
    Springer
    Diabetologia 27 (1984), S. 421-426 
    Details
    ISSN: 1432-0428
    Keywords: Type 1 diabetes ; complement-fixing islet cell antibodies ; endogenous insulin secretion
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Forty-four children with Type 1 (insulin-dependent) diabetes (aged 0.7–16.7 years) were observed from diagnosis for cytoplasmic islet cell antibodies and serum C-peptide concentrations. Islet cell antibodies were analysed by indirect immunofluorescence for both conventional IgG and complement-fixing antibodies. Thirty-seven children (84%) were found to be positive for conventional islet cell antibodies at diagnosis, and 21 (48%) remained positive over the observation period. Twenty-six patients (59%) were positive for complement-fixing antibodies at diagnosis and eight remained so during the follow-up period. The serum C-peptide concentrations increased significantly during the first 3 months after diagnosis, after which there was a gradual decrease in the levels. Those children who remained positive for complement-fixing antibodies over the observation period had significantly higher serum C-peptide concentrations on several occasions during the second year and had also a higher integrated serum C-peptide concentration over the initial 2 years than those who became negative for complement-fixing antibodies. These observations suggest that the continuous production of complement-fixing islet cell antibodies in those patients who are positive for these antibodies at diagnosis presupposes the preservation of a sufficient amount of functioning β cells for antigenic stimulation. These results support the view that the complement-fixing islet cell antibodies reflect ongoing destructive processes in the β cells.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00273904
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  • 6
    Electronic Resource
    Electronic Resource
    Evidence of an accelerated B-cell destruction in HLA-Dw3/Dw4 heterozygous children with Type 1 (insulin-dependent) diabetes (1986)
    Springer
    Diabetologia 29 (1986), S. 347-351 
    Details
    ISSN: 1432-0428
    Keywords: Type 1 diabetes ; C-peptide ; HLA ; clinical remission ; metabolic control
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The possible association between residual B-cell function and specific HLA antigens in Type 1 (insulin-dependent) diabetes was studied in a cross-sectional series of 144 diabetic children and adolescents, as well as in a prospective series of 44 newly diagnosed diabetic subjects who were observed for the initial 2 years of their diabetes. In the cross-sectional study, the HLA-Dw3/Dw4 heterozygotes had a lower mean serum C-peptide concentration during 1980, 0.03 ±0.01 nmol/l (mean ± SEM) vs. 0.09 ± 0.01 nmol/1 (p 〈 0.02), as well as a lower 24-h urinary C-peptide excretion, 0.27 ±0.06 nmol/m2 vs. 1.34 ± 0.19 nmol/m2 (p 〈 0.05), than the other subjects. In addition, the Dw3/Dw4 heterozygotes had a clinical remission of shorter duration, 113 ± 47 days vs. 203 ± 22 days (p 〈 0.05), and a higher mean glycosylated haemoglobin level during 1980, 14.8 ± 0.05% vs. 13.7 ± 0.2% (p 〈 0.05), than those without the Dw3/Dw4 combination. In the prospective study the serum C-peptide concentrations were of the same magnitude in the Dw3/Dw4 heterozygotes and the other subjects during the first month. Subsequently the C-peptide concentrations in the subjects with the Dw3/Dw4 combination started to decrease 2 months earlier than in the other subjects. The Dw3/Dw4 children had a significantly lower serum C-peptide concentration at 21 months, 0.01 ± 0.01 nmol/1 vs. 0.13 ± 0.02 nmol/1 (p〈0.01), and at 24 months, 0.03 ±0.01 nmol/1 vs. 0.12 ± 0.02 nmol/l (p 〈 0.05). Our observations suggest that Dw3/Dw4 heterozygosity is, at least in children, associated with a distinct form of Type 1 diabetes characterized by a rapid B-cell destruction, a clinical remission of short duration and poor metabolic control. This expands the concept of genetic heterogeneity within Type 1 diabetes in childhood, and may have important implications for research on the aetiology, pathogenesis and natural history of the disease.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00903342
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  • 7
    Electronic Resource
    Electronic Resource
    HLA-DQ beta-chain restriction fragment length polymorphism as a risk marker in Type 1 (insulin-dependent) diabetes mellitus: a Finnish family study (1990)
    Springer
    Diabetologia 33 (1990), S. 357-362 
    Details
    ISSN: 1432-0428
    Keywords: Type 1 (insulin-dependent) diabetes ; restriction fragment length polymorphism ; HLA-DQ ; prediction of Type 1 diabetes ; genetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Finnish Type 1 (insulin-dependent) diabetic families were analysed for HLA-DQ beta-chain polymorphism using a short intron-specific probe. A simple hybridization pattern was obtained in which all fragments were associated significantly with Type 1 diabetes. The simultaneous presence of two different risk markers, the allelic 12-kilobase and 4-kilobase fragments were strongly associated with Type 1 diabetes since 50% of the patients had this combination compared with only 2% of the control subjects. The cosegregated 7.5/3.0 kilobase fragments, which were associated with HLA-DR2 and DRw6 were not detected among the diabetic patients but were present in 48% of the control subjects. Our results provide further support for the location of susceptibility determining factors in the HLA-DQ gene area. The clear-cut, simple restriction fragment length polymorphism pattern obtained here, which bears a resemblance to a two allelic system, therefore makes this method applicable for estimating the risk of Type 1 diabetes at the population level.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00404640
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  • 8
    Electronic Resource
    Electronic Resource
    HLA haplotypes in Type 1 (insulin-dependent) diabetes mellitus: molecular analysis of the HLA-DQ locus (1992)
    Springer
    Diabetologia 35 (1992), S. 254-260 
    Details
    ISSN: 1432-0428
    Keywords: Type 1 (insulin-dependent) diabetes mellitus ; HLA haplotypes ; HLA-DQ ; restriction fragment length polymorphism ; genetics ; disease susceptibility
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary In Caucasians the predisposition to Type 1 (insulin-dependent) diabetes mellitus has been shown to associate with HLA-DR3,DQw2 and DR4,DQw8 and with the presence of amino acids other than aspartic acid at position 57 on the HLA-DQβ chain. In Finland the haplotype-specific absolute risk for developing Type 1 diabetes differs between various DR3 and DR4 positive haplotypes. The aim of our present analysis was to find out whether this variation is attributable to polymorphism at the DQ locus. As part of a nationwide prospective study including 757 serologically HLA genotyped families, we determined HLA-DQα and DQβ restriction fragment polymorphisms in 17 selected families with important susceptibility haplotypes. Additionally, the DQA1 alleles were determined from 19 haplotypes using sequence-specific oligonucleotide probes, and the DQB1 second exon was sequenced from nine haplotypes. The DR3 as well as DR4 positive haplotypes frequently found in Type 1 diabetic patients showed no variation at the HLA-DQ locus, and they were DQw2 and DQw8, respectively. The absolute risk for Type 1 diabetes for DR4,DQw8 positive haplotypes A2,Cw4,Bw35,DR4 A3,Cw3,Bw62,DR4, A24,Cw7,Bw39,DR4, A2,Cw3,Bw62, DR4, and A2,Cw1,Bw56,DR4 was 35/100,000, 130/100,000, 166/100,000, 196/100,000, and 218/100,000, respectively. The absolute risks for DR3,DQw2 positive haplotypes A1, Cw7,B8,DR3 and A2,Cw7,B8,DR3 were 68/100,000 and 103/100,000, respectively. These results provide further evidence that not only the polymorphism at the DQ locus but also other genes of the haplotypes contribute to susceptibility to Type 1 diabetes.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00400926
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  • 9
    Electronic Resource
    Electronic Resource
    Diet, cow's milk protein antibodies and the risk of IDDM in Finnish children (1994)
    Springer
    Diabetologia 37 (1994), S. 381-387 
    Details
    ISSN: 1432-0428
    Keywords: Infant feeding ; dairy products ; cow's milk protein antibodies ; IDDM ; childhood ; islet cell antibodies ; insulin autoantibodies
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Associations of infant feeding patterns and milk consumption with cow's milk protein antibody titres were studied in 697 newly-diagnosed diabetic children, 415 sibling-control children and 86 birth-date-and sex-matched population-based control children in the nationwide “Childhood Diabetes in Finland” study. IgA and IgG antibody titres to the proteins of cow's milk formula, BLG and BSA, and IgM antibody titres to cow's milk formula proteins were measured by ELISA. Several inverse correlations were observed between the duration of breast-feeding or age at introduction of dairy products and antibody titres, and positive correlations were observed between milk consumption and antibody titres in all three populations studied. Multivariate analyses which included the infant feeding variables, milk consumption and current age simultaneously showed that the earlier the introduction of dairy products and the greater the consumption of milk was, the higher several antibody titres were. High IgA antibody titres to cow's milk formula were associated with a greater risk of IDDM both among diabeticpopulation-control and diabetic-sibling-control pairs when adjusted for other cow's milk antibody titres, dietary variables and in diabetic-sibling-control pairs also for ICA. The results suggest that young age at introduction of dairy products and high milk consumption during childhood increase the levels of cow's milk antibodies and that high IgA antibodies to cow's milk formula are independently associated with increased risk of IDDM.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00408475
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  • 10
    Electronic Resource
    Electronic Resource
    Natural history of preclinical IDDM in high risk siblings (1994)
    Springer
    Diabetologia 37 (1994), S. 388-393 
    Details
    ISSN: 1432-0428
    Keywords: Preclinical IDDM ; islet cell antibodies ; early insulin response ; glucose elimination rate
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary To learn more about the preclinical phase of IDDM we observed for a median period of 46.5 months (range 0.5–69 months) a group of 57 siblings positive for ICA and/or IAA when first screened within 6 months of the diagnosis of the proband. Sequential blood samples and IVGTTs were obtained at intervals of 6–12 months. Seventeen siblings (29.8%) presented with IDDM during the observation period. The duration of the known preclinical period ranged from 0.5 to 51 months (median 29 months). The converters were younger than the other siblings (P〈0.05) and had higher initial ICA levels (P〈0.01). In addition they had a lower FPIR in the first IVGTT (P〈0.001). On all subsequent tests the converters had higher ICA levels and a lower FPIR (P〈0.05 or less), a lower glucose elimination rate from the third test onwards (P〈0.01 or less) and higher IAA levels at 3 years (P〈0.05). Some variation could be observed in the FPIR in the converters with an initial increase and subsequent decrease (P〈0.05 for both). Their levels of complement-fixing ICA increased up to 18 months (P〈0.05) and IAA levels up to 3 years (P〈0.01). Those high risk siblings who progress to clinical IDDM are characterized by young age, strong and increasing signs of islet-cell specific autoimmunity, reduced insulin secreting capacity and emerging glucose intolerance. The present observations seem to be incompatible with the hypothesis of beta-cell destruction occurring at a constant, predictable rate.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00408476
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