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  • 1
    Electronic Resource
    Electronic Resource
    Macrophages from High-Risk HLA-DQB1*0201/*0302 Type 1 Diabetes Mellitus Patients are Hypersensitive to Lipopolysaccharide Stimulation (2002)
    Oxford, UK : Blackwell Science Ltd
    Scandinavian journal of immunology 56 (2002), S. 0 
    Details
    ISSN: 1365-3083
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Levels of nonantigen-induced pro-inflammatory cytokines and prostaglandin in macrophages isolated from human leucocyte antigen (HLA)-matched type 1 diabetes mellitus patients, first-degree relatives and healthy controls were determined. We hypothesize that monocytes isolated from patients are sensitized or preactivated and therefore, have an altered response to in vitro stimulus compared with control groups as measured by levels of pro- and anti-inflammatory mediators. In this study, peripheral blood monocytes were differentiated to macrophages with macrophage-colony stimulating factor (M-CSF) to determine lipopolysaccharide (LPS)-stimulated tumour necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, IL-12 and prostaglandin E-2 (PGE-2) secretion from hetero- or homozygous HLA DQB1*0201 and *0302 type 1 diabetes mellitus patients, first-degree relatives and homozygous HLA DQB1*0602 healthy controls. LPS-stimulated secretion of TNF-α, IL-1β and IL-6 was immediate and markedly higher in the HLA-DQB1*0201/*0302 type 1 diabetes patients compared with all other groups including HLA-matched healthy first-degree relatives. In DQB1*0201/*0302 diabetes patients PGE-2 secretion was delayed but increased by LPS stimulation compared with HLA-matched healthy relatives. IL-12 was not detected at any condition. These data suggest that macrophages from DQB1*0201/*0302 type 1 diabetes patients are sensitized to secrete both cytokines and PGE-2 following nonantigenic stimulation. Sensitized macrophages may be important to high-risk DQB1*0201/*0302-associated type 1 diabetes.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1046/j.1365-3083.2002.01150.x
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  • 2
    Electronic Resource
    Electronic Resource
    POPULATION ANALYSIS OF PROTECTION BY HLA-DR AND DQ GENES FROM INSULIN-DEPENDENT DIABETES MELLITUS IN SWEDISH CHILDREN WITH INSULIN-DEPENDENT DIABETES AND CONTROLS (1995)
    Oxford, UK : Blackwell Publishing Ltd
    International journal of immunogenetics 22 (1995), S. 0 
    Details
    ISSN: 1744-313X
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Biology , Medicine
    Notes: A negative association between insulin-dependent diabetes mellitus (IDDM) and HLA-DR, DQA1 or DQB1 was found in a large population-based investigation of childhood-onset patients (more than 420 patients) and controls (more than 340 controls) from Sweden. The relative risk was decreased for several haplotypes that were negatively associated with IDDM: DR15-DQA1*0102-DQB1*0602, DR7-DQA1*0201-DQB1*0303, DR14-DQA1*0101-DQB1*0503, DRI1-DQAI*0501-DQB1*0301, DR13-DQA1*0103-DQB1*0603 and DR4-DQA1*0301-DQB1*0301. In a relative predispositional effect (RPE) analysis, however, only the DR15-DQA1*0102-DQB1*0602 haplotype was significantly decreased, which suggests that the major protective effect for IDDM is carried by this haplotype. This was supported by the observation that all genotypes which were negatively associated with IDDM, except DR7/13, included at least one allele from the DR15-DQA1*0102-DQB1*0602 haplotype. Relative predispositional effect (RPE) analysis of genotypes showed further that the DR15-DQA1*0102-DQB1*0602 haplotype was also negatively associated with IDDM when combined with any other haplotype, whether negatively or positively associated with IDDM. This supports previous suggestions that DR15-DQA1*0102-DQB1*0602 acts dominantly. However, both the stratification and the predispositional allele test failed to distinguish the negative association between IDDM and DR15 from that of DQBT0602. On the other hand, these tests indicated that DQA1*0102 was not likely to explain the negative association between IDDM and the DR15-DQA1*0102-DQB1*0602 haplotype. We conclude that the
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1111/j.1744-313X.1995.tb00282.x
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  • 3
    Electronic Resource
    Electronic Resource
    HLA class II is associated with the frequency of glutamic acid decarboxylase Mr 65 000 autoantibodies in Japanese patients with insulin-dependent diabetes mellitus (1996)
    Springer
    Acta diabetologica 33 (1996), S. 108-113 
    Details
    ISSN: 1432-5233
    Keywords: Key words  Autoantigen ; Autoimmunity ; Insulin-dependent diabetes mellitus ; Human leukocyte antigen
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract   Autoantibodies to glutamic acid decarboxylase (GAD65Ab) are common in both caucasian and Japanese patients with insulin-dependent diabetes mellitus (type 1), while the type 1-associated HLA haplotypes differ. In the present study, we analyzed GAD65Ab in relation to HLA-DQ and -DR alleles in Japanese type 1 patients. GAD65Ab were found in 58% short-duration (less than 5 years) type 1, 23% long-duration type 1, 56% slowly progressive type 1, 3% type 2 patients, and 1.7% healthy individuals. In 75 HLA-typed type 1 patients, the GAD65Ab frequency was higher in short-duration patients with DRB1*08 allele (100%, Pc〈0.05). GAD65Ab frequencies in DQB1*0302, DQB1*0303, and DRB1*09-positive, long-duration type 1 patients were lower than those in short-duration type 1 patients (14%, 19%, and 20%, Pc〈0.02 compared with short-duration type 1, 90%, 75%, and 71%, respectively), while the frequency varied less in DQB1*04 individuals (44% and 30% in short- and long-duration type 1 patients, respectively). These findings were also observed among patients with DRB1*04, i.e., the haplotype DRB1*0405-DQB1*0401 showed less variation in frequency of GAD65Ab (44% and 35% in short- and long-duration type 1 patients, respectively), while DRB1*04xx-DQB1*0302 showed lower frequency in long-duration type 1 than short-duration (13% and 100%, respectively). Thus, HLA class II is associated with frequency GAD65Ab, and this association might be affected by disease duration in Japanese type 1 patients.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00569419
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  • 4
    Electronic Resource
    Electronic Resource
    HLA class II is associated with the frequency of glutamic acid decarboxylase M r 65 000 autoantibodies in Japanese patients with insulin-dependent diabetes mellitus (1996)
    Springer
    Acta diabetologica 33 (1996), S. 108-113 
    Details
    ISSN: 1432-5233
    Keywords: Autoantigen ; Autoimmunity ; Insulin-dependent diabetes mellitus ; Human leukocyte antigen
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Autoantibodies to glutamic acid decarboxylase (GAD65Ab) are common in both caucasian and Japanese patients with insulin-dependent diabetes mellitus (type 1), while the type 1-associated HLA haplotypes differ. In the present study, we analyzed GAD65Ab in relation to HLA-DQ and-DR alleles in Japanese type 1 patients. GAD65Ab were found in 58% short-duration (less than 5 years) type 1,23% long-duration type 1,56% slowly progressive type 1,3% type 2 patients, and 1.7% healthy individuals. In 75 HLA-typed type 1 patients, the GAD65Ab frequency was higher in short-duration patients with DRB1*08 allele (100%,Pc〈0.05). GAD65Ab frequencies in DQB1*0302, DQB1*0303, and DRB1*09-positive, long-duration type 1 patients were lower than those in short-duration type 1 patients (14%, 19%, and 20%,Pc〈0.02 compared with short-duration type 1, 90%, 75%, and 71%, respectively), while the frequency varied less in DQB1*04 individuals (44% and 30% in short- and long-duration type 1 patients, respecitively). These findings were also observed among patients with DRB1*04, i.e., the haplotype DRB1*0405-DQB1*0401 showed less variation in frequency of GAD65Ab (44% and 35% in short- and long-duration type 1 patients, respectively), while DRB1*04xx-DQB1*0302 showed lower frequency in long-duration type 1 than short-duration (13% and 100%, respectively). Thus, HLA class II is associated with frequency GAD65Ab, and this association might be affected by disease duration in Japanese type 1 patients.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00569419
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  • 5
    Electronic Resource
    Electronic Resource
    Heterogeneity of islet pathology in two infants with recent onset diabetes mellitus (1995)
    Springer
    Virchows Archiv 425 (1995), S. 631-640 
    Details
    ISSN: 1432-2307
    Keywords: Recent-onset insulin dependent diabetes mellitus ; Insulitis ; Islet cell macrophages ; Glutamic acid decarboxylase ; Islet destruction
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The mechanisms by which the beta cells of pancreatic islets are destroyed in insulin-dependent diabetes mellitus (IDDM) are poorly understood. In this report the pancreatic histo- and immunopathology of two children, both HLA-DR 3/4, DQ 2/8 positive and who both died from cerebral oedema within a day of clinical diagnosis of IDDM, were investigated. Patient 1, a 14-month-old girl, had a 4-week history of polydipsia and polyuria. Patient 2, a 3-year-old boy, had 2 days of illness. Both patients had a similarly severe loss of insulin cells but differed markedly as to the extent of lymphocytic islet infiltration (insulitis). Apart from insulitis, marked islet macrophage infiltration was demonstrated in both patients with the HAM-56 monoclonal antibody. Neither patient showed aberrant expression of HLA class II antigens on insulin-immunoreactive cells, but allele-specific HLA-DQ8 expression was evident on endothelial cells. Glutamic acid decarboxylase immunoreactivity was detected in both insulin- and glucagon-immunoreactive cells. It is concluded that the heterogeneity of islet pathology, especially insulitis, may reflect different dynamics and extent rather than different pathomechanisms of immune destruction of islets in IDDM.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00199353
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  • 6
    Electronic Resource
    Electronic Resource
    Diagnostic sensitivity of immunodominant epitopes of glutamic acid decarboxylase (GAD65) autoantibodies in childhood IDDM (1996)
    Springer
    Diabetologia 39 (1996), S. 1091-1098 
    Details
    ISSN: 1432-0428
    Keywords: Keywords Insulin-dependent diabetes mellitus ; autoimmunity ; autoantibodies ; radioimmunoassay ; recombinant protein.
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The prevalence and titre of epitope-specific autoantibodies to glutamic acid decarboxylase (GAD65) in 155 insulin-dependent diabetic (IDDM) and 9 GAD65 antibody (Ab)-positive healthy children were determined using four GAD65/67 chimaeric molecules which discriminate among the N-terminal (N), middle (M) and C-terminal (C) epitopes of GAD65. Radioligand binding assays for IgG Ab used immunoprecipitation of in vitro translated 35S-GAD. We found autoantibodies to GAD65 in 116 of 155 (75 %), to GAD67 in 19 of 155 (12 %) (p 〈 0.0001) and to the GAD65-N-67 chimaera in 25 of 155 (16 %) (p 〈 0.0001) IDDM sera. GAD67Ab were found almost exclusively (17 of 19, 89 %) in GAD65Ab-positive sera and the levels of GAD67Ab correlated with those of GAD65Ab (r 2 = 0.5913; p = 0.009). GAD65Ab directed to GAD65-M were found in 104 of 155 (67 %), to GAD65-C in 104 of 155 (67 %) and to GAD65-M + C in 116 of 155 (75 %) of IDDM sera, and indicated reactivity to at least two distinct epitopes. Among the nine GAD65Ab-positive healthy children, two (22 %) were also positive with GAD67, nine (100 %) with GAD65-M + C, seven (78 %) with GAD65-M, eight (89 %) with GAD65-C and two (22 %) with GAD65-N-67. Titres of GAD65Ab (p = 0.007), GAD65-C-Ab (p = 0.002) and GAD65-C + M-Ab (p = 0.003), but not of GAD65-M-Ab (p = 0.101) were significantly higher in IDDM than in healthy children. We conclude that GAD65Ab in IDDM and healthy children are directed to middle and C-terminal epitopes, and propose that levels of antibodies specifically directed to the carboxy-terminal end of GAD65 may distinguish IDDM from healthy children. [Diabetologia (1996) 39: 1091–1098]
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00400659
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  • 7
    Electronic Resource
    Electronic Resource
    The beta cell glucokinase promoter variant is an unlikely risk factor for diabetes mellitus (1997)
    Springer
    Diabetologia 40 (1997), S. 959-962 
    Details
    ISSN: 1432-0428
    Keywords: Keywords IDDM ; NIDDM ; glucokinase gene ; polymerase chain reaction ; single strand conformational polymorphism ; islet cell antibodies ; GAD65 antibodies.
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Glucokinase plays an important role in the regulation of insulin secretion and is therefore an attractive candidate gene for both insulin dependent (IDDM) and non-insulin-dependent (NIDDM) diabetes mellitus. A single G-A nucleotide polymorphism at the –30 position of the beta-cell specific promoter region of the glucokinase gene was previously associated with reduced beta-cell function. In the present study we analysed 268 consecutive newly diagnosed Swedish patients classified with either IDDM (n = 205), NIDDM (n = 31) or unclassifiable (n = 32) diabetes between the ages of 15 and 35 years along with a group of 158 age- and sex-matched control subjects. The beta-cell promoter region was amplified by the polymerase chain reaction and the G-A variant identified by single strand conformational polymorphism. There was no significant difference in allele frequencies of G and A between any of the subject groups and likewise, no significant difference in the frequencies of the G/G, G/A, or A/A genotypes. Eight subjects were homozygous for the less common A allele, five had IDDM and three were control subjects. Our results suggest that the –30 beta-cell glucokinase promoter variant is not associated with IDDM. [Diabetologia (1997) 40: 959–962)
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s001250050774
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  • 8
    Electronic Resource
    Electronic Resource
    Glutamate decarboxylase (GAD65) and tyrosine phosphatase-like protein (IA-2) autoantibodies index in a regional population is related to glucose intolerance and body mass index (1999)
    Springer
    Diabetologia 42 (1999), S. 555-559 
    Details
    ISSN: 1432-0428
    Keywords: Keywords Autoimmunity ; beta-cell function ; BMI ; epidemiology ; sex ; glutamate decarboxylase ; IA-2 ; Type I and Type II diabetes ; OGTT.
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Aims/hypothesis. Our aims were to investigate the concentrations and prevalence of autoantibodies against the Mr 65.000 isoform of glutamate decarboxylase (GAD65) and the tyrosine phosphatase-like protein (IA-2) in adults and to test the hypothesis that GAD65 and IA-2 autoantibodies in a regional population are related to abnormal oral glucose tolerance. Methods. We analysed serum from 2157 Swedish subjects aged either 30, 40, 50 or 60 years old who, in 1988–1992, participated in the Västerbotten County Health Project and were subjected to the World Health Organisation (WHO) standard oral glucose tolerance test at entry into the study. Results. We found 23 of 2157 (1.1 %) and 17 of 2152 (0.8 %) subjects exceeded the 99th centile of GAD65 autoantibody index and IA-2 autoantibody index, respectively. In 18 subjects with diabetic oral glucose tolerance test, GAD65 autoantibody concentrations were higher than in those with normal oral glucose tolerance test (p = 0.02). Subjects with IGT (n = 416) and diabetes (n = 18), i. e. abnormal OGTT (n = 434), had a higher IA-2Ab index compared with those with normal OGTT (p = 0.008). A stepwise multiple logistic regression test showed that the odds ratios for subjects in the highest BMI group to exceed the 95th or 99th GAD65 autoantibody centile were 3.6 (CI 1.4–8.9) and 17.6 (CI 2.6–121.6), respectively. Conclusion/interpretation. GAD65 and IA-2 autoantibodies, are associated with impaired or diabetic glucose tolerance in an adult regional population. This observation together with the association between GAD65 autoantibody concentrations and body mass index indicate a possible relation between islet autoimmunity and beta-cell function abnormalities with obesity and insulin resistance. [Diabetologia (1999) 42: 555–559]
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s001250051194
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  • 9
    Electronic Resource
    Electronic Resource
    The lymphopenia (lyp ) gene controls the intrathymic cytokine ratio in congenic BioBreeding rats (1997)
    Springer
    Diabetologia 40 (1997), S. 786-792 
    Details
    ISSN: 1432-0428
    Keywords: Keywords Diabetes mellitus ; BioBreeding rat ; lymphopenia ; thymus ; cytokines.
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The lymphopenia gene (lyp ) on rat chromosome 4 is closely linked to autoimmune diabetes in the BioBreeding (BB) rat. Lyp controls the number of peripheral lymphocytes by reducing T cells of the RT6 + phenotype by almost 90 %. Following nine cycles of marker-assisted cross-intercross breeding we have developed congenic lyp/lyp, lyp/ + and + / + (wildtype) rats on the background of DR rats. Prediabetic and insulitis free lyp/lyp, lyp/ + and + / + rats were used to determine the effect of lyp on cytokine expression in the thymus. In situ hybridization of thymus cryosections showed that the interferon gamma (IFNγ) mRNA expression was highest in lyp/lyp rats and the hybridization signal was restricted to the medullary compartment. The frequency of IFNγ and interleukin (IL)-10 mRNA expressing cells in isolated thymocytes determined by quantitative image analysis, demonstrated an increased IFNγ:IL-10 ratio in thymocytes from lyp/lyp homozygotes compared to lyp/ + and + / + rats. This confirmed a lyp gene dose-dependent segregation of the IFNγhigh phenotype. Recombinant human glutamic acid decarboxylase (GAD65) increased the number of IFNγ and IL-10 mRNA expressing thymocytes after in vitro culture. We conclude that the quantitative ratio of cytokine producing thymocytes is associated with the lyp genotype. These potentially autoreactive thymocytes may explain the establishment of beta-cell directed autoimmunity in the BB rat despite peripheral lymphopenia. [Diabetologia (1997) 40: 786–792]
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s001250050750
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  • 10
    Electronic Resource
    Electronic Resource
    Sexual dimorphism in transmission of expression of islet autoantibodies to offspring (1995)
    Springer
    Diabetologia 38 (1995), S. 1353-1357 
    Details
    ISSN: 1432-0428
    Keywords: Islet autoantibodies ; offspring ; autoimmunity ; transmission
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary To help elucidate the mode of inheritance of insulin-dependent diabetes mellitus (IDDM), we measured GAD (glutamic acid decarboxylase) autoantibodies (GAD65Ab), insulin autoantibodies (IAA), and cytoplasmic islet cell autoantibodies (ICA) in 292 sequentially screened non-diabetic offspring of patients with IDDM. The prevalence of these islet autoantibodies was higher in offspring of diabetic fathers than in offspring of diabetic mothers. The prevalences of GAD65Ab, IAA, and ICA in the offspring of diabetic fathers were 11.5%, 10.8%, and 8.1% vs 2.1%, 1.4%, and 2.8%, respectively in the offspring of diabetic mothers (p〈0.002, p〈0.001, and p=0.06 NS). Amongst autoantibody-positive relatives the IAA and ICA levels were significantly higher in offspring of diabetic fathers than of diabetic mothers (p〈0.002 and p〈0.01, respectively). The frequencies of these autoantibodies were equal in male and female offspring. We conclude that IDDM mothers transmitted islet autoimmunity less frequently to their offspring than IDDM fathers. Given the markedly lower frequency of autoantibodies in offspring of mothers, larger sample sizes will be required to determine whether islet autoantibodies are influenced by age of IDDM onset of mothers, maternal age of pregnancy, and presence of diabetes in these mothers prior to conception.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00401769
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