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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Type I diabetes is the result of an autoimmune destruction of pancreatic beta cells. T cells appear to play a key role in this process. Thus far little information is available on the beta cell antigen or antigens recognized by auto-reactive T cells. Previously, we identified a 38 kD T cell antigen that appears to be localized in the membrane of insulin secretory granules and that is recognized by T cells from newly diagnosed type I diabetes patients. Other groups have reported T cell reactivity against glutamic acid decarboxylase (GAD). To obtain an indication of whether or not beta-cell reactive T cells from type I diabetes patients recognize a limited number of beta-cell antigens, we cloned T-cell lines reactive with rat insulinoma (RIN) membranes from two patients and analysed their antigen specificity. We also studied the antigen specificity of one RIN membrane reactive T-cell clone (1C5), previously isolated from a third patient. From the first patient two identical RIN membrane reactive T-cell clones (7A13) were isolated. The second patient yielded two identical (23A19) RIN membrane reactive T-cell clones, and one that was different (234A33). All clones were CD4+ and saw antigen in the context of different HLA class II alleles. The reactivity of the clones was, however, not restricted to beta cells: all clones showed cross-reactivity with one or more rat tissues, with some preference for those of neuroendocrine origin, but the cross-reactivity patterns were all different. All four clones recognized different fractions electro-eluted from RIN membranes: 29-36 kDa (7A13), 120-170 (23A19), 29-41 (23A33) and 56-72 kDa (1C5). The 23A33 clone reacted with the same 38 kDa fraction electro-eluted from insulinoma membranes as a beta-cell reactive clone (1C6) published previously, but none of the other known beta cell antigen preparations tested were recognized by the T-cell clones. Finally, the subcellular localization of the antigens recognized showed at least two different patterns. These data indicate that beta-cell reactive T cells from the peripheral blood of type I diabetes patients are not necessarily beta-cell specific and may be heterogeneous in regard to their antigen specificity and HLA class II restriction.
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PMID:Beta-cell reactive T-cell clones from type I diabetes patients are not beta cell specific and recognize multiple antigens. 882 13

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.
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PMID: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. 887 Aug 11

The problem of defining combinations of variants unique to a sequence is efficiently addressed as a set covering computation. The unique-combinations method is introduced, which identifies patterns in biological sequence data that distinguish a sequence from a group of other sequences. This method is further developed to describe features consistently present in one group of sequences but not in a second group. The approach is incorporated into a novel analytical tool, designed for use in studies of polymorphic sequence data, such as mitochondrial, human leukocyte antigen (HLA), or viral pathogen sequences. The unique combinations method is well suited to applications in medical genetics and evolutionary genetics. An example implementation of the unique-combinations method yields greatly improved risk assessment for insulin-dependent diabetes mellitus (IDDM) from amino acid patterns isolated in an analysis of HLA class II DQA1-DQB1 patient and control genotypes.
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PMID:On distinguishing unique combinations in biological sequences. 889 58

Insulin, glutamate decarboxylase (GAD) and the protein tyrosine phosphatase-like molecule IA-2 are major targets of humoral autoimmunity in insulin-dependent diabetes mellitus (IDDM). These autoantibodies are heterogeneous with respect to age and patient human leukocyte antigen (HLA) phenotype. We have previously demonstrated that GAD and IA-2 antibodies potentially identify different subsets of IDDM patients. The aim of this study was to determine whether GAD and IA-2 autoantibodies were associated with different HLA DR phenotypes. We studied 160 patients with IDDM onset before age 16 years. At disease onset serum was tested for GAD and IA-2 antibodies by immunoprecipitation by in vitro-translated 35S-methionine labelled recombinant proteins. IA-2 antibodies were significantly associated with HLA DR4: 67 (86%) of 78 patients with HLA DR4 vs 31 (38%) of 82 non-DR4 patients had IA-2 antibodies (Pc < 0.0001) and IA-2 antibody levels were higher in patients with HLA DR4 (Pc < 0.0001). In contrast, GAD antibodies were more prevalent (Pc < 0.05) and antibody levels highest (Pc < 0.01) in patients with HLA DR3 phenotypes. These data provide further evidence that, in IDDM, production and titre of major autoantibody specificities are associated with HLA class II alleles.
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PMID:Association of IA-2 autoantibodies with HLA DR4 phenotypes in IDDM. 889 11

We report here our analysis of HLA class II alleles in 180 Caucasian nuclear families with at least two children with insulin-dependent diabetes mellitus (IDDM). DRB1, DQA1, DQB1, and DPB1 genotypes were determined with PCR/sequence-specific oligonucleotide probe typing methods. The data allowed unambiguous determination of four-locus haplotypes in all but three of the families. Consistent with other studies, our data indicate an increase in DR3/DR4, DR3/DR3, and DR4/DR4 genotypes in patients compared to controls. In addition, we found an increase in DR1/DR4, DR1/DR3, and DR4/DR8 genotypes. While the frequency of DQB1*0302 on DR4 haplotypes is dramatically increased in DR3/DR4 patients, DR4 haplotypes in DR1/DR4 patients exhibit frequencies of DQB1*0302 and DQB1*0301 more closely resembling those in control populations. The protective effect of DR2 is evident in this data set and is limited to the common DRB1*1501-DQB1*0602 haplotype. Most DR2+ patients carry the less common DR2 haplotype DRB1*1601-DQB1*0502, which is not decreased in patients relative to controls. DPB1 also appears to play a role in disease susceptibility. DPB1*0301 is increased in patients (P < .001) and may contribute to the disease risk of a number of different DR-DQ haplotypes. DPB1*0101, found almost exclusively on DR3 haplotypes in patients, is slightly increased, and maternal transmissions of DRB1*0301-DPB1*0101 haplotypes to affected children occur twice as frequently as do paternal transmissions. Transmissions of DR3 haplotypes carrying other DPB1 alleles occur at approximately equal maternal and paternal frequencies. The complex, multigenic nature of HLA class II-associated IDDM susceptibility is evident from these data.
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PMID:The role of HLA class II genes in insulin-dependent diabetes mellitus: molecular analysis of 180 Caucasian, multiplex families. 890 Feb 44

Previous studies have indicated that certain alleles of HLA-DR and -DQ genes were strongly associated with susceptibility and resistance to insulin-dependent diabetes mellitus (IDDM), and the role of DQ molecule in IDDM has been suggested. To further clarify the association of DQ alleles with IDDM, we determined the nucleotide sequences of full-length cDNA from 13 DQA1 alleles and 14 DQB1 alleles. The sequencing analysis revealed sequence polymorphisms outside the hypervariable region of DQ genes. We then analyzed the DQA1 and DQB1 polymorphisms along with that of DRB genes in 86 B-lymphoblastoid cell lines (B-LCLs) from various ethnic groups and in healthy unrelated Japanese and Norwegian individuals. The allelic and haplotypic distributions in each population revealed the characteristic haplotypic formation in the HLA class II region. HLA genes in 139 Japanese and 100 Norwegian IDDM patients were analyzed. DQB1*0301 was negatively associated with IDDM in both ethnic groups, irrespective of associated DRB1 and DQA1 alleles. In DQB1*0302 positive populations, which represented a positive association with IDDM in both ethnic groups, DRB1*0401, *0404, *0802 haplotypes increased in the patients, whereas DRB1*0406 haplotype decreased. Considering about the hierarchy in DRB1 alleles with IDDM susceptibility (DRB1*0401>*0404>*0403 in Norwegian and DRB1*0802>*0403>*0406 in Japanese), the genetic predisposition to IDDM is suggested to be defined by the combination of DR-associated susceptibility and DQ-associated susceptibility and by the DQ-associated resistance which is a dominant genetic trait.
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PMID:Different contribution of HLA-DR and -DQ genes in susceptibility and resistance to insulin-dependent diabetes mellitus (IDDM). 892 11

It has been suggested that ITL are of importance in the pathogenesis of human autoimmune thyroid disease. Aim of our study was to investigate function and morphology of xenotransplanted human thyroid tissue in nude mice following systemic application of lymphocyte preparations from patients with Graves' disease (GD) and non-toxic nodular goiter (NTG). ITL obtained from 13 patients with GD and peripheral blood lymphocytes (PBL) from 12 patients with NTG were injected into nude mice bearing 8 weeks old xenografts of normal human thyroid tissue. ITL- and PBL-subsets were analyzed by flow cytometer (FACScan) before engraftment. Two days after injection the thyroid transplants were examined histologically (HE) as well as immunohistologically by staining with: CD3, CD31, CD45R, HLA class II, ICAM-1, VCAM-1, IgG, IgM and Ki67. Flow cytometry showed a significant higher number of the lymphocyte-subsets CD3, DR+ and CD4 in GD-ITL as compared to the subsets in NTG-ITL. After injection of GD-ITL to the nude mice also a significant higher number of CD3+ human lymphocytes was found in the transplants. GD-lymphocytes stimulated thyroid tissue function significantly more pronounced than NTG-lymphocytes (histomorphological evaluation). In addition, a significant increase of HLA-class II, ICAM-1-, VCAM-1-, CD45-expression and number of Ig presenting plasma cells were observed only after injection of GD-ITL. Our data demonstrate, for the first time in vivo (nude mouse model), that GD-lymphocytes of both peripheral and intrathyroidal origin selectively migrate into human thyroid transplants ("homing"). They survive there for at least two days and induce significant functional as well as histological changes, like expression of gene products and IgG synthesis. These results suggest an important role of ITL in the pathogenetic mechanisms and clinical course of GD.
Exp Clin Endocrinol Diabetes 1996
PMID:Effect of Graves' intrathyroidal lymphocytes. Effect of Graves' disease intrathyroidal lymphocytes (ITL) on xenotransplants of human thyroid tissue in athymic nude mice. 898 Oct 4

TSH receptor plays a pivotal role in the regulation of thyroid function and is intimately involved in the pathogenesis of common thyroid disorders. A lack of specificity and absence of down regulation upon stimulation renders the human TSH receptor susceptible to exogenous overstimulation, which forms the basis of hyperthyroidism in TSHoma, Graves' disease and gestational thyrotoxicosis. Further, TSH receptor activation in the absence of exogenous stimulators due to the expression of endogenously active mutant receptors has recently been described, and may in part account for hyperthyroidism in autonomously functioning thyroid nodules. Signal bifurcating by coupling of TSH receptor to different G proteins may be a likely mechanism to explain the multitude of distinct effects caused by TSH receptor activation including mainly hormone production and growth promotion. Also, TSH receptor appears to mediate immunological stimulation, its activation by TSH R Ab inducing expression of adhesion molecules and HLA class II antigens on thyrocytes. Increasing evidence suggests that TSH receptor is not restricted to thyroid and may be expressed in extrathyroidal tissues with a potential role in the pathogenesis of Graves' orbitopathy.
Exp Clin Endocrinol Diabetes 1996
PMID:Stimulation of thyroidal and extrathyroidal thyrotropin receptors. 898 Oct 10

Enteroviruses have been examined for their possible role in the etiology of IDDM for nearly 40 years, yet the evidence remains inconclusive. The mechanism of acute cytolytic infection of beta-cells, proposed by earlier studies, appears to be incompatible with the long preclinical period of autoimmunity preceding IDDM. Advances in molecular biology have improved our understanding of enteroviral biology and of potential alternative pathogenic mechanisms through which enteroviruses may cause diabetes. The focus of future human studies will likely shift from people with IDDM to those with prediabetic autoimmunity to determine whether acute enteroviral infections can promote progression from autoimmunity to overt diabetes. We propose that such studies use assays to detect enteroviral RNA, in addition to IgM serology. RNA assays can overcome sensitivity and type-specificity limitations of IgM assays as well as identify diabetogenic strains of enteroviruses, if such exist. Evaluation of the role of enteroviruses in triggering beta-cell autoimmunity in humans will require large prospective studies of young children. The Diabetes Autoimmunity Study in the Young--one of very few such studies currently underway--is focusing on potential interactions between HLA class II genes and enteroviral infections. Future studies will likely examine interactions between viral infections and non-HLA IDDM candidate genes, including those that may determine beta-cell tropism of candidate viruses.
Diabetes 1997 Feb
PMID:The role of enteroviral infections in the development of IDDM: limitations of current approaches. 900 Jun 90

Results from a recent study suggested that polymorphisms within the HLA class II genes LMP2 and LMP7 were associated with the susceptibility for developing IDDM, and that this association could not be explained by linkage disequilibrium to HLA-DR or -DQ genes. We typed 285 IDDM patients and 337 HLA-DRB1-DQA1-DQB1 genotypically matched control subjects from an ethnically homogeneous population for both the G/T polymorphism in intron 6 of the LMP7 gene and the Arg-His polymorphism in the LMP2 gene. In addition, we typed IDDM families in which at least one parent was homozygous for a DRB1-DQA1-DQB1 haplotype and performed a transmission/disequilibrium test of these LMP polymorphisms. Our data suggest that none of these LMP2 or LMP7 polymorphisms are independently associated with IDDM susceptibility, in contrast to what has been previously reported by others. Further, our results suggest that one partial explanation for the previously reported independent association between IDDM and these LMP polymorphisms may have been that patients and control subjects were not matched for DRB1*04 subtypes. Our results emphasize the need for a complete matching for DRB1, DQA1, and DQB1 alleles between patients and control subjects when attempting to detect independent effects of other polymorphisms in the HLA complex on IDDM susceptibility or protection.
Diabetes 1997 Feb
PMID:No independent associations of LMP2 and LMP7 polymorphisms with susceptibility to develop IDDM. 900 Jul 9


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