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

Inappropriate expression of HLA Class II (D/DR) molecules has been detected in the target cells of most autoimmune diseases including Type I (insulin-dependent) diabetes. The possibility that this phenomenon is due to the action of lymphocytes or some of their products has been investigated by analysing in vitro the modulation of HLA products in Beta cells. Monolayer cultures from 25 human pancreatic glands were supplemented with alpha-interferon (IFN), beta-IFN or gamma-IFN, interleukin 2 (IL-2) and supernatants from activated lymphocytes. In addition, lectins and a variety of other hormones, biological products and chemicals were tested. Major histocompatibility complex (MHC) expression was assessed by double immunofluorescence technique using monoclonal antibodies to non-polymorphic determinants of Class I and Class II molecules and the pancreatic cells were identified by antibodies to islet hormones and other cytoplasmic antigens. gamma-IFN and lectins produced a parallel enhancement of HLA-A,B,C expression in islet, exocrine/ductal cells and fibroblasts. HLA-D/DR was inducible in all pancreatic cell types, except endocrine islet cells which did not produce Class II molecules in response to any of the stimuli including supernatants from activated lymphocytes. Exocrine/ductal cells from glands of patients with chronic pancreatitis spontaneously expressed Class II products, but islet cells were devoid of any detectable D/DR. These data are consistent with recent observations which have indicated that in the 'diabetic' pancreas inappropriate Class II expression in the Beta cells occurs independently of the presence of lymphocytes infiltrating the islets, and make it necessary to postulate that other factors are responsible for the Class II induction in Beta cells in human Type I diabetes.
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PMID:Differential expression and regulation of MHC products in the endocrine and exocrine cells of the human pancreas. 309 71

Fifteen DR4-bearing haplotypes from twelve patients with insulin-dependent diabetes mellitus (IDDM) were analyzed serologically, cellularly, and biochemically. The HLA-Dw composition of these DR4-positive haplotypes was Dw4 (46%), Dw14 (22%), and Dw10 (33%). The biochemical analysis by two-dimensional electrophoresis (2D-PAGE) of the DR beta chains showed that each Dw specificity is characterized by a specific DR4 beta chain that appears to be identical in normal and diabetic individuals. Analysis of DQ beta chains in the DR4-bearing haplotypes revealed that certain Dw specificities such as Dw4 are characterized by the presence of either the DQw7 (formerly DQw3.1) or DQw8 (formerly DQw3.2) alleles, which generate the Dw4.1 or Dw4.2 subtypes, respectively. Others such as Dw14 and Dw10 are characterized by the presence of the DQw8 allele. In our sample of 12 patients the Dw4.2 (Dw4, DR4 beta I-4 DQw8) and Dw10 (Dw10, DR4 beta I-1, DQw8) subtypes were predominant. It is concluded that individual DR beta and DQ beta gene products from the DR4-bearing haplotype of IDDM patients are identical to those of normal control subjects and that Dw14 as well as Dw10 are involved in disease susceptibility. We suggest that disease susceptibility may be influenced by more than one locus within the HLA-D region.
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PMID:Analysis of DR and DQ gene products of the DR4 haplotype in patients with IDDM: possible involvement of more than one locus. 326 8

Graves' disease and type 1 (insulin-dependent) diabetes are common autoimmune endocrine disorders which may co-exist. Since the class II HLA-DR3 antigen is associated with both these diseases, and since an association between DR3 and the thyrotrophin receptor antibody (TRAb) has been suggested, we wished to determine whether TRAb levels were increased and were HLA-D related in diabetes mellitus. In 115 clinically euthyroid subjects (33 type 1 diabetics, 82 healthy controls) there was a correlation between age and TRAb levels (r = -0.39, p less than 0.001). TRAb levels were elevated in DR3 subjects (n = 32) compared to an age matched group of non-DR3 (n = 61) subjects [median (range): 18.1 (-1.7 to 47.4) versus 6.7 (-9.8 to 19.1), p less than 0.001]. Diabetic DR3 and control DR3 subjects had similar TRAb levels which were elevated when compared to their respective non-DR3 control group (both p less than 0.001). All but two subjects (both diabetic) had TRAb levels in our normal range. Thus TRAb levels are elevated in the subjects who possess the HLA-DR3 antigen. Since DR3 is found so commonly in type 1 diabetes this phenomenon may partly explain the association with Graves' disease in this patient population.
Diabetes Res 1988 Mar
PMID:Thyrotrophin receptor antibodies in type 1 (insulin-dependent) diabetes mellitus. 341 55

A new HLA-DQ-related genetic system with two alleles, 2B3 and TA10, defined serologically by MAbs and alloantisera, showed an almost perfect correlation with charge differences on DQ beta molecules, as well as with two polymorphic DNA fragments hybridizing with a DQ beta probe and various restriction enzymes on a panel of 14 DR4+ homozygous typing cells. It was therefore concluded that the serologically defined alleles 2B3 and TA10 are coded by the DQ beta gene and situated on the HLA-DQ beta chain. This 2B3/TA10 polymorphism is independent of HLA-D and segregates with HLA in families. The TA10 allele appears to be a new marker for resistance to type I diabetes, which is independent from the known resistance marker DR2, whereas no association was observed between this DQ beta polymorphism and rheumatoid arthritis.
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PMID:HLA-DO polymorphism associated with resistance to type I diabetes detected with monoclonal antibodies, isoelectric point differences, and restriction fragment length polymorphism. 346 3

The occurrence of HLA Class II expression by thyroid (and other endocrine) epithelia in autoimmune diseases suggests that these cells may facilitate their own destruction by immunogenically presenting autoantigens. This is supported by the findings that Class II+ thyrocytes can specifically stimulate virus-specific and autoreactive T cell clones, and that Class II expression by thyrocytes correlates with the occurrence of thyroid autoantibodies. A variety of factors may contribute to the regulation of Class II expression by thyrocytes: this is induced by interferon (IFN-gamma), and is enhanced by thyroid stimulating hormone (TSH) and by tumour necrosis factor (TNF). Conversely, epidermal growth factor (EGF) suppresses the induction of Class II in thyrocytes. This complex regulation is reflected in differences in HLA-D subregion expression between patients (DR greater than DP greater than DQ). The immune-based mechanisms of thyrocyte Class II regulation are clearly applicable to the on-going disease in an infiltrated thyroid, but the possibility of nonimmune Class II induction deserves attention, particularly in identifying factors which might contribute to the initial autoimmune attack. The possible involvement of such mechanisms in autoimmunity is supported by findings in Type I diabetes in which Class II+ islet beta cells can be found in the absence of infiltration. Further evidence is provided by the observation that a proportion of thyrocytes transformed with SV40 DNA constitutively express Class II molecules. Finally, the 'activated' state of capillary endothelial cells in organs subject to autoimmune attack suggests that they may play an important role in facilitating the autoreactive infiltration of the tissues.
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PMID:Thyrocyte HLA class II expression and regulation in relation to thyroid autoimmunity. 349 11

Susceptibility to IDDM is linked to the HLA-D locus on the short arm of chromosome 6, a region believed to be involved in the process of communication between cells which determines immune responses. Presumably an HLA molecule encoded by this region, unable to present a particular antigenic pathogen to the immune system, is inherited. The HLA-DR locus is quite complex, however. The gene which codes for this defective molecule may be identified by a combination of use of monoclonal antibodies and cloned gene probes which specifically hybridize to various portions of this region. Investigators are searching for HLA-DR4 containing chromosomes in IDDM which show similar patterns of restriction enzyme polymorphism. Hopefully, complete structural analysis of these related sequences will provide information about the mechanisms which confer susceptibility to develop IDDM. A strong genetic component is involved in NIDDM evidenced by a high concordance in monozygotic twins. Nevertheless, there is much evidence of genetic heterogeneity. At the present time no clear cut genetic marker has been defined. The human insulin gene has been cloned and by Southern blot hybridization analysis of peripheral leukocyte DNA, the insulin gene locus is being evaluated as a possible contributor to the genetic defect. Population studies at the present time have not identified any particular polymorphic insulin allele associated with NIDDM. Population studies are complicated by heterogeneity of NIDDM, racial and ethnic differences, and heterogeneity of insulin alleles. Linkage analysis in family studies will provide an alternative approach to population studies to determine what role if any the insulin gene plays in the genetic component of this disease. Because NIDDM is heterogeneous and perhaps polygenic in nature, these linkage analyses in families with NIDDM can be extended to other genes when they are cloned such as that coding for the insulin receptor. The familial aggregation of diabetes has long been noted (see ref. 1 for review). In relatives of diabetics, the prevalence ranges from 10-30%, while it is variously estimated to be between 0.1-3% in the general population. But familial aggregation of a trait may be caused either by genetic or environmental factors. One approach to dissecting the contribution of these factors is the study of concordance in twins. Pyke and associates observed that overall identical twins always show a higher concordance rate than dizygotic twins, irrespective of their age of diagnosis. Furthermore, they noted that identical twins of younger onset are often discordant for diabetes while identical twins of older onset are usually concordant.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:The genetics of type I and type II diabetes: analysis by recombinant DNA methodology. 389 68

DNA fragments complementary to cloned sequences encoding HLA-D region class II antigen alpha- and beta-chains were determined by genomic blotting with DNA from HLA-typed members of 22 complete families, 12 of which had a proband with insulin-dependent diabetes mellitus (IDDM). Analysis of genotypes showed that the DNA sequences were linked to HLA-DR and permitted confirmation of recombinations in two families. Digestion with the restriction enzymes BamHI, EcoRI, and PstI and hybridization with an HLA-D region beta-chain cDNA probe confirmed a BamHI 3.7 kilobase (kb) fragment present at low frequency among diabetic individuals and a BamHI 3.2 kb fragment that was also decreased among the diabetic subjects compared with siblings (P less than 0.05) as well as nonrelated control siblings (P less than 0.02) and their parents (P less than 0.01). BamHI 12.0 kb (P less than 0.05) and 5.8 kb (P less than 0.02, P less than 0.02), EcoRI 20 kb (P less than 0.05, P less than 0.02), and PstI 6.0 kb (P less than 0.05) fragments were more frequent in diabetic individuals compared with nonrelated control siblings or their parents, respectively. Analysis of individual haplotypes revealed that HLA-DR4-containing chromosomes were heterogeneous among controls but that the diabetic individuals showed a similar pattern of restriction fragment length polymorphism. Genomic blotting of blood lymphocyte DNA with a cDNA clone encoding the chain of HLA-D region class II antigens permits detection of fragments that are strongly associated with IDDM.
Diabetes 1984 Oct
PMID:Susceptibility to insulin-dependent diabetes defined by restriction enzyme polymorphism of HLA-D region genomic DNA. 609 Feb 47

Three groups of patients with insulin-dependent diabetes mellitus, ascertained by different procedures, were investigated for HLA-A, B, C and D antigens (n = 164), and a subset (n = 93) for HLA-DR. Both HLA-D/DR3 and D/DR4 were strongly positively associated and D/DR2 was negatively associated with insulin-dependent diabetes. HLA-DR+ was found to be a better marker for insulin-dependent diabetes than Dw4. The HLA-B associations (B8, B15 and B18) were clearly secondary to the increases of HLA-D/DR3 and D/DR 4. The HLA associations did not differ between familial and isolated cases indicating that these two groups may well have a common genetic background. Based on analysis of HLA-haplotype sharing in affected sibling pairs, a simple dominant model of inheritance could be ruled out, and a simple recessive model was found unlikely. The relative risks for the HLA-Dw3,4 and HLA-DR3,4 phenotype were 21.2 and 44.4 respectively and exceeded those of both the HLA-Dw3 and HLA-DR3 (5.6 and 4.3) as well as the HLA-Dw4 and DR4 (10.1 and 10.5) phenotypes. This argues against an intermediate genetic model but further studies are needed to clarify whether there is more than one susceptibility gene for insulin-dependent diabetes mellitus within the HLA-system.
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PMID:HLA-D and -DR antigens in genetic analysis of insulin dependent diabetes mellitus. 616 81

Homozygous typing cells from 13 normal HLA-A1, B8, Dw3, DR3 and five normal HLA-A26, Bw38, Dw10, DR4 individuals were typed for the following markers: HLA-SB, MB, MT; complement proteins BF, C2, C4A, C4B; and GLO. Ninety-one percent of A1, B8, Dw3, DR3 homozygous individuals (HI) tested were homozygous for BF*S, C2*C, C4A*QO, and C4B*1 (SCO1 complotype), which indicates that the SCO1 complotype is in linkage disequilibrium with the A1, B8, DR3 haplotype in randomly selected normal populations. Sixty-seven percent of HLA-A1, B8, Dw3, DR3, SCO1 positive HI also expressed SB1; since the frequency of SB1 in random Caucasian populations is 11.2%, this finding indicates that SB1 is in linkage disequilibrium with the A1, B8, DR3, SCO1 extended haplotype. All HI with the A26, Bw38, Dw10, DR4 haplotype were homozygous for both SC21 and SB4, suggesting that SC21 and SB4 should be included in the A26, Bw38, Dw10, DR4 extended haplotype. On the other hand, neither of the GLO markers were found in association with either haplotype. The results of this study indicate that HLA-SB is included in some extended haplotypes and may be important in these markers for diseases such as insulin-dependent diabetes mellitus. This study also demonstrated an apparent influence of HLA-SB on primary mixed lymphocyte culture (MLC) responses. The mean relative response of primary MLCs between individuals matched for HLA-A, B, D, DR, MB and MT but not SB was 40% of that for the MLCs with mismatched HLA-D, significantly higher than the MLCs matched for all HLA and complotypes.
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PMID:Linkage disequilibrium of HLA-SB1 with the HLA-A1, B8, DR3, SCO1 and of HLA-SB4 with the HLA-A26, Bw38, Dw10, DR4, SC21 extended haplotypes. 623 24

The human HLA-D histocompatibility region encodes class II antigens each of which consists of two polypeptide chains (alpha and beta) inserted in the plasma membrane. These molecules are implicated in the regulation of the immune response but several human diseases are also found to be associated with certain HLA-DR antigens. The occurrence of insulin-dependent (type I) diabetes (IDDM) is strongly associated with HLA-DR3 and/or 4 (ref. 5). The class II antigens, however, show a marked genetic polymorphism associated with the beta-chains which seem, from hybridization studies, to be encoded by several genes. We have therefore used the beta-chain cDNA probe, pDR-beta-1 (refs 8, 10) to test whether there are differences in hybridization pattern between DNA from healthy individuals and diabetic patients, after digestion with restriction endonucleases. Among the HLA-DR 4 and 3/4 individuals, the IDDM patients showed an increased frequency of a PstI 18 kilobase (kb) fragment. A BamHI 3.7 kb fragment, frequent among controls (30-40%), was rarely detected in the IDDM patients (0-2%). These differences may be related to susceptibility to develop the disease.
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PMID:HLA-D region beta-chain DNA endonuclease fragments differ between HLA-DR identical healthy and insulin-dependent diabetic individuals. 630 68


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