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At least 1,009 records · Page 56Linked to original sources
PubMed2003

Ketosis-prone diabetes: dissection of a heterogeneous syndrome using an immunogenetic and beta-cell functional classification, prospective analysis, and clinical outcomes.

Ketosis-prone diabetes is heterogeneous. Its causes could include novel beta-cell functional defects. To characterize such defects, 103 patients with diabetic ketoacidosis were evaluated for beta-cell autoimmunity and human leukocyte antigen (HLA) class II alleles, with longitudinal measurements of beta-cell function and biochemical and clinical parameters. They were classified into four A beta groups, based on the presence of glutamic acid decarboxylase (GAD)65, GAD67, or IA-2 autoantibodies (A+ or A-) and beta-cell functional reserve (beta+ or beta-). The group distribution was: 18 A+beta-, 23 A-beta-, 11 A+beta+, and 51 A-beta+. Collectively, the two beta- groups differed from the two beta+ groups in earlier onset and longer duration of diabetes, lower body mass index, less glycemic improvement, and persistent insulin requirement. HLA class II genotyping showed that the A-beta- group differed from the A+beta- group in having lower frequencies of two alleles strongly associated with autoimmune type 1 diabetes susceptibility: DQA*03 and DQB1*02. Similarly, the A-beta+ group differed from the A+beta+ group in having a lower frequency of DQB1*02. Ketosis-prone diabetes comprises at least four etiologically distinct syndromes separable by autoantibody status, HLA genotype, and beta-cell functional reserve. Novel, nonautoimmune causes of beta-cell dysfunction are likely to underlie the A-beta+ and A-beta- syndromes.

Adolescent↗
PubMed2004

Endocrine and immunogenetic testing in individuals with type 1 diabetes and 21-hydroxylase autoantibodies: Addison's disease in a high-risk population.

Individuals with type 1 diabetes mellitus (T1D) at risk for Addison's disease (AD) can be identified with RIAs for autoantibodies to the adrenal antigen 21-hydroxylase (21-OHAA). Screening individuals with T1D for 21OH-AA shows a relatively high prevalence of positive autoantibodies (1.4%, 38 of 2696 subjects). After detection of 21-OHAA, individuals were evaluated with endocrine testing, including baseline cortisol, ACTH, and plasma renin activity and low (1 mug) and high (250 mug) dose cortrosyn stimulation. Typing for DR and DQ alleles and for the major histocompatibility complex class I-related chain A (MICA) gene polymorphisms was performed. Six individuals were diagnosed with AD; five were identified on initial endocrine evaluation. Follow-up over 2.9 yr yielded one additional diagnosis of AD. Endocrine testing showed a correlation between baseline ACTH and peak cortisol (r = -0.61; P < 0.0001), baseline and peak cortisol (r = 0.70; P < 0.0001), and stimulated cortisol after low- and high-dose testing (r = 0.92; P < 0.0001). DR3-DQ2/DR4-DQ8 with DRB1* 0404 was associated with expression of 21-OHAA. At 2 yr, individuals homozygous for MICA5.1 had AD-free survival of 60% compared with 100% AD-free survival in those who were not homozygous for MICA5.1. Homozygosity for MICA5.1 may increase progression to overt AD among 21-OHAA-positive individuals.

Addison Disease↗
PubMed1992

Conjugal multiple sclerosis: immunogenetic characterization and analysis of T- and B-cell reactivity to myelin proteins.

We describe two families with conjugal multiple sclerosis. Onset of symptoms in the husbands occurred 11 and 17 years after onset of relapsing/remitting symptoms in their wives. There were no similarities regarding clinical manifestations of MS within each family. Evaluation of T-cell repertoire by enumeration of cells secreting interferon-gamma in response to proteolipid protein (PLP), myelin basic protein (MBP), and to various synthetic MBP peptides revealed similar patterns of T-cell reactivity within the families both in MS-affected parents and unaffected children. Genomic HLA-DR-DQ typing showed that T-cell reactivity was independent of HLA class II phenotype. Analysis of B-cell responses in blood showed low numbers of cells secreting IgG, IgA, or IgM antibodies against MBP, PLP, myelin-associated glycoprotein, and myelin-oligodendrocyte glycoprotein both in MS-affected and unaffected family members. In conclusion, our study of two families with conjugal MS has shown a dominant T-cell response against the same MBP peptide within the family both in MS-affected parents and unaffected children, and this T-cell response seems to be independent of the HLA class II phenotypes of the family members.

Adult↗
PubMedDate not supplied

Exposure to superantigens as an immunogenetic explanation of type I diabetes mini-epidemics.

Insulin-dependent diabetes mellitus (IDDM) is considered to be an autoimmune disease. Autoimmune diseases result from the breakdown of self-tolerance elicited by environmental factors on a susceptible genetic background. This reduced tolerance allows immunocompetent cells to attack normal structures present on an individual's tissues. The study of the T cells present in the islets of patients who died at the onset of the disease allowed the recognition of "superantigens" as etiopathogenetic factors in the development of IDDM. Since superantigens are the product of bacteria or viruses able to quickly stimulate a large number of the peripheral T cells sharing the same T cell receptor V beta segments once presented by certain HLA class II molecules, a number of observations in genetics, immunology, virology and epidemiology can now find a unifying explanation.

Adolescent↗
PubMed1985

Endocrine and immunogenetic evaluation of an XX male infant with perineoscrotal hypospadias.

To clarify the origin of the genital ambiguity occasionally associated with the XX male syndrome, a series of endocrinological studies were undertaken in an affected 6 months old infant with perineoscrotal hypospadias. The patient fulfilled all the diagnostic criteria of the syndrome: the testes were descended bilaterally, the Mullerian derivatives were absent, the 46,XX chromosome complement was ascertained in different cell lines, and male levels of H-Y antigen were detected in cultured skin fibroblasts. Circulating gonadotrophin levels and pituitary LRH responsiveness were within normal limits for the age group. Serum testosterone (T) levels were normal, and gonadal stimulation with hCG caused a significant rise on serum T. Incubations of [3H]T with fibroblasts from genital skin revealed normal activity of steroid 5 alpha-reductase. Moreover, normal concentrations of thermostable cytosol androgen receptors were revealed in cultured fibroblasts. Altogether the results indicated that ambiguity of the external genitalia in this patient was the result of neither abnormal T biosynthesis, peripheral A-ring T reduction, nor androgen intracellular specific binding, and suggested that the nature of the incomplete virilization could be a non-endocrine independent event associated to this disorder. The data are also consistent with the notion that testicular impairment observed in adult XX males develops later in life.

3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗
PubMed1990

Immunogenetic analysis of beta-cell autoimmunity in NOD mice. Relationship of insulitis to T-lymphocyte-receptor beta nod and A beta nod genes.

An early molecular event in the evolution of insulin-dependent diabetes in humans and NOD mice appears to involve the interaction of MHC class II molecules, beta-cell autoantigen-derived peptides, and receptor molecules of helper T lymphocytes. To examine the influence of T-lymphocyte-receptor beta-genes on the development of beta-cell autoimmunity, (NOD x NZW)F1 x NOD backcrossed (BC) mice were studied for the development of insulitis, because insulitis is the pathognomonic histological lesion of autoimmune diabetes. Heterozygosity for H-2nod was permissive for the development of pancreatic interstitial inflammation and peri-islet insulitis, whereas homozygosity for H-2nod was highly associated with insulitis. However, (NOD x NZW)F1 x NOD BC mice developed insulitis regardless of homozygosity or heterozygosity for T-lymphocyte receptor beta nod. Therefore, in our study, T-lymphocyte receptor beta nod did not function as an autosomal-recessive beta-cell autoimmunity gene.

Animals↗
PubMed1991

Epidemiology and immunogenetic background of islet cell antibody--positive nondiabetic schoolchildren. Ulm-Frankfurt population study.

Islet cell antibodies (ICAs) were determined in a large cohort of white nondiabetic schoolchildren (n = 4287) from a homogenous population in southern Germany. The prevalence of ICA levels greater than or equal to 5 Juvenile Diabetes Foundation (JDF) U was 1.05% (95% confidence interval 0.8-1.4%). Analysis of HLA-DR beta and -DQ beta alleles revealed that the specificities found to be increased in insulin-dependent (type I) diabetic subjects with the same ethnic background were also associated with ICA positivity in the nondiabetic schoolchildren. HLA-DR3 (P less than 0.01) and -DR4 (P less than 0.01) phenotypes and absence of Asp residue (P less than 0.01) at codon 57 of the HLA-DQ beta-chain were significantly increased in ICA+ compared with control subjects. High levels of ICAs, which were categorized as either greater than or equal to 17 or greater than or equal to 30 JDF U, were found to be associated with amino acids other than Asp at position 57 of the HLA-DQ beta-chain. No association of ICA level was found for HLA-DR phenotypes.

Adolescent↗
PubMed1995

Differential immunogenetic determinants of polyclonal insulin autoimmune syndrome (Hirata's disease) and monoclonal insulin autoimmune syndrome.

The insulin autoimmune syndrome (IAS), or Hirata's disease, is characterized by the combination of fasting hypoglycemia, high concentration of total serum immunoreactive insulin, and presence of autoantibodies to native human insulin in serum. Autoantibody production is classified as monoclonal or polyclonal, with the majority of IAS cases classified as polyclonal. Previously, we observed a striking association between the human leukocyte antigen (HLA) class II alleles DRB1*0406/DQA1* 0301/DQB1*0302 and Japanese IAS patients with polyclonal insulin autoantibodies (IAAs) and T-cell recognition of human insulin in the context of DRB1*0406 molecules. Because of such a strong HLA association in IAS, we performed intra- and interethnic studies on IAS-associated DRB1 alleles and searched for the critical amino acid residue(s) for IAS pathogenesis. Glutamate at position 74 in the HLA-DR4 beta 1-chain was presumed to be essential to the production of polyclonal IAA in IAS, whereas alanine at the same position of the HLA-DR beta 1-chain might be important in the production of monoclonal IAA.

Adult↗
PubMedDate not supplied

Evaluation of epidemiology and immunogenetics of IDDM in Spanish- and Portuguese-heritage registries. A key to understanding the etiology of IDDM? Diabetes Epidemiology Research International Group.

There appears to be extraordinary international variation in the incidence of insulin-dependent diabetes mellitus (IDDM), the reasons for which are not known. By evaluating the incidence of IDDM in Spanish- and Portuguese-heritage populations, important insight into reasons for the major worldwide differences in IDDM risk may be gained. The limited data that are available for Hispanic populations suggest that there is at least a 10-fold difference in risk between individuals of Hispanic ancestry in Colorado and Mexicans in Mexico City. Standard methods for assessing IDDM incidence are needed to further elucidate the patterns of risk among populations of iberian heritage. Therefore, we propose that comparable IDDM registries be established in the Spanish- and Portuguese-speaking world. Once registries are established, further investigation of the characteristics of IDDM among various populations (including seasonal distributions, sex differences, age at onset, and changing trends over time) may help explain the large international incidence differences among not only Spanish- and Portuguese-heritage populations but also among all children.

Diabetes Mellitus, Type 1↗
PubMed1990

Mutagenesis and expression of putative class II susceptibility genes: a "reverse immunogenetics" approach to analysis of HLA and disease.

Immune activation events regulated by the human MHC are triggered by interactions between HLA class II molecules, antigenic peptides, and reactive T cells. In most autoimmune diseases, little is known about the latter two elements of this trimolecular complex, while the HLA class II contribution is being deciphered in increasingly sophisticated detail. In two cases in particular, type I diabetes and rheumatoid arthritis, susceptibility is tied to structural elements within specific HLA class II genes. Site-directed mutagenesis and gene expression studies provide a means to directly test the contribution of specific residues within individual candidate disease susceptibility genes to peptide and T cell interactions.

Antigen-Presenting Cells↗
PubMed1997

Immunogenetics and the cause of autoimmune disease.

Autoimmune disease results from the action of environmental factors on a predisposed genotype. In this review, the role of genetic susceptibility in the aetiology of autoimmune disease is examined. As the genetics of autoimmune diabetes has been studied more intensively than that of other autoimmune diseases, supporting evidence is drawn principally from that example. Autoimmune diseases are not inherited as entities but as constitutions which confer an increased probability of developing disease. It is proposed that there are two components to autoimmune disease susceptibility. One confers susceptibility to autoimmunity per se, while the other determines tissue specificity. In this review, the concept of liability is introduced as a tool used in quantitative genetics and is applied to the analysis of autoimmune diabetes by considering a threshold model. In this example, empirically derived incidence figures are used to calculate heritability which is a relative measure of the influence of genetics and environmental factors. The validity of applying the concept of liability to diabetes is confirmed by examining the values of heritability calculated from empirical data obtained from different kindred relationships, and by confirming that the assumptions on which liability is based are supported by recent gene mapping data. Finally, the physiological significance of liability is considered and its significance to the cause of autoimmunity discussed.

Animals↗
PubMed1981

Immunogenetic markers in essential hypertension.

In a series of 148 patients with essential hypertension, the presence of the atherosclerotic C3-F gene and HLA-antigen frequences were investigated, and the results were compared with those in 62 age and sex matched normotensive controls. The frequency of C3-F was significantly higher in patients (p less than 0.03), as was HLA-B15 in patients with a positive family history of hypertension (p less than 0.05). The presence of the C3-F gene was associated with an increased risk (= 10.2) for coronary heart disease, and B15 was associated with an increased risk (= 6.0) for cerebral events in both familial and non familial cases of hypertension. It is suggested that determination of the C3-F gene and HLA-antigens might be a tool in the identification of hypertensive patients at particular high risk for vascular events, irrespective of BP levels. The study support the suggestions that some genetic factors may act via immunological pathways.

Adolescent↗
PubMed1991

Immunogenetics of the HLA system.

The study of the HLA system was primarily initiated to understand the basis for the histocompatibility between recipients and tissue donors. HLA typing methods are being continuously improved and biochemical and molecular typing, in particular, are expected to provide precise typing of the HLA system. Conventional HLA typing methods can define antigen specificities, while biochemical and molecular methods will provide direct allele typing that is based on the actual sequence polymorphism. The precise tissue typing will definitely improve the outcome of transplantation. Structural studies have revealed the highly polymorphic nature of the HLA system and given insight to understanding the molecular basis of the HLA polymorphism. One big immunological puzzle remaining to be answered is how T-cell receptor molecules recognize peptide antigen in conjunction with the HLA molecule. The crystallization of the T-cell receptor molecule, an experiment currently underway, will eventually reveal the structural basis of the trimolecular interaction.

Animals↗
PubMed1981

Immunogenetic studies on low-density lipoprotein allotypes in chickens (Lcp1 and Lcp2).

Two blood plasma lipoprotein allotypes are described. Specific antiallotypic reagents were obtained from alloimmune precipitating sera produced against normal plasma and subsequently against lipoprotein fraction of d less than 1.072 g/ml. Identification studies by means of centrifugation and specific staining show that Lcp1 and Lcp2 are markers of the low-density lipoprotein class, 1.006 less than d less than 1.063 g/ml. Serological and genetic studies indicate that the two alloantigens behave as products of allelic genes, each occurring with varying frequencies in 20 lines studies. The Lcp1 antigen is always accompanied by Lcp2; however, the latter was also found to occur in plasma of birds lacking the Lcp1 marker.

Animals↗