==================================BSR17================================== 17. Autoantibodies in human insulin-dependent (type-1) diabetes mellitus. - islet cell antibodies (ICA) - islet cell surface antibodies (ICSA) - gastric parietal cells - thyroid, thryoglobulin - lymphocytes. 1 UI - 87119930 AU - Ratzmann KP TI - Does mumps infection play a role in the etiology and pathogenesis of insulin-dependent diabetes mellitus? AB - Numerous experimental findings in animals as well as epidemiological and clinical observations support the hypothesis that certain viruses play a role in the pathogenesis of insulin-dependent diabetes mellitus (IDDM). Directly or via immune and/or autoimmune processes viruses might induce a beta-cell damage. An attempt is made to evaluate critically the arguments for the role of the mumps virus in the pathogenesis of IDDM. Based on their own experience, the authors hold the opinion that at present a causal connection between mumps infection and the development of IDDM cannot be proved beyond doubt. Prospective studies in humans including appropriate techniques of humoral and cellular immunity in relation to the beta-cell damage are required. MH - Adolescence ; Animal ; Autoantibodies/IMMUNOLOGY ; Autoimmune Diseases/ COMPLICATIONS ; Diabetes Mellitus, Insulin-Dependent/*ETIOLOGY/IMMUNOLOGY ; Human ; HLA-DR Antigens/IMMUNOLOGY ; Mumps/*COMPLICATIONS/IMMUNOLOGY ; Rats ; Rats, Inbred Strains ; Retrospective Studies ; Review SO - Med Interne 1986 Oct-Dec;24(4):245-52 2 UI - 87107644 AU - Bottazzo GF ; Todd I ; Mirakian R ; Belfiore A ; Pujol-Borrell R TI - Organ-specific autoimmunity: a 1986 overview. AB - The normally functioning immune system is subject to intricate networks of regulatory mechanisms: it is therefore not surprising to find that autoimmune diseases present a complex pathogenic picture in which the relative contributions of various factors probably determine the precise nature and course of disease. This is particularly evident in the effector mechanisms of organ-specific autoimmunity which are described in this chapter. These ultimately give rise to the disease symptoms, and can be directly cytotoxic, or may either stimulate or block functional activity or growth of the target cells. Their various contributions to human diseases are becoming more firmly established, as in Type I diabetes, or are only now being described, as in the case of EC-Ab in protracted diarrhea of infancy and as evidenced by the growing lists of receptor-stimulating or -blocking antibodies. The nature and precise location of relevant autoantigens is also coming under closer scrutiny. The answers to the question of why these diseases arise in the first place remain more elusive. However, it is again likely that a variety of factors can contribute. The attractive possibility of a role for idiotypic interactions is gaining ground, particularly within the context of antibodies to hormones and their receptors. Another potential mechanism which we believe may be of central importance, particularly in the development of organ-specific destructive autoimmunity, and which we have discussed here in detail, is the aberrant expression of HLA Class II molecules by target cells. Whether this is actually an initiating factor is presently not known, but its potential for promoting pathogenesis both early and late in the process is clear. Furthermore, the complex nature of the regulation of epithelial Class II expression may help to explain the heterogeneity of features and course of disease in different patients with the same underlying pathology. All these advances in our basic understanding of the disease processes should ultimately lead to more effective and specific means of therapeutic intervention. MH - Animal ; Antibody Specificity ; Antigens, Immune Response/IMMUNOLOGY ; Autoantibodies/IMMUNOLOGY ; Autoimmune Diseases/*IMMUNOLOGY ; B Lymphocytes/IMMUNOLOGY ; Diabetes Mellitus, Insulin-Dependent/IMMUNOLOGY ; Endocrine Glands/*IMMUNOLOGY ; Epithelium/IMMUNOLOGY ; Hormones/ IMMUNOLOGY ; Human ; Intestines/IMMUNOLOGY ; Receptors, Endogenous Substances/IMMUNOLOGY ; Review ; Sex Factors ; Support, Non-U.S. Gov't SO - Immunol Rev 1986 Dec;94:137-69 3 UI - 87078882 AU - Roman SH ; Davies TF ; Witt ME ; Ginsberg-Fellner F ; Rubinstein P TI - Thyroid autoantibodies in HLA-genotyped type 1 diabetic families: sex-limited DR5 association with thyroid microsomal antibody. AB - Thyroid autoantibodies are common in Type 1 diabetics and their first degree relatives and may be part of the autoimmune diathesis present within such families. We have measured the prevalence of microsomal (M-Ab) and thyroglobulin (Tg-Ab) autoantibodies in 84 HLA-typed families having a Type 1 diabetic child, using enzyme-linked immunosorbent assay techniques. Thyroid autoantibodies were detectable in 201/407 (49%) individuals in these families. Both autoantibodies were significantly more frequent in the subsets of parents, diabetic children and their non-diabetic siblings than in groups of control adults and children. The prevalence of these autoantibodies in the diabetic families was increased in both sexes with a female:male ratio of 1.4:1. Antigen DR5 was significantly associated with M-Ab production but only for male subjects (P = 0.005 after correction for the number of DR antigens tested). No significant associations were encountered for Tg-Ab. Within-family analyses indicated that thyroid autoantibodies occurred with increased prevalence in HLA-identical or haplo-identical siblings of autoantibody-positive index cases in comparison to control children. We conclude the DR association with thyroid autoantibody production in this diabetes-selected population was thyroiditis-related and not diabetes-related, and the DR5 association was restricted to males and the production of M-Ab. These data are consistent with the hypothesis that multiple genetic and non-genetic factors played a role in the high prevalence of thyroid autoantibodies in this population. MH - Adolescence ; Adult ; Aged ; Autoantibodies/*IMMUNOLOGY ; Child ; Child, Preschool ; Diabetes Mellitus, Insulin-Dependent/FAMILIAL & GENETIC/ *IMMUNOLOGY ; Enzyme-Linked Immunosorbent Assay ; Female ; Histocompatibility Testing ; Human ; HLA Antigens/ANALYSIS ; Infant ; Infant, Newborn ; Male ; Middle Age ; Support, Non-U.S. Gov't ; Support, U.S. Gov't, P.H.S. ; Thyroid Gland/*IMMUNOLOGY SO - Clin Endocrinol (Oxf) 1986 Jul;25(1):23-33 4 UI - 87058978 AU - Gerling I ; Baekkeskov S ; Lernmark A TI - Islet cell and 64K autoantibodies are associated with plasma IgG in newly diagnosed insulin-dependent diabetic children. AB - There is a high prevalence of islet cell antibodies (ICA) and autoantibodies detected against an islet cell protein of Mr 64,000 at the time of clinical diagnosis of insulin-dependent diabetes (IDDM). In view of the biphasic immune response after antigen presentation, the purpose of this study was to determine the presence of ICA and antibodies against the 64,000 islet antigen after separation of IgM from IgG to prevent interference between the two antibody classes. Plasma samples from 10 newly diagnosed IDDM children and 10 healthy controls were precipitated with polyethylene glycol (PEG), and the crude Ig was subjected to Sephacryl S-300 chromatography to separate IgM and IgG. ICA determined by indirect immunofluorescence on frozen sections of human pancreas showed reduced background immunofluorescence intensity in the purified fractions compared with crude plasma. The number of ICA-positive samples among the IDDM patients increased from 7/10 in plasma to 9/10 in the IgG fraction. There was an increase in the ICA titer in 6/9 of the positive samples. All purified IgM samples were ICA negative. Immunoprecipitation experiments by using Nonidet P-40 detergent lysates of [35S]methionine-labeled neonatal rat islets demonstrated that the 64,000 autoantibodies were in the IgG fraction. We found 7/10 IDDM samples to be positive, whereas all controls were negative. The background in the autoradiographic analysis was markedly reduced in the IgG fractions compared with immunoprecipitates with crude or PEG-purified plasma and the IgM fraction. ICA titers did not correlate to the ability of the IgG fraction to precipitate the 64,000 autoantigen. It is concluded that both the ICA and 64,000 autoantibodies are primarily of the IgG class at the time of clinical onset of IDDM, and that purification of IgG from human IDDM plasma facilitates the detection of the rat islet cell 64,000 antigen. MH - Animal ; Antigens/*IMMUNOLOGY ; Autoantibodies/*ANALYSIS ; Autoimmune Diseases/*IMMUNOLOGY ; Child ; Diabetes Mellitus, Insulin-Dependent/ *IMMUNOLOGY ; Fluorescent Antibody Technic ; Human ; IgG/*ANALYSIS ; IgM/ ANALYSIS ; Islands of Langerhans/*IMMUNOLOGY ; Rats ; Support, Non-U.S. Gov't ; Support, U.S. Gov't, P.H.S. SO - J Immunol 1986 Dec 15;137(12):3782-5 5 UI - 87054290 AU - Peters WH ; Lester FT ; Kohnert KD ; Hildmann W TI - The frequency of islet cell surface antibodies in newly diagnosed diabetics from Ethiopia. AB - Forty-three newly diagnosed diabetic patients from Ethiopia were studied for the frequency of islet cell surface antibodies and other clinical features which are relevant to the aetiopathogenesis and classification of diabetes mellitus. In preliminary investigations of a small number of controls and noninsulin-dependent diabetics we found, as expected, no circulating antibodies. Four first-degree relatives of ICSA-positive sibs were negative, too. However, 3 out of 7 known insulin-treated diabetics displayed ICSA in the blood serum. In our study of newly diagnosed diabetics we found ICSA in 39% (17/43). Five patients who were assigned to the NIDDM subclass had no antibodies. 37 diabetics required insulin treatment after clinical diagnosis and 16 (43%) of these were ICSA-positive. There were no differences in the assessed clinical parameters between ICSA-positive and -negative patients. One ICSA-positive patient initially controlled with oral hypoglycaemic agents became insulin-dependent within our study period. Our observations in newly diagnosed diabetics from Ethiopia revealed a lower frequency of ICSA than in Caucasians, however, the results provide evidence for the occurrence of auto-immune phenomena in the aetiopathogenesis of diabetes mellitus in this ethnic group. MH - Adult ; Autoantibodies/*ANALYSIS ; Diabetes Mellitus/CLASSIFICATION/ *IMMUNOLOGY ; Diabetes Mellitus, Insulin-Dependent/IMMUNOLOGY ; Diabetes Mellitus, Non-Insulin-Dependent/IMMUNOLOGY ; Ethiopia ; Female ; Human ; Islands of Langerhans/*IMMUNOLOGY ; Male SO - Exp Clin Endocrinol 1986 Aug;87(3):326-32 6 UI - 87030371 AU - Lorini R ; Larizza D ; Livieri C ; Cammareri V ; Martini A ; Plebani A ; Zanaboni D ; Severi F TI - Auto-immunity in children with diabetes mellitus and in their relatives. AB - Islet cell antibodies (ICA-IgG and complement-fixing-ICA), parietal cell antibodies (PCA), intestinal epithelial cell antibodies (IECA), thyroglobulin (TgA) and thyroid microsomal antibodies (MsA), antinuclear (ANA) and reticulin antibodies (RA), were studied in 55 insulin-dependent diabetic patients (30 males and 25 females), aged 2-19 years with diabetes from a few days up to 14 years. In 58% of the diabetics one or more autoantibodies were found: ICA-IgG (31%), CF-ICA (16%), PCA (34%), TgA (9%), MsA (9%), ANA (13%), RA (2%). Autoantibodies were significantly more frequent in females (76%) than in males (43%) (P less than 0.025). ICA-IgG, CF-ICA, PCA, ANA were significantly more frequent in patients than in controls. The frequency of ICA-IgG and CF-ICA was significantly higher during the first 3 years of disease than afterwards (P less than 0.001); a similar pattern was observed for PCA, TgA, MsA. Of the 87 parents and 30 siblings screened for ICA-IgG, CF-ICA, PCA, IECA, TgA, MsA, ANA and RA, 42 (44%) had one or more autoantibodies, which were more frequent in females than in males. Seven relatives (6%) were ICA-IgG positive (four mothers, two fathers and one brother), and only one mother, ICA-IgG negative, was CF-ICA positive. Other autoantibodies were also more frequent in parents than in controls. Autoantibody-positive relatives have been asymptomatic up to now. MH - Adolescence ; Adult ; Autoantibodies/*IMMUNOLOGY ; Child ; Child, Preschool ; Complement Fixation Tests ; Diabetes Mellitus, Insulin-Dependent/FAMILIAL & GENETIC/*IMMUNOLOGY ; Epithelium/IMMUNOLOGY ; Female ; Human ; IgG/IMMUNOLOGY ; Intestines/IMMUNOLOGY ; Male ; Microsomes/IMMUNOLOGY ; Middle Age ; Parietal Cells, Gastric/IMMUNOLOGY ; Reticulin/IMMUNOLOGY ; Thyroglobulin/IMMUNOLOGY ; Thyroid Gland/ IMMUNOLOGY SO - Eur J Pediatr 1986 Aug;145(3):182-4 USER: 7 UI - 87021916 AU - Dyrberg T TI - Humoral autoimmunity in the pathogenesis of insulin-dependent diabetes mellitus. Studies in the spontaneously diabetic BB rat. AB - The present review describes the autoimmune aspects of the pathogenesis of insulin-dependent diabetes mellitus (IDDM) in man and in the BB rat, and the requirements for effective prevention. Using a xenotypic mouse islet cell antiserum, we demonstrated the presence of antibodies reacting specifically with the pancreatic beta cells and recognizing a Mr 40,000 plasma membrane glycoprotein. The existence of beta cell-specific surface antigens, which hypothetically could act as targets in an autoimmune response, might explain the selective disappearance of the beta cells in IDDM. The BB rat spontaneously develops an insulin-dependent diabetes much like IDDM in man. Diabetes in BB rats, as in IDDM of humans, is associated with a high incidence of islet cell surface antibodies. These antibodies precipitate a Mr 64,000 protein from lysates of islets of Langerhans isolated from normal rats. In the BB rat, islet cell antibodies precede the appearance of insulitis and the clinical onset of diabetes. We investigated the beneficial effects of early treatment with low doses of cortisone on diabetes in the BB rat, because comparable experiments in children with newly diagnosed IDDM have given inconclusive results. In the BB rat there was no effect on the incidence or severity of diabetes or on the diabetes-related, islet cell-directed autoimmune phenomena. However, immunologic intervention that prevents IDDM from developing in potentially susceptible individuals is a promising area for research on this disease. MH - Animal ; Antigenic Determinants ; Autoantibodies/*BIOSYNTHESIS ; Cell Membrane/IMMUNOLOGY ; Cortisone/ADMINISTRATION & DOSAGE ; Diabetes Mellitus, Insulin-Dependent/*IMMUNOLOGY/PREVENTION & CONTROL ; Human ; Islands of Langerhans/IMMUNOLOGY ; Rats ; Rats, Inbred BB ; Support, Non-U.S. Gov't SO - Acta Endocrinol [Suppl] (Copenh) 1986;280:1-29 8 UI - 87014574 AU - Kaye WA ; Adri MN ; Soeldner JS ; Rabinowe SL ; Kaldany A ; Kahn CR ; Bistrian B ; Srikanta S ; Ganda OP ; Eisenbarth GS TI - Acquired defect in interleukin-2 production in patients with type I diabetes mellitus. AB - Deficient production of interleukin-2 has been reported in Type I diabetes, but its cause has not been elucidated. We therefore measured interleukin-2 production in 27 patients with Type I diabetes, 20 patients with Type II diabetes (6 requiring insulin), 5 monozygotic twin pairs discordant for Type I diabetes, and 10 nondiabetic persons with islet-cell antibodies. Interleukin-2 production was decreased in patients with Type I diabetes as compared with controls (35.8 +/- 2.5 vs. 61.6 +/- 4.6 percent, P less than 0.001). Interleukin-2 production did not differ between patients with Type II diabetes and controls, regardless of whether the patients used insulin. Twins with Type I diabetes had decreased interleukin-2 production as compared with normal controls (33.2 +/- 5.4 vs. 61.6 +/- 4.6 percent, P less than 0.001) and with their nondiabetic twins (33.2 +/- 5.4 vs. 54.5 +/- 3.4 percent, P less than 0.005). Interleukin-2 production in nondiabetic twins and in nondiabetic persons with islet-cell antibodies was normal. There was no correlation between glycosylated hemoglobin levels and interleukin-2 production in any diabetic group. We conclude that patients with Type I diabetes have an acquired defect in interleukin-2 production, whereas patients with Type II diabetes do not, and that this defect is not correlated with an ongoing autoimmune process, with hyperglycemia, or with insulin administration or oral hypoglycemic therapy. Thus, the defect appears to be related to marked beta-cell destruction, although not to the metabolic consequences thereof or the responsible autoimmune process. MH - Adult ; Autoantibodies/ANALYSIS ; Child ; Diabetes Mellitus, Insulin-Dependent/FAMILIAL & GENETIC/*IMMUNOLOGY/METABOLISM ; Diabetes Mellitus, Non-Insulin-Dependent/IMMUNOLOGY/METABOLISM ; Diseases in Twins ; Glucose Tolerance Test ; Hemoglobin A, Glycosylated/ANALYSIS ; Human ; Interleukin 2/*BIOSYNTHESIS ; Islands of Langerhans/IMMUNOLOGY ; Middle Age ; Support, Non-U.S. Gov't ; Support, U.S. Gov't, P.H.S. SO - N Engl J Med 1986 Oct 9;315(15):920-4 9 UI - 87005684 AU - Gregor I ; Iberg N ; Berger W ; Fl:uckiger R TI - Albumin-directed antibodies in diabetes: demonstration of human serum albumin-directed IgM autoantibodies. AB - Sera of 406 individuals, 174 Type 1 (insulin-dependent) diabetic patients, 125 non-diabetic family members and 107 unrelated control subjects, were screened for the presence of antibodies against glycated albumin. In none of these sera could such antibodies be detected. However, antibodies directed towards monomeric, unmodified human serum albumin were detected in 13 sera. These albumin autoantibodies were of the IgM class, and occurred in sera from nondiabetic persons (0.9-1.6%) and with a five-fold higher frequency in sera from diabetic patients (5.2%). The presence of albumin antibodies was neither related to the presence of diabetic late complications, islet cell antibodies, HLA-status nor duration of diabetes. The albumin antibodies were also found in sera from persons carrying antibodies against mumps (17%) or Epstein-Barr virus. MH - Autoantibodies/*ISOLATION & PURIFICATION ; Diabetes Mellitus, Insulin-Dependent/FAMILIAL & GENETIC/*IMMUNOLOGY ; Female ; Glycosylation ; Human ; IgM/*ISOLATION & PURIFICATION ; Male ; Serum Albumin/ *IMMUNOLOGY ; Support, Non-U.S. Gov't SO - Diabetologia 1986 Aug;29(8):481-4 10 UI - 86275653 AU - Atkinson MA ; Maclaren NK ; Riley WJ ; Winter WE ; Fisk DD ; Spillar RP TI - Are insulin autoantibodies markers for insulin-dependent diabetes mellitus? AB - Recent studies have shown that insulin autoantibodies occur in patients with newly diagnosed insulin-dependent diabetes mellitus (IDDM) before exogenous insulin treatment. Our study was designed to test the hypothesis that insulin autoantibodies, like cytoplasmic islet cell antibodies (ICAs), can identify individuals with ongoing autoimmune beta-cell destruction and increased risk of IDDM development. Insulin autoantibodies detected by use of a radioligand-binding assay were found in 1.4% of normal controls, 4% of first-degree relatives of IDDM patients, and in 37% of newly diagnosed IDDM patients. A strong positive correlation between insulin autoantibodies and ICAs was observed. HLA typing of insulin-autoantibody-positive first-degree relatives of IDDM patients, as well as in the general population, revealed a strong association with HLA-DR3 and/or-DR4, suggesting that insulin autoantibodies are restricted to persons genetically susceptible to IDDM. In an ongoing study of beta-cell function in ICA-positive nondiabetic individuals, the additional presence of insulin autoantibodies significantly increased the likelihood of beta-cell dysfunction. After intravenous glucose stimulation, insulinopenia was present in 70% of ICA and insulin-autoantibody-positive individuals in contrast to only 23% of ICA-positive, insulin-autoantibody-negative persons. These data document a significant association between insulin autoantibodies and ICAs and support the contention that insulin autoantibodies, like ICAs, are markers of ongoing beta-cell destruction. MH - Antigens, Immune Response/IMMUNOLOGY ; Autoantibodies/*IMMUNOLOGY ; Child ; Diabetes Mellitus, Insulin-Dependent/FAMILIAL & GENETIC/*IMMUNOLOGY ; Family ; Female ; Human ; HLA Antigens/IMMUNOLOGY ; Insulin/*IMMUNOLOGY ; Male ; Support, Non-U.S. Gov't ; Support, U.S. Gov't, P.H.S. SO - Diabetes 1986 Aug;35(8):894-8 11 UI - 86319136 AU - H:aggl:of B ; Rabinovitch A ; Mackay P ; Huen A ; Rubenstein AH ; Marner B ; Nerup J ; Lernmark A TI - Islet cell and other organ-specific autoantibodies in healthy first-degree relatives to insulin-dependent. AB - The presence of organ-specific autoantibodies including islet cell surface, cytoplasmic and cytotoxic as well as thyroid-gastric antibodies were determined in healthy, non-diabetic, first-degree relatives to 30 insulin-dependent diabetic (IDDM) children. Thirty healthy families without family-history of diabetes mellitus served as controls. The prevalence of organ-specific autoantibodies among the healthy members in the diabetic families was increased compared to the control families (p less than 0.005). Islet cell cytoplasmic antibodies were only detected in diabetes families, since 23% (7/30) of the probands and 7% (2/31) of the siblings were positive and all others negative. Organ-specific autoantibodies were associated with HLA DR3 only in the diabetes families (p less than 0.025) while autoantibody positive members in the control families were associated with HLA B7 (p less than 0.01). This study suggests that childhood IDDM occurs in families with an increased prevalence of organ-specific autoantibodies. MH - Adolescence ; Adult ; Antibody-Dependent Cell Cytotoxicity ; Antinuclear Factors/ANALYSIS ; Autoantibodies/*ANALYSIS/GENETICS ; Child ; Child, Preschool ; Diabetes Mellitus, Insulin-Dependent/*FAMILIAL & GENETIC/ IMMUNOLOGY ; Female ; Human ; Male ; Middle Age ; Parietal Cells, Gastric/ IMMUNOLOGY ; Support, Non-U.S. Gov't ; Support, U.S. Gov't, P.H.S. ; Thyroglobulin/IMMUNOLOGY ; Thyroid Gland/IMMUNOLOGY SO - Acta Paediatr Scand 1986 Jul;75(4):611-8 12 UI - 86302361 AU - Freinkel N ; Metzger BE ; Phelps RL ; Simpson JL ; Martin AO ; Radvany R ; Ober C ; Dooley SL ; Depp RO ; Belton A TI - Gestational diabetes mellitus: a syndrome with phenotypic and genotypic heterogeneity. AB - One hundred ninety-nine gravida with gestational diabetes mellitus (GDM) defined as "carbohydrate intolerance of varying severity with onset or first recognition during pregnancy: have been stratified into subgroups on the basis of fasting plasma glucose and evaluated for further phenotypic and genotypic heterogeneity. A significantly greater proportion of the women in all our groups were older and heavier than in a "control: population of 148 consecutive gravida with documented normal oral glucose tolerance. After correction for age and weight by covariate analysis, absolute insulinopenia in response to oral glucose could be demonstrated in all GDM groups, although exceptions were present in each. The incidence of diabetes in the mothers of our patients with GDM was 8-fold greater than in controls; the incidence in fathers did not deviate from control patterns. HLA-DR3 and DR4 antigens were more frequently present in GDM and the increase was statistically significant in blacks. At the time of diagnosis, cytoplasmic islet cell antibodies (ICA) were significantly more common in GDM associated with elevated fasting plasma glucose than in controls; the frequency of ICA was 18.4% (7/38) in women with fasting plasma glucose greater than or equal to 130 mg/dl. Our findings indicate that GDM entails genotypic as well as phenotypic diversity and may include patients with slowly-evolving Type I diabetes mellitus, as well as patients with Type II diabetes mellitus, and women with asymptomatic diabetes which antedated the pregnancy (i.e. pregestational diabetes mellitus). Appreciation of this heterogeneity should be incorporated into any evaluation of intervention strategies for women with GDM or into prognoses concerning their postpartum metabolic status. MH - Adult ; Age Factors ; Antigens, Immune Response/ANALYSIS ; Autoantibodies/ ANALYSIS ; Blood Glucose/ANALYSIS ; Body Weight ; Diabetes Mellitus, Insulin-Dependent/FAMILIAL & GENETIC/IMMUNOLOGY ; Diabetes Mellitus, Non-Insulin-Dependent/FAMILIAL & GENETIC/IMMUNOLOGY ; Female ; Genotype ; Glucose Tolerance Test ; Human ; Insulin/SECRETION ; Male ; Phenotype ; Pregnancy ; Pregnancy in Diabetes/*CLASSIFICATION/FAMILIAL & GENETIC/ IMMUNOLOGY ; Review ; Support, Non-U.S. Gov't ; Support, U.S. Gov't, P.H.S. SO - Horm Metab Res 1986 Jul;18(7):427-30 13 UI - 86301598 AU - Takahashi A ; Tsujihata M ; Yokota A ; Yamaguchi Y ; Ueda Y ; Akazawa S ; Miyake S ; Nagataki S TI - A new method of detection of islet cell antibodies (ICA) using peroxidase-labeled protein A, and incidence of ICA in type 1 (insulin-dependent) diabetes. AB - We have developed a new method of detecting islet cell antibodies using peroxidase-labeled protein A, and have determined the incidence of ICA in Type 1 (insulin-dependent) diabetes in Japan. In our method, fresh frozen sections of human pancreas and serum samples were incubated and then treated with peroxidase-labeled protein A at room temperature. Conjugates of peroxidase and protein A were subjected to Sephadex G-200 column chromatography, and only the 80,000 dalton peak was employed. The treated sections were allowed to react with haematoxylin and eosin (HE) to confirm the localization of islet cells. With this method, human pancreatic tissues can be used regardless of age and blood type, and the stained sections can be stored for more than 5 years. Serum samples obtained from 52 patients with Type 1 diabetes, 54 with Type 2 (non-insulin-dependent) diabetes and 100 control subjects were examined. In patients with Type 1 diabetes, islet cell antibodies were detected in 14 of 14 (0.5 years after onset), 3 of 6 (0.5-1 years after onset), 7 of 16 (1-5 years after onset) and 2 of 16 (more than 5 years after onset). In contrast, only 4 of 54 patients with Type 2 diabetes and none of the controls were ICA positive. It is concluded that, with our newly developed method using peroxidase-labeled protein A, ICA is present in all Japanese Type 1 diabetic patients whose diabetic manifestations are less than 0.5 years duration from onset. MH - Adult ; Aged ; Autoantibodies/*ANALYSIS ; Comparative Study ; Diabetes Mellitus, Insulin-Dependent/*IMMUNOLOGY ; Female ; Fluorescent Antibody Technic ; Human ; *Immunoenzyme Technics ; Islands of Langerhans/ *IMMUNOLOGY ; Japan ; Male ; Middle Age ; Pancreas/IMMUNOLOGY ; Staphylococcal Protein A SO - Diabetologia 1986 Jun;29(6):378-82 14 UI - 86300083 AU - Faber OK ; Binder C TI - C-peptide: an index of insulin secretion. AB - Insight into the natural history of beta cell function in IDDM patients obtained by C-peptide measurements is reviewed. It is argued that residual insulin secretion of metabolic importance is present in all IDDM patients during the initial course of the disease. After some months, beta cell function reaches its maximum; thereafter it declines at different rates dependent on the age at onset of diabetes and, possibly, on the presence of ICA and HLA-antigens. As many as 15% of IDDM patients retain life-long beta cell function that persists at approximately 10% of that observed in nondiabetic individuals. The residual endogenous insulin secretion is characterized by reduced capacity, as well as abnormal insulin secretory kinetics; these defects in residual insulin secretion can be modulated by changes in metabolic regulation as well as by immunosuppression during the initial course of the disease. MH - Age Factors ; Animal ; Autoantibodies/ANALYSIS ; Blood Glucose/METABOLISM ; C-Peptide/*BLOOD/SECRETION ; Diabetes Mellitus, Insulin-Dependent/ IMMUNOLOGY/*METABOLISM ; Human ; IgG/ANALYSIS ; Insulin/*SECRETION ; Islands of Langerhans/IMMUNOLOGY/*SECRETION ; Kinetics ; Review SO - Diabetes Metab Rev 1986;2(3-4):331-45 15 UI - 86284189 AU - Baekkeskov S TI - Immunoreactivity to a 64,000 Mr human islet cell antigen in sera from insulin-dependent diabetes mellitus patients and individuals with abnormal glucose tolerance. AB - Autoantibodies in sera from newly diagnosed insulin-dependent diabetes mellitus (IDDM) patients recognize a 64,000 Mr human islet cell antigen. The incidence of these antibodies was 86% in 28 insulin-dependent diabetes mellitus patients, 100% in seven first-degree relatives with abnormal glucose tolerance, 6% in 34 healthy individuals, 17% in 29 patients with Hashimoto's or Graves' disease, and 0% in five systemic lupus erythematosis patients. It is suggested that the 64,000 Mr human islet cell protein is the major target antigen of islet cell autoantibodies in insulin-dependent diabetes mellitus. MH - Antigens/*IMMUNOLOGY ; Autoantibodies/*IMMUNOLOGY ; Autoantigens/ *IMMUNOLOGY ; Autoimmune Diseases/IMMUNOLOGY ; Diabetes Mellitus, Insulin-Dependent/FAMILIAL & GENETIC/*IMMUNOLOGY ; Human ; Islands of Langerhans/*IMMUNOLOGY ; Molecular Weight ; Prediabetic State/FAMILIAL & GENETIC/IMMUNOLOGY ; Support, Non-U.S. Gov't ; Support, U.S. Gov't, P.H.S. SO - Mol Biol Med 1986 Apr;3(2):137-42 16 UI - 86284188 AU - Henson V ; Maclaren N ; Winter W ; Riley W ; Rotter J ; Wakeland EK TI - Molecular genetics of insulin-dependent diabetes mellitus. AB - Insulin-dependent diabetes mellitus is an autoimmune disease the development of which is influenced by genetic factors (Cahill & McDevitt, 1981). As concordance for IDD is less than 50% in identical twins, environmental factors are also required for the development of IDD. Although viral agents have been implicated in the past, the specific environmental components leading to IDD remain unknown. This paper reviews current research focused on the genetic factors that influence susceptibility to IDD. MH - Antigens, Immune Response/GENETICS ; Autoantibodies/GENETICS ; Diabetes Mellitus, Insulin-Dependent/*FAMILIAL & GENETIC/IMMUNOLOGY ; Female ; Human ; HLA Antigens/GENETICS ; Insulin/GENETICS ; Male ; Polymorphism (Genetics) ; Review ; Sex Factors ; Stomach/IMMUNOLOGY ; Support, Non-U.S. Gov't ; Support, U.S. Gov't, P.H.S. ; Thyroid Gland/IMMUNOLOGY SO - Mol Biol Med 1986 Apr;3(2):129-36 17 UI - 86284187 AU - Srikanta S ; Eisenbarth GS TI - Islet cell antigens. Initial studies of their biology and function. AB - Differentiation antigens expressed by pancreatic islet cells presumably play important roles in islet physiology and pathophysiology. We have developed a series of monoclonal antibody probes directed towards islet endocrine cells. Utilizing these antibodies we have identified and biochemically characterized several glycoprotein and glycolipid islet cell antigens. Many islet cell antibodies appear to react with unique carbohydrate residues on their antigen molecules. Islet cells share several monoclonal antibody-defined antigens and antigenic determinants with other neuroendocrine and related cell types. The detailed molecular structure, ontogeny, function and pathogenetic relevance of these islet antigens are being investigated. MH - Antibodies, Monoclonal/IMMUNOLOGY ; Antigenic Determinants/IMMUNOLOGY ; *Antigens ; Autoantibodies/IMMUNOLOGY ; *Autoantigens ; Cell Differentiation ; Diabetes Mellitus, Insulin-Dependent/IMMUNOLOGY ; Glycolipids/IMMUNOLOGY ; Glycoproteins/IMMUNOLOGY ; Human ; Islands of Langerhans/*IMMUNOLOGY ; Support, Non-U.S. Gov't ; Support, U.S. Gov't, P.H.S. SO - Mol Biol Med 1986 Apr;3(2):113-27 18 UI - 86249111 AU - Bhatia E ; Mehra NK ; Malaviya AN ; Ahuja MM TI - HLA and autoimmunity in North Indian type I (insulin-dependent) diabetic multiplex families. AB - The HLA haplotype segregation and autoantibody spectrum in 7 type I (insulin-dependent) diabetic multiplex families of North Indian origin were determined. Of the total of 17 diabetic sibs, 7 shared both haplotypes and 3 shared one haplotype with the proband. No HLA-non-identical sibs were observed. This distribution of haplotypes was non-random (P approximately equal to 0.005). The mode of inheritance was compatible with an autosomal recessive model, while a dominant model was unlikely. Pancreatic islet-cell antibodies were found in 23.5% of affected sibs, but in no healthy family member. A high incidence of other autoantibodies (parietal-cell and thyroglobulin/thyroid microsomal antibodies) was detected in both the diabetic patients (26.3%), and in healthy first-degree relatives (22.2%). These findings emphasize the role of HLA-linked genes and autoimmunity in the pathogenesis of type I diabetes in North India. MH - Adolescence ; Adult ; Autoantibodies/*GENETICS ; Diabetes Mellitus, Insulin-Dependent/FAMILIAL & GENETIC/*IMMUNOLOGY ; Female ; Gene Frequency ; Genes, Recessive ; Human ; HLA Antigens/*GENETICS ; India ; Male ; Pedigree ; Support, Non-U.S. Gov't SO - Horm Metab Res 1986 May;18(5):331-4 19 UI - 86249110 AU - Betterle C ; Zanette F ; Presotto F ; Pedini B ; Tessari P ; Valerio A ; Tiengo A TI - Alpha cell autoantibodies: immunological and metabolic follow-up study. AB - We studied glucagon responses to OGTT and insulin and arginine stimulation in 12 out of 21 patients who were found positive for alpha cell autoantibodies (ACA) during routine screening procedures for autoimmunity in a group of 4080 individuals. The study was repeated in 8 subjects after an average observation period of 42 months. In both studies glucagon plasma levels were normal and independent of ACA titres, ACA ability to fix complement and ACA ability to cross-react with duodenal alpha cells. The clinical significance of ACA remains to be elucidated. MH - Adolescence ; Adult ; Aged ; Autoantibodies/*ANALYSIS ; Child ; Child, Preschool ; Diabetes Mellitus, Insulin-Dependent/FAMILIAL & GENETIC/ IMMUNOLOGY ; Duodenum/IMMUNOLOGY ; Female ; Glucagon/BLOOD ; Human ; Islands of Langerhans/*IMMUNOLOGY ; Male ; Middle Age ; Support, Non-U.S. Gov't ; Time Factors SO - Horm Metab Res 1986 May;18(5):327-30 20 UI - 86246545 AU - Josephsen PG ; Permin H ; Juhl F ; Enk B ; Svehag SE TI - Circulating immune complexes, insulin antibodies, and deposits of immunoglobulins in the skin in diabetes. AB - Sixty-five insulin-dependent diabetes mellitus (IDDM) patients at the Steno-Memorial Hospital entered the present study. Of these, 43.1 percent had one or more late diabetic complication, 19.3 percent had circulating immune complexes (CIC)--there was a tendency for CIC to be related to late diabetic complications (P = 0.1) - and 16.9 percent had elevated total S-IgG. Elevated S-IgG values were related neither to CIC, to complications, nor to IgG deposits in the skin. Three patients had elevated total S-IgM, IgD and, IgE, respectively. No patients had elevated total S-IgA. Insulin antibodies were present in 41.9 percent. They were related to neither CIC nor clinical complications. No patients had rheumatoid factors (RF) or granulocyte-specific antinuclear antibodies (ANA). 12.3 percent had a low titre of organ non-specific ANA. No relationship could be established between ANA and complications or CIC. As regards skin deposits IgG was present at the dermo-epidermal junction zone (DEJ) and/or in the dermal vessels in 75.4 percent of the patients; IgA was present in 35.4 percent; and IgM in 32.3 percent. IgD and IgE were absent in all patients. Fibrinogen deposits were found in 80 percent and complement C3 in 32.3 percent. No correlation was found between skin deposits and CIC, on one hand, or clinical complications, on the other. From the present work, we conclude that humorally mediated immunological processes are active in IDDM. However, the exact role of this activity still remains to be defined. MH - Adolescence ; Adult ; Antigen-Antibody Complex/*IMMUNOLOGY ; Autoantibodies/IMMUNOLOGY ; Child ; Complement 3/IMMUNOLOGY ; Diabetes Mellitus, Insulin-Dependent/BLOOD/*IMMUNOLOGY ; Female ; Fibrinogen/ IMMUNOLOGY ; Human ; IgA/IMMUNOLOGY ; IgG/IMMUNOLOGY ; IgM/IMMUNOLOGY ; Immunoglobulins/*IMMUNOLOGY ; Insulin Antibodies/*IMMUNOLOGY ; Male ; Middle Age ; Skin/*IMMUNOLOGY SO - Dan Med Bull 1986 Jun;33(3):171-4 21 UI - 86230208 AU - Mandel TE ; Cuthbertson RA TI - Low-dose immunosuppression may unmask type I diabetes mellitus by specific inactivation of suppressor cells. AB - Type I diabetes mellitus is strongly genetically linked to the major histocompatibility complex but relatively few potentially susceptible people, who are presumably frequently exposed to appropriate triggering factors (e.g. viral illness, environmental agents), develop overt disease. It is possible that some such individuals show latent disease (e.g. islet cell antibodies and perhaps local pancreatic pathology) that does not progress. On the basis of animal data and some clinical evidence we speculate that latent disease is controlled by suppressor cells. We suggest that physiological immunosuppression (e.g. with glucocorticoids) may selectively inactivate such T suppressor cells. Such immunomodulation may allow further islet cell destruction to occur and repeated episodes could eventually produce diabetes. Such episodes of altered immunoregulation may be due to intercurrent viral illness, stress, or therapy with low doses of immunosuppressive agents. MH - Animal ; Autoantibodies/BIOSYNTHESIS ; Diabetes Mellitus, Experimental/ ETIOLOGY ; Diabetes Mellitus, Insulin-Dependent/*ETIOLOGY/FAMILIAL & GENETIC/IMMUNOLOGY ; Human ; *Immune Tolerance ; Islands of Langerhans/ IMMUNOLOGY/PATHOLOGY ; Mice ; Models, Biological ; Rats ; Review ; Suppressor Cells/*IMMUNOLOGY SO - Med Hypotheses 1986 Apr;19(4):325-31 22 UI - 86224457 AU - Shoelson SE ; Marshall S ; Horikoshi H ; Kolterman OG ; Rubenstein AH ; Olefsky JM TI - Antiinsulin receptor antibodies in an insulin-dependent diabetic may arise as autoantiidiotypes. AB - An insulin-requiring diabetic patient with intermittent periods of increased insulin requirements and insulin resistance was studied. The patient was found to have high titers of antiinsulin antibodies; subfractionation of the patient's serum revealed several populations of antiinsulin antibodies with differing affinities and titers for insulin. The ability of one of the insulin antibody fractions to bind [125I]iodoinsulin was markedly inhibited by the patient's serum (insulin depleted) and by purified total immunoglobulin G from which antiinsulin antibodies and insulin were removed. These findings suggested an antiidiotypic antibody in the patient's immunoglobulin G fraction reacting specifically with the antiinsulin antibody subfraction. Finally, the patient's serum contained an antiinsulin receptor antibody, as demonstrated by the ability of serum to specifically immunoprecipitate covalently labeled soluble insulin receptors. In conclusion, these results suggest that this patient generated a widespread polyclonal response to insulin, with the development of several populations of antiinsulin antibodies. An antiidiotypic antibody to a specific insulin antibody subfraction was present in the patient's serum which we believe had structural similarity to the binding site of the insulin molecule, accounting for the reactivity of the antiidiotypic antibody with the insulin receptor. MH - Affinity Labels ; Aged ; Anti-Antibodies/*BIOSYNTHESIS ; Autoantibodies/ *BIOSYNTHESIS ; Case Report ; Diabetes Mellitus, Insulin-Dependent/ *IMMUNOLOGY/METABOLISM ; Female ; Human ; Immunoglobulin Idiotypes/ *IMMUNOLOGY ; Insulin Antibodies/*IMMUNOLOGY ; Insulin Resistance ; Photochemistry ; Receptors, Insulin/*IMMUNOLOGY SO - J Clin Endocrinol Metab 1986 Jul;63(1):56-61 23 UI - 86218947 AU - Sugiura M ; Hashimoto A ; Shizawa M ; Tsukada M ; Maruyama S ; Ishido T ; Kasahara T ; Hirata Y TI - Heterogeneity of anterior pituitary cell antibodies detected in insulin-dependent diabetes mellitus and adrenocorticotropic hormone deficiency. AB - A sensitive assay method for pituitary cell antibodies (PitCA) was established by a biotin/avidin system using rat pituitary. Results in 24 cases out of 81 insulin-dependent diabetic patients and 10 cases of 21 adrenocorticotropic hormone (ACTH) deficient patients were positive for autoantibodies to anterior pituitary cell cytoplasm. PitCA observed in the sera of insulin-dependent diabetic patients were suspected of being pituitary specific and independent with islet cell antibodies (ICA) and islet cell surface antibodies (ICSA). In the sera of ACTH deficient patients, PitCA were frequently absorbed with liver acetone powder. Populations of insulin-dependent diabetes mellitus (IDDM) are almost equal in males and females. A total of 16 cases out of 21 ACTH deficient patients were female. These results suggest that heterogenous PitCA are involved in the sera of those patients with IDDM and ACTH deficiency. MH - Adrenocorticotropic Hormone/*DEFICIENCY ; Autoantibodies/*ANALYSIS ; Avidin ; Biological Assay/METHODS ; Biotin ; Diabetes Mellitus, Insulin-Dependent/*IMMUNOLOGY ; Female ; Human ; Male ; Pituitary Gland, Anterior/*IMMUNOLOGY SO - Diabetes Res 1986 Mar;3(3):111-4 24 UI - 86164574 AU - Kolb H ; Zielasek J ; Treichel U ; Freytag G ; Wrann M ; Kiesel U TI - Recombinant interleukin 2 enhances spontaneous insulin-dependent diabetes in BB rats. AB - Treatment of BB rats with recombinant interleukin 2 (IL2) enhanced the development of spontaneous diabetes in these animals. A dose of 20 micrograms IL 2/kg body weight was administered twice daily for 80 days starting at 42 days of age. The rate of diabetes was doubled after IL 2 administration (53% vs. 23%) and the onset of diabetes was found to be accelerated by a mean of 18 days. Histological analysis showed enhanced inflammation of islets and in addition interstitial pancreatis. It is concluded that IL 2 has a regulatory effect on spontaneous organ-specific autoimmunity. MH - Animal ; Autoantibodies/IMMUNOLOGY ; Diabetes Mellitus, Insulin-Dependent/ *ETIOLOGY/PATHOLOGY ; Dose-Response Relationship, Drug ; Female ; *Interleukin 2 ; Islands of Langerhans/DRUG EFFECTS ; Lymphocyte Transformation ; Lymphocytes/IMMUNOLOGY ; Male ; Pancreas/PATHOLOGY ; Rats ; Rats, Inbred BB ; Recombinant Proteins/TOXICITY ; Support, Non-U.S. Gov't SO - Eur J Immunol 1986 Feb;16(2):209-12 25 UI - 86060936 AU - Greiner DL ; Handler ES ; Nakano K ; Mordes JP ; Rossini AA TI - Absence of the RT-6 T cell subset in diabetes-prone BB/W rats. AB - Diabetes-prone Bio-breeding/Worcester (DP) rats exhibit a severe T cell lymphopenia and autoimmune pancreatic insulitis. The present results indicate that the T cell lymphopenia is due in large part, if not entirely, to the absence of the RT-6+ peripheral T cell subset, which includes members of both the helper/inducer (W3/25) and suppressor/cytotoxic (OX 8) antigenic phenotypes. Delineation of the causal mechanism(s) for the selective absence of RT-6+ T cells in DP rats may provide important insights into the cellular basis of the insulin-dependent diabetes mellitus syndrome in these animals. MH - Animal ; Antibodies, Monoclonal ; Antigens, Surface/ANALYSIS/IMMUNOLOGY ; Autoantibodies/BIOSYNTHESIS ; Cell Differentiation ; Diabetes Mellitus, Insulin-Dependent/FAMILIAL & GENETIC/*IMMUNOLOGY ; Female ; Histocompatibility Antigens/ANALYSIS/GENETICS/*IMMUNOLOGY ; Immunity, Natural ; Leukocyte Count ; Lymphopenia/FAMILIAL & GENETIC/IMMUNOLOGY ; Male ; Phenotype ; Rats ; Rats, Inbred BB/*IMMUNOLOGY ; Rats, Inbred LEW ; Rats, Inbred Strains/*IMMUNOLOGY ; Rats, Inbred WF ; Spleen/PATHOLOGY ; Support, Non-U.S. Gov't ; Support, U.S. Gov't, P.H.S. ; T Lymphocytes/ *CLASSIFICATION/IMMUNOLOGY/PATHOLOGY SO - J Immunol 1986 Jan;136(1):148-51 26 UI - 86196721 AU - Garzelli C ; Taub FE ; Jenkins MC ; Drell DW ; Ginsberg-Fellner F ; Notkins AL TI - Human monoclonal autoantibodies that react with both pancreatic islets and thyroid. AB - Transformation of human peripheral blood lymphocytes with Epstein-Barr virus and rapid screening on rat insulinoma cells by an enzyme-linked immunosorbent assay were used to identify monoclonal autoantibodies that reacted with human pancreatic islets. Six such monoclonal autoantibodies were isolated and cloned. All six also were found to react with human thyroid. It is concluded that lymphocytes able to make autoantibodies that react with both the pancreas and thyroid are common in the human B cell repertoire. MH - Animal ; Antibodies, Monoclonal/*IMMUNOLOGY ; Autoantibodies/*IMMUNOLOGY ; Cell Transformation, Viral ; Cells, Cultured ; Child ; Diabetes Mellitus, Insulin-Dependent/IMMUNOLOGY ; Epstein-Barr Virus ; Female ; Human ; Immunoglobulins/BIOSYNTHESIS ; Insulinoma/IMMUNOLOGY ; Islands of Langerhans/*IMMUNOLOGY ; Male ; Pancreatic Neoplasms/IMMUNOLOGY ; Rats ; Thyroid Gland/*IMMUNOLOGY SO - J Clin Invest 1986 May;77(5):1627-31 27 UI - 86194039 AU - Omar MA ; Bottazzo GF ; Asmal AC TI - Islet cell antibodies and other autoantibodies in South African blacks and indians with insulin dependent diabetes mellitus (IDDM). AB - The presence or absence of islet cell antibodies and other autoantibodies was determined in 47 African and 34 Indian patients with IDDM and 37 controls. Islet cell antibodies (ICA-IgG) were found in over a third of the patients and in only 2 controls. Complement fixing antibodies (ICA-Cf) were found in 10% of patients, but in none of the controls. Persistence of ICA beyond 3 years was more frequent in Black compared to Indian patients. Parietal cell antibodies were found more often in patients (20%) than controls (5%) as were thyroid microsomal antibodies (11% vs. 0%). None of the patients or controls had adrenal antibodies. MH - Adolescence ; Adult ; Anti-Antibodies/ANALYSIS ; Antibodies/*ANALYSIS ; Autoantibodies/*ANALYSIS ; Blacks ; Child ; Child, Preschool ; Complement/ IMMUNOLOGY ; Diabetes Mellitus, Insulin-Dependent/BLOOD/*IMMUNOLOGY ; Female ; Human ; IgG/IMMUNOLOGY ; India/ETHNOLOGY ; Islands of Langerhans/ CYTOLOGY/*IMMUNOLOGY ; Male ; South Africa ; Support, Non-U.S. Gov't SO - Horm Metab Res 1986 Feb;18(2):126-8 28 UI - 86181538 AU - Haines DM TI - A re-examination of islet cell cytoplasmic antibodies in diabetic dogs. AB - Serum samples were obtained from 48 dogs with recently diagnosed untreated diabetes mellitus. Serums were tested for cytoplasmic autoantibodies to normal canine pancreatic islet antigens by indirect immunofluorescence, peroxidase-anti-peroxidase, and avidin-biotin complex, immunohistochemistry. Autoantibodies were not detectable in any of the samples. Serums were also examined from 20 diabetic dogs maintained on exogenous insulin therapy for periods of one month to five years. Positive reactions were seen in 11 dogs. These positive responses were completely absorbed by preincubation of serums with commercial insulin preparations or with purified pork or beef insulin. Newly diagnosed diabetic dogs do not have readily detectable autoantibodies to islet cytoplasmic antigens. Our previous report (Haines and Penhale, 1985) of islet antibody in diabetic dogs with unknown clinical histories was likely demonstrating antibody to insulin in patients treated with exogenous insulin. Antibodies to insulin were detected in approximately half of the insulin treated dogs tested. These antibodies were induced by commercial beef and pork insulin preparations and were found to be broadly cross-reactive recognizing epitopes on canine, bovine and porcine insulins. MH - Animal ; Autoantibodies/ANALYSIS ; Autoimmune Diseases/DRUG THERAPY/ IMMUNOLOGY/*VETERINARY ; Cattle/IMMUNOLOGY ; Cross Reactions ; Diabetes Mellitus, Insulin-Dependent/DRUG THERAPY/IMMUNOLOGY/*VETERINARY ; Dog Diseases/DRUG THERAPY/*IMMUNOLOGY ; Dogs ; Female ; Immunologic Technics ; Insulin/IMMUNOLOGY/THERAPEUTIC USE ; Islands of Langerhans/*IMMUNOLOGY ; Male ; Species Specificity ; Support, Non-U.S. Gov't ; Swine/IMMUNOLOGY SO - Vet Immunol Immunopathol 1986 Mar;11(3):225-33 29 UI - 86165431 AU - Karjalainen J ; Knip M ; Mustonen A ; Ilonen J ; Akerblom HK TI - Relation between insulin antibody and complement-fixing islet cell antibody at clinical diagnosis of IDDM. AB - To test the hypothesis that insulin-binding antibodies (IBAs) appearing in the circulation before insulin treatment are markers of beta-cell damage, we studied the prevalence of IBAs and both conventional (IF-ICAs)-and complement (CF-ICAs)-fixing cytoplasmic islet cell antibodies in 60 newly diagnosed diabetic children with a mean age of 9.5 yr. Seventeen (28.3%) had an insulin binding exceeding the upper range (2.8%) of that observed in 68 age-matched controls. The IBA-positive subjects were characterized by a younger age of onset [6.2 +/- 4.0 (SD) vs. 10.8 +/- 3.2 yr; P less than 0.001], lower glycosylated hemoglobin A1 levels (14.1 +/- 3.1 vs. 16.0 +/- 3.0%; P less than 0.05), lower serum C-peptide concentrations (0.12 +/- 0.07 vs. 0.20 +/- 0.17 nmol/L; P less than 0.05), and an increased frequency of HLA-Dw4 (9/13 vs. 11/37; P less than 0.05). There was no significant relation between IBAs and serum C-peptide concentrations after age adjustment by multiple regression analysis. Forty-three children (75%) were positive for IF-ICA and 38 (63.3%) for CF-ICA. Twelve IBA-positive diabetics (70.6%) had IF-ICA as well as CF-ICA in their serum. No association could be observed between IBA and either IF-ICA or CF-ICA, however. The results suggest that IBAs developing before diagnosis serve as an indicator of clinical and genetic heterogeneity within IDDM rather than as a marker of autoimmune beta-cell destruction. MH - Adolescence ; Age Factors ; Antibodies/ANALYSIS/*IMMUNOLOGY ; Antigens, Immune Response/IMMUNOLOGY ; Autoantibodies/IMMUNOLOGY ; Child ; Complement Fixation Tests ; Diabetes Mellitus, Insulin-Dependent/ DIAGNOSIS/*IMMUNOLOGY ; Female ; Human ; Insulin/*IMMUNOLOGY ; Islands of Langerhans/*IMMUNOLOGY ; Male ; Support, Non-U.S. Gov't SO - Diabetes 1986 May;35(5):620-2 30 UI - 86155126 AU - Boitard C ; Debray-Sachs M ; Bach JF TI - Autoimmune disorders in diabetes. AB - The development of IDDM correlates with the presence of biologic markers pointing to the involvement of the immune system in the disease process. In addition to clinical observations of association of IDDM with other autoimmune disease and morphologic evidence of a mononuclear cell infiltration of the islets of Langerhans at the onset of the disease, anti-islet cell antibodies are detected in the serum of IDDM patients. Moreover, a strong genetic association with HL-A DR3 and DR4 identifies a genetic background compatible with autoimmune phenomena. Whether autoimmune phenomena are primary or secondary to an initial damage of the islets by infectious agents or other environmental factors is unknown. Whether or not the autoimmune response participates in the selective destruction of insulin-secreting cells has been a major issue in the past five years. The presence of T lymphocytes and anti-islet cell antibodies, which selectively inhibit or lyse insulin-secreting cells in vitro, strongly suggests that it may be the case. A definitive demonstration is difficult to provide in human IDDM. The development of animal models for IDDM has allowed useful insight into the pathogenetic mechanisms responsible for IDDM. In both the BB rat and the low-dose streptozotocin mouse model, the role of the immune system in the destruction of the islets of Langerhans is supported by the prevention of the disease by treatments interfering with the immune system. The BB rat develops a spontaneous autoimmune disease on a genetic background defined by the association with a major histocompatibility complex allele without any evidence for a role in initial damage of islets of a triggering infectious or chemical process. The low-dose streptozotocin model is an autoimmune IDDM secondary to the selective damage of islet cells by a toxin. The present scheme of an islet cell target and specific autoreactive T and B lymphocyte clones raises two major issues: what is the target antigen on islet cells and what is the role at the molecular level of class II major histocompatibility complex genes in susceptibility for IDDM? The first issue is presently being addressed in several laboratories using the hybridoma technology. The second issue is addressed at the biochemical level by studying restriction site polymorphism of major histocompatibility genes in susceptible individuals and IDDM patients, and at the functional level by studying the action of monoclonal antibodies to class II antigen on the development of IDDM in animal models. These steps are likely to be a prerequisite to antigen-specific immunotherapy in IDDM. MH - Animal ; Antibody-Dependent Cell Cytotoxicity ; Antigen-Antibody Complex/ IMMUNOLOGY ; Antigens, Surface/IMMUNOLOGY ; Autoantibodies/*IMMUNOLOGY ; Autoimmune Diseases/FAMILIAL & GENETIC/*IMMUNOLOGY/THERAPY ; Cytotoxicity, Immunologic ; Diabetes Mellitus, Experimental/IMMUNOLOGY ; Diabetes Mellitus, Insulin-Dependent/FAMILIAL & GENETIC/*IMMUNOLOGY/ THERAPY ; Disease Models, Animal ; Genetic Marker ; Human ; HLA Antigens/ GENETICS/IMMUNOLOGY ; Islands of Langerhans/IMMUNOLOGY ; Mice ; Rats ; Rats, Inbred BB ; Review ; T Lymphocytes/IMMUNOLOGY SO - Adv Nephrol 1986;15:281-305 31 UI - 86109187 AU - Srikanta S ; Ricker AT ; McCulloch DK ; Soeldner JS ; Eisenbarth GS ; Palmer JP TI - Autoimmunity to insulin, beta cell dysfunction, and development of insulin-dependent diabetes mellitus. AB - Circulating insulin autoantibodies (INSAAb) were measured in discordant monozygotic twins, first-degree relatives, and other groups at "high risk: for the development of insulin-dependent diabetes mellitus (IDDM), and these results correlated with both islet cell antibody (ICAb) status and beta cell function. INSAAb were positive in 31.6% (12 of 38) ICAb-positive subjects but in only 3.1% (3 of 97) ICAb-negative subjects (X2 = 22.4; P less than 0.001). Elevated levels of INSAAb tended to correlate with younger age and were observed in individuals irrespective of the prevailing degree of their beta cell function. Eight of 15 subjects detected to be INSAAb positive have thus far progressed to clinical IDDM (X2 = 18.3; P less than 0.001). Thus, autoantibodies reactive with the insulin molecule (1) appear to constitute an additional serologic marker of ongoing autoimmunity and development of IDDM, and (2) may reflect heterogeneity in the pathogenesis of IDDM. MH - Adolescence ; Adult ; Aged ; Autoantibodies/*IMMUNOLOGY ; Child ; Child, Preschool ; Diabetes Mellitus, Insulin-Dependent/FAMILIAL & GENETIC/ *IMMUNOLOGY ; Diseases in Twins/IMMUNOLOGY ; Glucose Tolerance Test ; Human ; Infant ; Insulin/*IMMUNOLOGY ; Islands of Langerhans/ *PHYSIOPATHOLOGY ; Middle Age ; Support, Non-U.S. Gov't ; Support, U.S. Gov't, P.H.S. ; Twins, Monozygotic SO - Diabetes 1986 Feb;35(2):139-42