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A Lernmark

Publications and source records attributed to A Lernmark.

At least 37 records · Page 2Linked to original sources
PubMed1991

Interleukin-1 beta regulation of islet and thyroid autoimmunity in the BB rat.

Daily injections of high dose human recombinant interleukin-1 beta (IL-1 beta) accelerated the onset of both insulin-dependent diabetes mellitus and lymphocytic thyroiditis in genetically prone BB rats. In diabetes-resistant BB rats, high dose IL-1 beta failed to induce diabetes. Additionally, the presence of neutralizing IL-1 beta antibodies in these rats strongly correlated with inhibition of lymphocytic thyroiditis. Since low dose IL-1 beta protects diabetes-prone rats from IDDM, we conclude that IL-1 beta is a potent modulator of autoimmune diabetes and thyroid disease in genetically susceptible rats.

Adrenal Glands↗
PubMed1991

Islet cell cytoplasmic antibodies (ICA) in diabetes and disorders of glucose tolerance.

Islet cell cytoplasmic antibodies were determined in 85 individuals 60 to 74 years old with fasting hyperglycaemia, in 65 patients with cystic fibrosis, in 113 patients with pancreatitis, in 21 patients with Turner's phenotype, and in 135 first-degree relatives of patients with Type 1 (insulin-dependent) diabetes. Islet cell antibodies were absent in all 60 to 74-year-old subjects with fasting hyperglycaemia detected by screening, and who did not require insulin treatment within 3 years. Islet cell antibodies were also absent in all patients with pancreatitis, cystic fibrosis, or Turner's phenotype. Islet cell antibodies were detected in 2 out of 135 (1.5%) first-degree relatives of new Type 1 diabetic patients, and in 1 out of 371 (0.3%) non-diabetic control subjects. During 12 years of follow-up 1 of the 2 first-degree relatives with islet cell antibodies and the only positive control developed Type 1 diabetes. It is suggested that islet cell antibodies are primarily associated with Type 1 diabetes and not with other disorders of glucose tolerance.

Acute Disease↗
PubMed1991

Effects of ginkgolide B, a platelet-activating factor inhibitor on insulitis in the spontaneously diabetic BB rat.

The BB rat spontaneously develops insulin-dependent diabetes mellitus (IDDM) in association with marked insulitis in the islet of Langerhans. Since platelet-activating factor (PAF-acether) is involved in allergic and inflammatory reactions, we tested a PAF antagonist, Ginkgolide B (BN 52021) for potential effects on islet inflammation and diabetes. Diabetes prone BB/Wor rats were treated daily from weaning at 25 days until 105 days of age with either saline (n = 30, controls), 10 (n = 25, low dose) or 20 (n = 30, high dose) mg/kg body weight of BN 52021. The overall incidence of IDDM was unaffected by treatment. Quantitative analysis of insulin area showed a dose-dependent protection of beta cells by Ginkgolide B, reflected in a 6- (low dose) to 8-fold (high dose) (P less than 0.01-0.005) increase in the insulin/glucagon cell ratio compared to the saline treated rats. Ginkgolide B reduced severe insulitis from 84% in the saline rats developing IDDM to 59% (n.s.) in the low and to 33% (P less than 0.001) in the high dose group. These data suggest that PAF inhibitors may prove useful in immunomodulator therapy of IDDM since beta cells are preserved.

Animals↗
PubMed1991

Autoimmunity of diabetes.

Insulin-dependent diabetes mellitus is associated with a growing number of immune abnormalities. At the time of clinical onset, most patients developing the disease as children or young adults have autoantibodies reactive with islet beta cells. Current autoantibody markers for IDDM are not sufficient to predict the disease in the general population. Studies in first-degree relatives indicate the presence of a subclinical disease characterized by beta cell dysfunction, which may or may not progress to overt IDDM. Although IDDM is genetically linked to certain HLA-DQ class II molecules, it needs to be clarified whether these molecules determine the propensity to react to certain antigens, the failure to maintain tolerance, or the ability to produce disease-associated autoantibodies. Circumstantial evidence suggests that yet another gene outside the HLA complex on chromosome 6 is more important. The interaction with the environment needs to be clarified, and the etiologic role of viruses has not been substantiated. An underlying systemic autoimmune propensity may influence environmental insults and perpetuate islet beta cell destruction. Until these mechanisms are understood, clinicians should periodically check their patients with IDDM for other organ-specific as well as non--organ-specific autoimmune diseases. Our understanding of these phenomena is poor, which may explain why clinical trials with immunosuppressive agents have been of limited success. Further studies on the molecular biology of the immune response against islet beta cell-specific antigens are necessary for the development of both predictive tests and novel measures to prevent IDDM.

Autoantibodies↗
PubMed1990

IL-1 beta modulation of spontaneous autoimmune diabetes and thyroiditis in the BB rat.

Long term effects of in vivo treatment with human rIL-1 beta on diabetogenesis and thyroid disease were determined in the Biobreeding rat. Administration of high dose (10 micrograms/kg) IL-1 beta accelerated the onset of insulin-dependent diabetes mellitus compared to saline-injected controls. High dose treatment resulted in goiter development, pronounced LT, reduced serum T4 levels, and overall growth reduction. In contrast, low dose IL-1 beta (0.5 microgram/kg) administration significantly reduced the frequency of insulin-dependent diabetes mellitus (48%) compared to placebo (86%) and high dose IL-1 beta (93%) treatment groups. Rats protected by low dose IL-1 beta had unaffected growth rates and minimal to no pancreatic and thyroid pathology. Our results demonstrate that exogenous administration of IL-1 beta modulates Biobreeding rat idiopathic autoimmune diabetes and thyroid disease in a dose-dependent manner.

Animals↗
PubMed1990

A novel affinity purification method to isolate peptide specific antibodies.

Site-specific, high affinity polyclonal antisera are effectively and successfully produced by immunizing rabbits with synthetic peptides. The use of these antisera in subsequent immune analysis is often limited because of non-specific binding. We describe a new and simple method to effectively affinity-purify anti-peptide antibodies. To test our system, rabbits were immunized with model peptides representing sequences of the putative rabbit growth hormone receptor and several HLA-DQ beta-chain molecules. Polystyrene plastic beads were coated with peptides. Immune serum was incubated with the beads and after a wash step the bound antibodies were eluted in 1 M acetic acid. The eluted material was composed predominantly of intact immunoglobulin as evidenced by the presence of heavy and light chain bands in SDS-PAGE. The eluted antibodies were peptide specific in ELISA and bound only to intact, antigenic protein in immunoblot analyses. The sequence-specific nature of the eluted antibodies was confirmed since binding to the antigenic proteins could be displaced by the immunizing but not by unrelated peptides.

Animals↗
PubMed1990

Cellular and subcellular localization of an Mr 64,000 protein autoantigen in insulin-dependent diabetes.

Antibodies to an Mr 64,000 protein from human or rat islets have been detected at high frequency in newly diagnosed insulin-dependent diabetic patients. In this study, we show that the antigenic and amphiphilic properties of the rat islet Mr 64,000 protein resemble that of the human protein. We have analyzed the expression of the Mr 64,000 protein in populations of pancreatic beta and non-beta cells and in selected rat tissues by immunoprecipitation of [35S]methionine-radiolabeled proteins with sera from diabetic patients or from healthy control individuals. When islet cell populations enriched in beta or non-beta cells were tested for the expression of the Mr 64,000 antigen, the protein was primarily observed in the beta cells. On analyzing preparations of islets, liver, kidney, thyroid, adrenal, pituitary, spleen, and thymus, the protein could only be detected in islets. The protein was also characterized in terms of its subcellular localization by Percoll density gradient centrifugation and was recovered in a fraction enriched in the plasma membrane marker, 5'-nucleotidase. These results are consistent with a beta cell-restricted plasma membrane expression of the protein and support the hypothesis that this protein is a target antigen of beta cell-specific autoimmunity in insulin-dependent diabetes.

Animals↗
PubMed1990

Islet cell antibodies and fasting C-peptide predict insulin requirement at diagnosis of diabetes mellitus.

The differential diagnosis between Type 1 (insulin-dependent) and Type 2 (non-insulin-dependent) diabetes is complicated since no specific markers are available for either disease. In this study, 244 consecutive patients were diagnosed with diabetes mellitus during two years in Malmö (230,000 inhabitants), corresponding to an incidence rate of 53.100,000(-1).year-1. Age, body mass index, HbA1c, C-peptide, and levels of islet cell antibodies were determined at the clinical onset, and related to the classification at diagnosis and at follow-up (n = 233) after a median time of 31 (range 1-49) months. After diagnosis, 42 of 244 (17%) were started on insulin while 202 of 244 (83%) were not. Islet cell antibodies were present in 25 of 42 (60%), and in 18 of 183 (10%), respectively. In the non-insulin treated group, patients with islet cell antibodies had lower body mass index (p less than 0.001), higher HbA1c (p less than 0.004), and lower C-peptide (p less than 0.001) than patients without. At follow-up, 11 of 18 (61%) islet cell positive patients were changed to insulin treatment, as were six other patients. Insulin was discontinued in five initially insulin-treated but islet cell antibody negative patients. The sensitivity, specificity and predictive value for insulin treatment at follow-up were for islet cell antibody positivity; 72%, 96% and 84%, respectively, and for low C-peptide value; 60%, 96%, and 80%, respectively. Islet cell antibodies and low C-peptide at diagnosis of diabetes mellitus are concluded to be useful markers to predict insulin dependence.

Adolescent↗
PubMed1990

Immunoreactive trypsin(ogen) in the sera of children with recent-onset insulin-dependent diabetes and matched controls. The Swedish Childhood Diabetes Group.

To evaluate the exocrine pancreatic function at the time of diagnosis of insulin-dependent diabetes mellitus, we determined immunoreactive anodal and cathodal trypsin(ogen) levels in sera from almost all children (n = 375) 0-14 years of age in Sweden in whom diabetes developed during 1 year, and in sex-, age-, and geographically matched control subjects (n = 312). The median level of anodal trypsin(ogen) was 5 (quartile range, 3-7) micrograms/L in children with newly diagnosed diabetes, compared with a median level of 7 (quartile range, 4-8) micrograms/L in control subjects (p less than 0.0001). Similarly, the median level of cathodal trypsin(ogen) was 8 (quartile range, 4-10) micrograms/L in children with diabetes, compared with a median level of 11 (quartile range, 7-15) micrograms/L in control subjects (p less than 0.0001). The median of the individual ratios between cathodal and anodal trypsin(ogen) was 1.4 in the diabetic patients and 1.7 in the control children (p less than 0.001). In a multivariate test, however, only the decrease in cathodal trypsin(ogen) concentration was associated with diabetes. The levels of trypsin(ogen)s did not correlate with levels of islet cell antibodies, present in 81% of the diabetic children. Several mechanisms may explain our findings, for example, similar pathogenetic factors may affect both the endocrine and exocrine pancreas simultaneously, a failing local trophic stimulation by insulin on the exocrine cells may decrease the trypsinogen production, and there may be an increased elimination of trypsin(ogen) because of higher filtration through the kidneys in the hyperglycemic state.

Adolescent↗
PubMed1990

HLA heterozygosity in insulin-dependent diabetes is most frequent at the DQ locus.

Restriction fragment length polymorphism using an HLA-DQ beta-chain genomic probe showed that 63 children with insulin-dependent (type 1) diabetes mellitus (IDDM) were all (100%) positive for the BamH1 fragments 12 kb and/or 4 kb compared to 98% (62/63) for HLA-DR3 and/or 4 and 75% (47/63) for HLA-B8 and/or 15. The 36 (56%) DR3-positive children were all 4-kb-positive; however, a total of 44 (70%) children were 4-kb-positive (P less than 0.02). The 55 (87%) DR4-positive children were all 12-kb-positive, but a total of 56 (89%) were 12-kb-positive (NS). The heterozygosity at the HLA region increased from 11/63 (18%) for HLA-B8/15 to 29/63 (46%) for HLA-DR3/4 (P less than 0.0004) and to 37/63 (59%) for the HLA-DQ 4 kb/12 kb fragments (P less than 0.02). The test of an equal probability of a positive result under the adjacent pair of tests indicates that the increased risk of developing IDDM in association with HLA-DQ is to a great extent due to heterozygosity at this locus. There were no differences between the 4 kb/12 kb and the DR3/4-positive IDDM children with respect to fasting or meal-stimulated C peptide, insulin requirement, or levels of insulin antibodies formed during the first 12 months of insulin therapy. Our results support the hypothesis that HLA-DQ is closely associated with an increased risk of childhood IDDM, and when typed for at this locus parameters of the clinical course were homogeneous, suggesting that factors other than HLA-DQ may determine previously observed differences between IDDM children in clinical or functional parameters.

Adolescent↗
PubMed1990

Lack of systematically found insulin autoantibodies in spontaneously diabetic BB rats.

Insulin autoantibodies (IAAs) occur in newly diagnosed human insulin-dependent diabetes mellitus (IDDM) patients, but their presence in BB rats is controversial, possibly due to assay differences or variability in the animals studied. To resolve this controversy, IAAs were measured in well-characterized inbred BB rats both in radioligand assays with 125I-labeled rat insulin I or II, respectively, and in an enzyme-linked immunosorbent assay (ELISA) with rat insulin as antigen. In prospective studies, a total of 57 serums from 16 diabetes-prone (DP) BB rats were obtained during an interval ranging from 15 wk to the last week before onset and at onset of diabetes. At comparable ages, 21 serums were obtained from 8 DP BB rats not developing diabetes, and 70 matched serums were obtained from 19 diabetes-resistant (DR) BB rats. Levels of antibody binding increased slightly with increasing age in DP and matched DR rats. Two rats were positive at onset of IDDM in all assays but not in earlier samples. Otherwise, only few isolated serums from both types of rats regardless of diabetes had increased binding in one of the assays. In a cross-sectional study, the insulin-binding levels in 150-day-old DP rats (n = 20) that had not yet developed diabetes did not correlate with insulitis present in 3 of 20 rats and did not differ from 150-day-old DR BB rats (n = 20).(ABSTRACT TRUNCATED AT 250 WORDS)

Aging↗
PubMed1989

Site-specific antibodies distinguish single amino acid substitutions in position 57 in HLA-DQ beta-chain alleles associated with insulin-dependent diabetes.

The HLA-DQ beta-chain gene shows a close association with susceptibility or resistance to autoimmune insulin-dependent diabetes mellitus (IDDM) and it has been suggested that the amino acid in position 57 may be of pathogenetic importance. To study the expression of the IDDM associated HLA-DQ beta-chain alleles, we immunized rabbits with 12 to 13 amino acid long peptides representing HLA-DQw7 and -DQw8 allelic sequences, differing only by one amino acid in position 57 being aspartic acid (Asp) and alanine (Ala), respectively. Immunoblot analysis of lymphoblastoid cells showed that several antisera recognized a 29-kDa protein, equivalent to the expected molecular size of the HLA-DQ beta-chain to yield two antisera specific for HLA-DQw7 (pos. 57Asp) and three antisera for HLA-DQw8 (pos. 57Ala) positive cells. Analysis of HLA-DR 3/4 positive IDDM patients (n = 24) and controls (n = 19) showed that all (100%) patients were positive for pos. 57Ala antiserum compared to 13 of 19 (68%) of the controls. The remaining six controls reacted with the pos. 57Asp antisera, whereas none of the patients did. We have therefore successfully been able to generate site-specific antibodies that distinguish single amino acid substitutions in predetermined positions of allelic HLA-DQ beta-chain gene products. Such sera should become useful to detect and investigate HLA associated susceptibility to autoimmune diseases in man.

Alleles↗
PubMed1989

Islet cell and other organ-specific autoantibodies in all children developing type 1 (insulin-dependent) diabetes mellitus in Sweden during one year and in matched control children.

The majority (about 90%) of children developing Type 1 (insulin-dependent) diabetes mellitus do not have a first-degree relative with the disease. Nearly all (389/405, 96%) children (0-14 years) in Sweden, who developed diabetes during one year, were therefore studied to compare islet cell, thyroid peroxidase, thyroglobulin, and gastric H+, K+-ATPase antibodies with 321 age, sex, and geographically matched, but non-related, control children. Islet cell (cytoplasmic) antibodies were found in 81% (316/389) of the patients and in 3% (9/321) of the control children (p less than 0.001). The median islet cell antibody levels were 70 (range 3-8200) Juvenile Diabetes Foundation (JDF) Units in the islet cell antibody positive patients, and 27 (range 17-1200) JDF Units in the control children (NS). Autoantibodies against thyroid peroxidase (8%), thyroglobulin (6%), and gastric H+, K+-ATPase (3%) were all increased in the patients compared with the control children, being 2% (p less than 0.001), 2% (p less than 0.01), and 0.3% (p less than 0.01), respectively. During an observation time of 20-34 months, two of the nine islet cell antibody positive control children developed Type 1 diabetes, after 8 and 25 months respectively, while the others remained healthy and became islet cell antibody negative. None of the islet cell antibody negative control children developed diabetes during the same time of observation. This first investigation of an unselected population of diabetic children and matched control children shows: that islet cell antibodies are strongly associated with newly diagnosed childhood diabetes, that other autoantibodies are more frequent among diabetic children than control children, and that the frequency of islet cell antibodies in the background population of children is higher than previously documented, and could also be transient, underlining that factors additional to islet cell antibodies are necessary for the later development of Type 1 diabetes.

Autoantibodies↗