Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A monoclonal islet cell antibody, HISL-19, reactive with human, bovine, and porcine pancreatic islets has been used to identify and characterize a novel group of islet cell proteins (p120, p69, p67, and p56). Besides the islets, HISL-19-reactive antigenic determinants are also expressed on selected cell types, namely, gut endocrine cells, thyroid parafollicular cells (p120), anterior pituitary cells (p40 and p24), specific hypothalamic neuroendocrine cells, and a single layer of large pyramidal cells of the cerebral cortex, thus defining a new family of neuroendocrine molecules.
Diabetes 1986 Mar
PMID:Islet cell proteins defined by monoclonal islet cell antibody HISL-19. 351 40

Early exposure to cow milk proteins was linked to the development of type I diabetes by consistent epidemiology, and by feeding and tolerization studies in diabetes-prone rodents. Dietary BSA was suggested as the culprit because patients and relevant rodents have elevated anti-BSA Abs that precipitate the recently cloned protein, p69, from beta cell lysates. A total of 68 of 78 children with recent onset diabetes had BSA-reactive T cells at the time of diagnosis. Here we 1) map the fine specificity of these T cells, 2) delineate a homologous peptide sequence near the N-terminus of p69, and 3) demonstrate T cell recognition of this p69 sequence (T cell epitope p69, Tep69) by patient T cells. The Tep69 sequence is conserved in p69 of patients and diabetes-prone rodents. Whereas BSA triggers T cell proliferation, recombinant p69 and a synthetic Tep69 peptide induce early stages of T cell activation (IL-2R transcription) but insufficient IL-2 production and thus anergy. Exogenous IL-2 overrides anergy and allows proliferative expansion of p69-responsive T cells. In mixing experiments, p69 and Tep69 peptide prevented proliferative responses to BSA even at 100-fold smaller concentrations. These findings imply that high-affinity self-peptide triggers anergy, whereas low-affinity mimicry Ag triggers proliferative expansion of these T cells. This implies a disease model in which mimicry Ag would rescue autoreactive cells from ablation by self-Ag.
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PMID:T cell activation and anergy to islet cell antigen in type I diabetes. 782 11

Triggering of autoimmunity in insulin-dependent diabetes was linked to dietary bovine serum albumin (BSA). Anti-BSA antibodies from diabetes-prone rats precipitate a protein, p69, from islet cell lysates. We have used these antibodies to identify rat p69 cDNAs. Human p69 cDNA was identified by crosshybridization. The p69 coding regions show 87% nucleotide and 89% amino acid homology. Recombinant p69 is recognized by autoantibody and T cells from diabetic children.
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PMID:Cloning of human and rat p69 cDNA, a candidate autoimmune target in type 1 diabetes. 791 78

Epidemiological and experimental evidence suggested that denial of dietary cow milk protein early in life protects genetically susceptible children and animals from insulin-dependent diabetes (IDDM). Bovine serum albumin (BSA) was proposed as a candidate milk-borne mimicry antigen responsible for the diabetogenic cow milk effect. Elevated anti-BSA antibodies have been observed in patients and diabetic rodents, and these antibodies precipitate p69 from islet cell lysates. IDDM is a T cell mediated disorder but efforts to detect BSA-specific T cells in diabetic children have so far failed. We describe here a culture system which allowed the detection of BSA-specific T cells and we mapped this response to the ABBOS peptide (pre-BSA position 152-169) previously identified as a possible mimicry epitope. ABBOS-sensitized T cells were found in 28/31 children with recent onset IDDM but not in non-diabetic controls nor in children with SLE or JRA. T cell proliferative responses declined within the first few years of diabetes diagnosis. Although no effector cell role for BSA/ABBOS specific T lymphocytes has been demonstrated, the presence of BSA peptide-specific T cells strengthens the postulated link between a cow milk protein and IDDM.
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PMID:T cells from children with IDDM are sensitized to bovine serum albumin. 799 51

The development of type 1 (insulin dependent) diabetes mellitus (IDDM) requires a genetically susceptible host and exposure, early in life, to environmental trigger molecules that induce diabetic autoimmunity to insulin producing islet cells. We previously identified islet cell protein p69 as a candidate autoimmune target in IDDM. Here we describe a human genomic p69 fragment which allowed us to map the gene (ICA1) to chromosome 7p22.
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PMID:ICA1 encoding p69, a protein linked to the development of type 1 diabetes, maps to human chromosome 7p22. 816 6

Based on the detection of specific antibodies and T-cell sensitization in patients with IDDM, islet cell antigen p69 (ICAp69) has been suggested to be a target antigen of diabetic autoimmunity. The biological function, tissue expression, and developmental kinetics of ICAp69 are largely unknown. We analyzed ICAp69 expression at the gene transcription and protein level in human and rodent tissues. By using template-calibrated quantitative reverse transcriptase polymerase chain reaction (RT-PCR), high levels of ICAp69 mRNA were found in human pancreatic islets and brain. In mouse and rat, ICAp69 gene expression peaked in islet cell lines followed by testis, islets, and brain. ICAp69 mRNA was found at low levels in other organs by RT-PCR but not by Northern blot analysis. In mice, ICAp69 transcription becomes detectable in fetal life, and fetal and adult gene expression patterns are similar. Western blot analysis of human and mouse tissues showed high expression of ICAp69 in brain, testis, pancreatic tissue, and islet cell lines. In these organs, ICAp69 immunoreactivity is predominately localized at the blood brain barrier (capillary endothelium), at the blood testis barrier (Sertoli cells and spermatids), and in pancreatic islets (beta-cells). The subcellular localization of ICAp69 to endoplasmic reticulum, Golgi complex, and vesicles by immune electron microscopy suggests a role of this neuroendocrine molecule in cellular protein traffic and processing.off
Diabetes 1996 Apr
PMID:Gene expression of islet cell antigen p69 in human, mouse, and rat. 860 75

Islet cell antigen p69 (ICAp69) is a target self-antigen in autoimmune (insulin-dependent) diabetes mellitus. Distributed over more than 100 kb on chromosome 6 (6{A1-A2}), the single murine genomic locus contains 14 coding exons, 39-271 bp in length. The identified human and mouse intron-exon junctions are identical, with intron sizes ranging from 94 bp to 24 kb and with conserved flanking region intron sequences. cDNA cloning identified alternatively spliced ICAp69 mRNA transcripts. The predominating alpha-transcripts lack exon 4, while beta-transcripts include this exon, which codes translation termination in all reading frames and a truncated molecule following in vitro expression. gamma-Transcripts show splice removal of exons 8-12, while delta-transcripts exclude exon 11. Transcripts use alternative polyadenylation signals including a less frequent ATTAAA sequence. 5'-Untranslated cDNA and genomic sequencing and long PCR analysis suggest the presence of more noncoding exons. All splice variants encode the conserved T-cell epitope (in exon 2) recognized by autoreactive T cells in diabetic children and diabetes-prone NOD mice.
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PMID:Genomic organization and transcript analysis of ICAp69, a target antigen in diabetic autoimmunity. 897 15

Islet cell antigen p69 (ICA69) is a target autoantigen in IDDM. Studies of T-cells from newly diabetic children suggested possible antigenic mimicry between human ICA69 (in particular the Tep69 T-cell epitope, aa 36-47) and the ABBOS region in bovine serum albumin (BSA; aa 152-169), one of several cow's milk proteins that evoke abnormal immunity in diabetes-prone hosts. We recently found the sequence of Tep69 regions to be identical in the four alternatively spliced human and rodent ICA69 isoforms. Immunization of nonobese diabetic (NOD) mice with BSA or ICA69 generates fully cross-reactive T-cell responses to both Tep69 and ABBOS as the immunodominant, naturally generated, and presented T-cell mimicry epitopes. Such responses are absent or weak in healthy strains of mice. NOD mouse recipients of adoptive spleen cell grafts from diabetic donors spontaneously generate easily detectable pools of T-cells specific for ICA69/BSA, as well as the unrelated GAD65. NOD mice injected neonatally with ABBOS or Tep69 show cross-tolerance, but ABBOS-induced tolerance is transient. Neonatal injection of Tep69 reduces disease incidence (23 vs. 68% IDDM, P < 0.02), while neonatal injection of ABBOS has little effect. In contrast, systemic immunization of young NOD females with ABBOS (but not Tep69) reduces the diabetes incidence and delays disease expression, with protected mice generating ABBOS-specific T-cell repertoires unable to recognize the Tep69 mimicry antigen. Our observations demonstrate a loss of self-tolerance to ICA69 in NOD mice, and they establish antigenic mimicry between the two T-cell epitopes in ICA69 and BSA. Further studies are necessary to understand the molecular basis of this mimicry and how either T-cell peptide can modify the disease course.
Diabetes 1997 Oct
PMID:Loss of self-tolerance to ICA69 in nonobese diabetic mice. 931 48

The expression of pro(insulin) in the thymus may lead to the negative selection of pro(insulin) autoreactive T cells and peripheral tolerance to this autoantigen in type 1 diabetes (T1D). We investigated whether proinsulin is expressed in the thymus of young nonobese diabetic (NOD) mice, whether T cells from naive NOD female mice at weaning are reactive to mouse proinsulin, and the role of proinsulin as a pathogenic autoantigen in T1D. Proinsulin II mRNA transcripts were detected in the thymus of 2-wk-old NOD mice at similar levels to other control strains. Despite this expression, proinsulin autoreactive T cells were detected in the periphery of 2- to 3-wk-old naive NOD mice. Peripheral T cells reactive to the insulin, glutamic acid decarboxylase 65 (GAD65), GAD67, and islet cell Ag p69 autoantigens were also detected in these mice, indicating that NOD mice are not tolerant to any of these islet autoantigens at this young age. T cell reactivities to proinsulin and islet cell Ag p69 exceeded those to GAD67, and T cell reactivity to proinsulin in the spleen and pancreatic lymph nodes was directed mainly against a p24-33 epitope that spans the B chain/C peptide junction. Intraperitoneal immunization with proinsulin perinatally beginning at 18 days of age delayed the onset and reduced the incidence of T1D. However, s.c. immunization with proinsulin initiated at 5 wk of age accelerated diabetes in female NOD mice. Our findings support the notion that proinsulin p24-33 may be a primary autoantigen epitope in the pathogenesis of T1D in NOD mice.
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PMID:Evidence that a peptide spanning the B-C junction of proinsulin is an early Autoantigen epitope in the pathogenesis of type 1 diabetes. 1167 98