Summary
The diabetic syndrome in the DP-BB rat results from progressive beta-cell destruction by autoimmune responses. However, the initial events causing the autoimmune destruction of beta cells remain largely unknown. Our recent experimental results suggest that the delayed expression of a beta-cell-specific autoantigen may result in the initiation of beta-cellspecific autoimmunity. The present investigation was initiated to identify such an autoantigen. Islets were isolated from DP-BB rats of several different ages, and protein extracts from the membrane fraction of the islet preparations were immunoprecipitated with sera from diabetic DP-BB rats. We have found that a membrane-bound islet cell-specific 38 kDa autoantigen is not expressed early in the life of DP-BB rats, but is delayed-expressed by approximately 30 days of age, the time at which immunological effectors begin to recognize beta cells. In contrast, a 64 kDa islet cell protein is expressed from birth in DP-BB rats. On the basis of these observations, we suggest that delayed expression of a gene encoding for the membrane-bound islet cell-specific 38 kDa autoantigen may result in a breakdown of self-tolerance, leading to beta-cell-specific autoimmune IDDM in the BB rat. [Diabetologia (1994) 37: 460-465]
Article PDF
Similar content being viewed by others
Abbreviations
- IDDM:
-
Insulin-dependent diabetes mellitus
- BB:
-
BioBreeding
- WF:
-
Wistar Furth
- DP-BB:
-
diabetes-prone Bio-Breeding
- DR-BB:
-
diabetes-resistant BioBreeding
- GAD:
-
glutamic acid decarboxylase
- APC:
-
antigen-presenting cell
Reference
Rossini AA, Greiner DL, Friedman HP, Mordes JP (1993) Immunopathogenesis of diabetes mellitus. Diabetes Rev 1: 43–75
Yoon JW (1990) Role of viruses and environmental factors in induction of diabetes. In: Baekkeskov S, Hansen B (eds) Current topics in microbiology and immunology, vol 164. Springer-Verlag, New York, pp 95–123
Bach JF (1988) Mechanisms of autoimmunity in insulin-dependent diabetes mellitus. Clin Exp Immunol 72:1–8
Eisenbarth GS (1986) Type 1 diabetes mellitus. A chronic autoimmune disease. New Engl J Med 314:1360–1368
Ihm SH, Lee KU, Yoon JW (1991) Studies on autoimmunity for the initiation of beta cell destruction: VII. Evidence for antigenic changes on the beta cells leading to the autoim- mune destruction of beta cells in BB rats. Diabetes 40:269- 274
Lee KU, Pak CY, Amano K, Yoon JW (1988) Prevention of lymphocytic thyroiditis and insulitis in diabetes-prone BB rats by the depletion of macrophages. Diabetologia 31:400- 402
Amano K, Yoon JW (1990) Studies on autoimmunity for the initiation of beta cell destruction: V. Decrease of macrophage-dependent T lymphocytes and NK cytotoxicity in silica treated DP-BB rats. Diabetes 39:590–596
Herge OD, Marshall S, Schulte BA et al. (1983) Nonenzymic in vitro isolation of perinatal islets of Langerhans. In Vitro 19:611–620
Sutton R, Peter M, McShane P, Gray DWR, Morris PJ (1986) Isolation of rat pancreatic islets by ductal inj ection of collagenase. Transplantation 42:689–691
Baekkeskov S, Anstoot H-J, Christgau S et al. (1990) Identification of the 64 K autoantigen in insulin-dependent diabetes as the GABA-synthesizing enzyme glutamic acid decarboxylase. Nature 347:151–156
Ko IY, Ihm SH, Yoon JW (1991) Studies on autoimmunity for the initiation of beta cell destruction: VIII. Pancreatic beta cell-dependent autoantibody to a 38 kilodalton protein precedes the clinical onset of diabetes in BB rats. Diabetologia 34:548–554
Adams TE, Alpert S, Hanahan D (1987) Non-tolerance and autoantibodies to a transgenic self antigen expressed in pancreatic beta cells. Nature 325:223–228
Buschard K, Jorgensen M, Aaen K, Bock T, Josefsen D (1990) Prevention of diabetes mellitus in BB rats by neonatal stimulation of ji cells. Lancet 335:134–135
Baekkeskov S, Nielsen JH, Marner B, Bilde T, Ludvigsson J, Lernmark A (1982) Autoantibodies in newly diagnosed diabetic children immunoprecipitate human pancreatic islet cell proteins. Nature 298:167–169
Oschilewski U, Kiesel U, Kolb H (1985) Administration of silica prevents diabetes in BB rats. Diabetes 34:194–199
Tillakaratne NJK, Erlander MG, Collard MV, Greif KF, Tobin AJ (1992) Glutamate decarboxylase in nonneural cells of rat testis and oviduct: differential expression of G AD65 and GAD67. J Neurochem 58:618–627
Erdo SL, Wolff JR (1990) 7-Aminobutyric acid outside the mammalian brain. J Neurochem 54:363–371
Petersen JS, Ressel S, Marshall MO et al. (1993) Differential expression of glutamic acid decarboxylase in rat and human islets. Diabetes 42:484–495
Smith DK, Kassam T, Singh B, Elliot JF (1992) Escherichia coli has two homologous glutamate decarboxylase genes that map to distinct loci. J Bacteriol 174:5820–5826
Kaufman D, Clare-Salzler M, Tian J et al. (1993) Spontaneous loss of T-cell tolerance to glutamic acid decarboxylase in murine insulin-dependent diabetes. Nature 366:69–72
Tisch R, Yang X, Singer S, Liblau R, Fugger L, McDevitt H (1993) Immune response to glutamic acid decarboxylase correlates with insulitis in non-obese diabetic mice. Nature 366:72–75
Roep BO, Arden SD, De Vries RRP, Hutton JC (1990) T-cell clones from a type 1 diabetes patient respond to insulin secretory granule proteins. Nature 345:632–634
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Ko, I.Y., Jun, H.S., Kim, G.S. et al. Studies on autoimmunity for initiation of beta-cell destruction X. Delayed expression of a membrane-bound islet cell-specific 38 kDa autoantigen that precedes insulitis and diabetes in the diabetes-prone BB rat. Diabetologia 37, 460–465 (1994). https://doi.org/10.1007/s001250050132
Received:
Revised:
Issue Date:
DOI: https://doi.org/10.1007/s001250050132