Male-specific beta-cell dysfunction and diabetes resulting from increased expression of a syngeneic MHC class I protein in the pancreata of transgenic mice.
It is well established that insulin-dependent diabetes (IDDM) is an autoimmune disease with a strong genetic link to the HLA locus. It is less well understood, however, how the destruction of the insulin-producing beta cells is effected and why neighboring non-beta islet cells are spared. Also incompletely explained are the observations that, unlike other autoimmune diseases such as multiple sclerosis, IDDM does not preferentially affect females, the incidence of the disease is highest among young adults, and there are temporal correlations between the onset of the disease and emotional trauma. We have addressed some of these questions by using transgenic mice that constitutively express the MHC class I antigen Dd in the beta cells of the pancreas. Although both male and female Ins.Dd mice expressed equivalent amounts of the Dd protein only the males developed diabetes. The diabetes in the males could be reversed by castration, and the normoglycemic females became diabetic following either ovariectomy and the implantation of a slow-release pellet containing testosterone or the inclusion of dexamethasone in the drinking water. In contrast, transgenic mice that expressed the herpes simplex virus type 1 glycoprotein D in the pancreatic beta cells were normoglycemic and showed no obvious histopathological consequences. The observation that the beta-cell dysfunction by the increased expression of the MHC class I protein Dd cannot be induced by the herpes viral protein suggests that the cellular damage is related to a specific structure or function of the MHC proteins.(ABSTRACT TRUNCATED AT 250 WORDS)
Martin
L
L
Department of Pharmacological Sciences, Genentech, Inc., South San Francisco, CA 94080.
Keller
G A
GA
Liggitt
D
D
Oakley
H
H
Pitts-Meek
S L
SL
Siegel
M W
MW
Terrell
T
T
Stewart
T A
TA
D000818:Animals; D003907:Dexamethasone / Q000494:pharmacology; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology* / Q000473:pathology; D005260:Female; D015395:Histocompatibility Antigens Class I / Q000276:immunology*; D015994:Incidence; D007515:Islets of Langerhans / Q000276:immunology*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic / Q000276:immunology; D010052:Ovariectomy; D018139:Simplexvirus / Q000276:immunology*; D013739:Testosterone / Q000378:metabolism; D014759:Viral Envelope Proteins / Q000276:immunology*
D015395:Histocompatibility Antigens Class I; D014759:Viral Envelope Proteins; C039447:glycoprotein D, Human herpesvirus 1; D013739:Testosterone; D003907:Dexamethasone