ICA69(null) nonobese diabetic mice develop diabetes, but resist disease acceleration by cyclophosphamide.
ICA69 (islet cell Ag 69 kDa) is a diabetes-associated autoantigen with high expression levels in beta cells and brain. Its function is unknown, but knockout of its Caenorhabditis elegans homologue, ric-19, compromised neurotransmission. We disrupted the murine gene, ica-1, in 129-strain mice. These animals aged normally, but speed-congenic ICA69(null) nonobese diabetic (NOD) mice developed mid-life lethality, reminiscent of NOD-specific, late lethal seizures in glutamic acid decarboxylase 65-deficient mice. In contrast to wild-type and heterozygous animals, ICA69(null) NOD congenics fail to generate, even after immunization, cross-reactive T cells that recognize the dominant Tep69 epitope in ICA69, and its environmental mimicry Ag, the ABBOS epitope in BSA. This antigenic mimicry is thus driven by the endogenous self Ag, and not initiated by the environmental mimic. Insulitis, spontaneous, and adoptively transferred diabetes develop normally in ICA69(null) NOD congenics. Like glutamic acid decarboxylase 65, ICA69 is not an obligate autoantigen in diabetes. Unexpectedly, ICA69(null) NOD mice were resistant to cyclophosphamide (CY)-accelerated diabetes. Transplantation experiments with hemopoietic and islet tissue linked CY resistance to ICA69 deficiency in islets. CY-accelerated diabetes involves not only ablation of lymphoid cells, but ICA69-dependent drug toxicity in beta cells that boosts autoreactivity in the regenerating lymphoid system.
Winer
Shawn
S
The Hospital For Sick Children, Research Institute, University of Toronto, 555 University Avenue, Toronto, Ontario, Canada, M5G 1X8.
Astsaturov
Igor
I
Gaedigk
Roger
R
Hammond-McKibben
Denise
D
Pilon
Marc
M
Song
Aihua
A
Kubiak
Violetta
V
Karges
Wolfram
W
Arpaia
Enrico
E
McKerlie
Colin
C
Zucker
Peter
P
Singh
Bhagirath
B
Dosch
H-Michael
HM
D019264:Adoptive Transfer; D000818:Animals; D001324:Autoantigens / Q000235:genetics* / Q000276:immunology / Q000502:physiology*; D015551:Autoimmunity; D029742:Caenorhabditis elegans Proteins; D002478:Cells, Cultured; D003520:Cyclophosphamide / Q000494:pharmacology*; D003922:Diabetes Mellitus, Type 1 / Q000209:etiology* / Q000473:pathology; D018450:Disease Progression; D000939:Epitopes / Q000276:immunology; D005260:Female; D018390:Gene Targeting; D016381:Islets of Langerhans Transplantation; D008213:Lymphocyte Activation; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D018716:Molecular Mimicry; D013601:T-Lymphocytes / Q000276:immunology / Q000637:transplantation
D001324:Autoantigens; D029742:Caenorhabditis elegans Proteins; D000939:Epitopes; C490184:Ica1 protein, mouse; C490186:ric-19 protein, C elegans; D003520:Cyclophosphamide