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ICA69(null) nonobese diabetic mice develop diabetes, but resist disease acceleration by cyclophosphamide
Shawn Winer1, Igor Astsaturov, Roger Gaedigk
1The Hospital For Sick Children, Research Institute, University of Toronto, 555 University Avenue, Toronto, Ontario, Canada, M5G 1X8.
Abstract:
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.
Insights
Islet cell antigen 69 (ICA69) deficiency protects against cyclophosphamide-accelerated diabetes in NOD mice. ICA69 in beta cells, not T cell recognition, drives drug toxicity and autoreactivity.
Area of Science:
- Immunology
- Endocrinology
- Neuroscience
Background:
- Islet cell antigen 69 (ICA69) is a diabetes-associated autoantigen highly expressed in beta cells and brain.
- Its homologue in C. elegans, ric-19, is crucial for neurotransmission, suggesting a role in neuronal function.
- The precise function of ICA69 and its role in autoimmune diabetes remain largely unknown.
Purpose of the Study:
- To investigate the function of ICA69 in autoimmune diabetes using a murine knockout model.
- To determine the role of ICA69 in T cell recognition of self and environmental antigens.
- To elucidate the mechanism behind cyclophosphamide-accelerated diabetes and ICA69's involvement.
Main Methods:
- Generation of ICA69 knockout mice (ica-1 null) on a 129 strain background.
- Speed-congenic development of ICA69(null) nonobese diabetic (NOD) mice.
- Immunization studies to assess T cell responses to ICA69 and BSA epitopes.
- Analysis of insulitis, diabetes development, and cyclophosphamide (CY) acceleration.
- Transplantation experiments using hemopoietic and islet tissue.
Main Results:
- ICA69(null) NOD mice exhibited mid-life lethality, distinct from wild-type NOD mice.
- ICA69(null) NOD mice failed to generate cross-reactive T cells recognizing ICA69 and BSA epitopes.
- Antigenic mimicry was driven by endogenous ICA69, not environmental factors.
- Spontaneous and transferred diabetes, as well as insulitis, developed normally in ICA69(null) NOD mice.
- ICA69(null) NOD mice were unexpectedly resistant to CY-accelerated diabetes.
- CY resistance was linked to ICA69 deficiency in islets, involving beta-cell drug toxicity.
Conclusions:
- ICA69 is not an obligate autoantigen for spontaneous diabetes development in NOD mice.
- ICA69 plays a critical role in beta-cell toxicity induced by cyclophosphamide, exacerbating autoreactivity.
- The findings reveal a novel function of ICA69 in drug-induced exacerbation of autoimmune diabetes.