Minimal impact of a de novo-expressed beta-cell autoantigen on spontaneous diabetes development in NOD mice.
During an autoimmune process, the autoaggressive response spreads from the initiating autoantigen to other antigens expressed in the target organ. Based on evidence from experimental models for multiple sclerosis, such "antigenic spreading" can play an important role in the exacerbation of clinical disease. We evaluated whether pathogenesis of spontaneous diabetes in NOD mice could be accelerated in a similar way when a novel autoantigen was expressed in pancreatic beta-cells. Unexpectedly, we found that the expression of the lymphocytic choriomeningitis virus nucleoprotein only led to marginal enhancement of diabetes, although such NOD-nucleoprotein mice were not tolerant to nucleoprotein. Although the frequency of nucleoprotein-specific CD8 T-cells in the pancreatic draining lymph node was comparable with the frequency of islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP)-specific T-cells, more IGRP-specific CD8 T-cells were found both systemically and in the islets where there was a fourfold increase. Interestingly, and in contrast to nucleoprotein-specific CD8 T-cells, IGRP-specific T-cells showed increased CXCR3 expression. Thus, autoreactivity toward de novo-expressed beta-cell autoantigens will not accelerate autoimmunity unless large numbers of antigen-experienced autoreactive T-cells expressing the appropriate chemokine receptors are present.
Martinic
Marianne M
MM
Immune Regulation Lab DI-3, La Jolla Institute for Allergy and Immunology, 9420 Athena Circle, La Jolla, CA 92037, USA. marmar@liai.org
Juedes
Amy E
AE
Bresson
Damien
D
Homann
Dirk
D
Skak
Kresten
K
Huber
Christoph
C
Ling
Eleanor
E
Ejrnaes
Mette
M
Wolfe
Tom
T
Togher
Lisa
L
Christen
Urs
U
von Herrath
Matthias G
MG
D000818:Animals; D001324:Autoantigens / Q000276:immunology*; D003001:Cloning, Molecular; D017931:DNA Primers; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology / Q000503:physiopathology*; D004797:Enzyme-Linked Immunosorbent Assay; D007328:Insulin / Q000032:analysis; D050417:Insulin-Secreting Cells / Q000276:immunology*; D008217:Lymphocytic choriomeningitis virus / Q000235:genetics; D051379:Mice; D016688:Mice, Inbred NOD; D008822:Mice, Transgenic; D009698:Nucleoproteins / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014764:Viral Proteins / Q000235:genetics
D001324:Autoantigens; D017931:DNA Primers; D007328:Insulin; D009698:Nucleoproteins; D014764:Viral Proteins