Distinct effector mechanisms in the development of autoimmune neuropathy versus diabetes in nonobese diabetic mice.
NOD mice deficient for the costimulatory molecule B7-2 (NOD-B7-2KO mice) are protected from autoimmune diabetes but develop a spontaneous autoimmune peripheral neuropathy that resembles human diseases Guillain-Barre syndrome and chronic inflammatory demyelinating polyradiculoneuropathy. Similar observations have now been made in conventional NOD mice. We have shown previously that this disease was mediated by autoreactive T cells inducing demyelination in the peripheral nervous system. In this study, we analyzed the molecular pathways involved in the disease. Our data showed that neuropathy developed in the absence of perforin or fas, suggesting that classic cytotoxicity pathways were dispensable for nerve damage in NOD-B7-2KO mice. In contrast, IFN-gamma played an obligatory role in the development of neuropathy as demonstrated by the complete protection from disease and infiltration in the nerves in NOD-B7-2KO mice deficient for IFN-gamma. This result was consistent with the inflammatory phenotype of T cells infiltrating the peripheral nerves. Importantly, the relative role of perforin, fas, and IFN-gamma appears completely different in autoimmune diabetes vs neuropathy. Thus, there are sharp contrasts in the pathogenesis of autoimmune diseases targeting different tissues in the same NOD background.
Bour-Jordan
Hélène
H
University of California, San Francisco (UCSF) Diabetes Center, Department of Medicine, University of California, San Francisco, CA 94143, USA.
Thompson
Heather L
HL
Bluestone
Jeffrey A
JA
D000818:Animals; D001327:Autoimmune Diseases / Q000209:etiology*; D051940:B7-2 Antigen / Q000502:physiology; D003922:Diabetes Mellitus, Type 1 / Q000209:etiology*; D007371:Interferon-gamma / Q000096:biosynthesis; D008562:Membrane Glycoproteins / Q000502:physiology; D051379:Mice; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D054353:Perforin; D010523:Peripheral Nervous System Diseases / Q000209:etiology*; D052899:Pore Forming Cytotoxic Proteins; D018417:Th1 Cells / Q000502:physiology
D051940:B7-2 Antigen; D008562:Membrane Glycoproteins; D052899:Pore Forming Cytotoxic Proteins; D054353:Perforin; D007371:Interferon-gamma