Molecular mimicry between neurons and an intracerebral pathogen induces a CD8 T cell-mediated autoimmune disease.
To identify basic mechanisms of how infections may induce a neuron-specific autoimmune response, we generated mice expressing OVA as neuronal autoantigen under control of the neuron-specific enolase promoter (NSE-OVA mice). Intracerebral, but not systemic, infection with attenuated Listeria monocytogenes-secreting OVA induced an atactic-paretic neurological syndrome in NSE-OVA mice after bacterial clearance from the brain, whereas wild-type mice remained healthy. Immunization with attenuated Listeria monocytogenes-secreting OVA before intracerebral infection strongly increased the number of intracerebral OVA-specific CD8 T cells aggravating neurological disease. T cell depletion and adoptive transfer experiments identified CD8 T cells as decisive mediators of the autoimmune disease. Importantly, NSE-OVA mice having received OVA-specific TCR transgenic CD8 T cells developed an accelerated, more severe, and extended neurological disease. Adoptively transferred pathogenic CD8 T cells specifically homed to OVA-expressing MHC class I(+) neurons and, corresponding to the clinical symptoms, approximately 30% of neurons in the anterior horn of the spinal cord became apoptotic. Thus, molecular mimicry between a pathogen and neurons can induce a CD8 T cell-mediated neurological disease, with its severity being influenced by the frequency of specific CD8 T cells, and its induction, but not its symptomatic phase, requiring the intracerebral presence of the pathogen.
Sanchez-Ruiz
Monica
M
Abteilung für Neuropathologie, Universitätsklinikum Köln, Köln, Germany.
Wilden
Laura
L
Müller
Werner
W
Stenzel
Werner
W
Brunn
Anna
A
Miletic
Hrvoje
H
Schlüter
Dirk
D
Deckert
Martina
M
D019264:Adoptive Transfer; D000818:Animals; D001324:Autoantigens / Q000008:administration & dosage* / Q000235:genetics / Q000276:immunology; D001927:Brain Diseases / Q000201:enzymology / Q000235:genetics / Q000276:immunology* / Q000382:microbiology; D015496:CD4-Positive T-Lymphocytes / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D018414:CD8-Positive T-Lymphocytes / Q000201:enzymology / Q000276:immunology* / Q000382:microbiology / Q000637:transplantation; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D002645:Chickens; D006801:Humans; D008089:Listeria monocytogenes / Q000235:genetics / Q000276:immunology; D008088:Listeriosis / Q000201:enzymology / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018716:Molecular Mimicry / Q000276:immunology*; D020721:Nervous System Autoimmune Disease, Experimental / Q000201:enzymology / Q000235:genetics / Q000382:microbiology* / Q000473:pathology; D009474:Neurons / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology*; D010047:Ovalbumin / Q000008:administration & dosage / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D010751:Phosphopyruvate Hydratase / Q000008:administration & dosage / Q000096:biosynthesis / Q000235:genetics; D011401:Promoter Regions, Genetic; D051381:Rats
D001324:Autoantigens; D010047:Ovalbumin; D010751:Phosphopyruvate Hydratase