The third signal in T cell-mediated autoimmune disease?
The initial event in the pathogenesis of autoimmune disease is thought to be the priming of naive autoreactive T cells by an infection with a cross-reactive microorganism. Although such cross-reactive priming should be a common event, autoimmune disease does not frequently develop. This situation is reflected after the immunization of C57BL/6 mice with the neuroantigen myelin oligodendrocyte glycoprotein (MOG) with CFA, which primes a type 1 T cell response but does not lead to clinical or histological manifestation of experimental allergic encephalomyelitis unless pertussis toxin is injected in addition. We show in this study that, in MOG:CFA-primed mice, the autoimmune CNS pathology develops after intracerebral deposition of TLR9-activating CpG oligonucleotides, but not following non-CpG oligonucleotide injection or after aseptic cryoinjury of the brain. Thus, access of primed MOG-specific Th1 cells to the uninflamed CNS or to CNS undergoing sterile inflammation did not suffice to elicit autoimmune pathology; only if the APC in the target organ were activated in addition by the TLR9-stimulating microbial product did they exert local effector functions. The data suggest that such licensing of APC in the target organ by microbial stimuli represents a checkpoint for functional self-tolerance. Therefore, microorganisms unrelated to the cross-reactive agent that primes the autoreactive T cells could dictate the onset and exacerbation of autoimmune diseases.
Darabi
Kamruz
K
Department of Pathology, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, OH 44118, USA.
Karulin
Alexey Y
AY
Boehm
Bernhard O
BO
Hofstetter
Harald H
HH
Fabry
Zsuzsa
Z
LaManna
Joseph C
JC
Chavez
Juan C
JC
Tary-Lehmann
Magdalena
M
Lehmann
Paul V
PV
D000818:Animals; D000938:Antigen-Presenting Cells / Q000502:physiology; D001324:Autoantigens / Q000276:immunology; D001327:Autoimmune Diseases / Q000209:etiology*; D001921:Brain / Q000276:immunology; D019013:CD40 Antigens / Q000096:biosynthesis; D018925:Chemokines / Q000096:biosynthesis; D004268:DNA-Binding Proteins / Q000502:physiology; D005260:Female; D007108:Immune Tolerance; D007114:Immunization; D051379:Mice; D008810:Mice, Inbred C57BL; D009185:Myelin Proteins; D018992:Myelin-Associated Glycoprotein / Q000276:immunology; D063308:Myelin-Oligodendrocyte Glycoprotein; D009838:Oligodeoxyribonucleotides / Q000494:pharmacology; D011956:Receptors, Cell Surface / Q000502:physiology; D013601:T-Lymphocytes / Q000276:immunology*; D051217:Toll-Like Receptor 9
D001324:Autoantigens; D019013:CD40 Antigens; C408982:CPG-oligonucleotide; D018925:Chemokines; D004268:DNA-Binding Proteins; C571327:Mog protein, mouse; D009185:Myelin Proteins; D018992:Myelin-Associated Glycoprotein; D063308:Myelin-Oligodendrocyte Glycoprotein; D009838:Oligodeoxyribonucleotides; D011956:Receptors, Cell Surface; C495370:Tlr9 protein, mouse; D051217:Toll-Like Receptor 9