Viral delivery of an epitope from Haemophilus influenzae induces central nervous system autoimmune disease by molecular mimicry.
Multiple sclerosis (MS) is an autoimmune CNS demyelinating disease in which infection may be an important initiating factor. Pathogen-induced cross-activation of autoimmune T cells may occur by molecular mimicry. Infection with wild-type Theiler's murine encephalomyelitis virus induces a late-onset, progressive T cell-mediated demyelinating disease, similar to MS. To determine the potential of virus-induced autoimmunity by molecular mimicry, a nonpathogenic neurotropic Theiler's murine encephalomyelitis virus variant was engineered to encode a mimic peptide from protease IV of Haemophilus influenzae (HI), sharing 6 of 13 aa with the dominant encephalitogenic proteolipid protein (PLP) epitope PLP(139-151). Infection of SJL mice with the HI mimic-expressing virus induced a rapid-onset, nonprogressive paralytic disease characterized by potent activation of self-reactive PLP(139-151)-specific CD4(+) Th1 responses. In contrast, mice immunized with the HI mimic-peptide in CFA did not develop disease, associated with the failure to induce activation of PLP(139-151)-specific CD4(+) Th1 cells. However, preinfection with the mimic-expressing virus before mimic-peptide immunization led to severe disease. Therefore, infection with a mimic-expressing virus directly initiates organ-specific T cell-mediated autoimmunity, suggesting that pathogen-delivered innate immune signals may play a crucial role in triggering differentiation of pathogenic self-reactive responses. These results have important implications for explaining the pathogenesis of MS and other autoimmune diseases.
Croxford
J Ludovic
JL
Department of Microbiology-Immunology, and Interdepartmental Immunobiology Center, Northwestern University Medical School, Chicago, IL 60611, USA.
Anger
Holly A
HA
Miller
Stephen D
SD
D000595:Amino Acid Sequence; D000818:Animals; D001324:Autoantigens / Q000276:immunology; D001933:Brain Stem / Q000276:immunology / Q000473:pathology; D002465:Cell Movement / Q000276:immunology; D002531:Cerebellum / Q000276:immunology / Q000473:pathology; D004306:Dose-Response Relationship, Immunologic; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology* / Q000382:microbiology / Q000473:pathology / Q000821:virology; D018984:Epitopes, T-Lymphocyte / Q000008:administration & dosage / Q000276:immunology; D005260:Female; D005822:Genetic Vectors; D006193:Haemophilus influenzae / Q000235:genetics / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D018716:Molecular Mimicry / Q000235:genetics / Q000276:immunology*; D008969:Molecular Sequence Data; D018991:Myelin Proteolipid Protein / Q000008:administration & dosage / Q000276:immunology; D010446:Peptide Fragments / Q000008:administration & dosage / Q000276:immunology; D013116:Spinal Cord / Q000276:immunology / Q000473:pathology; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism; D017945:Theilovirus / Q000235:genetics / Q000276:immunology*
D001324:Autoantigens; D018984:Epitopes, T-Lymphocyte; D018991:Myelin Proteolipid Protein; D010446:Peptide Fragments; C435023:myelin proteolipid protein (139-151)