Persistent infection with Theiler's virus leads to CNS autoimmunity via epitope spreading.
Multiple sclerosis (MS) is a T cell-mediated autoimmune demyelinating disease, which may be initiated by a virus infection. Theiler's murine encephalomyelitis virus (TMEV), a natural mouse pathogen, is a picornavirus that induces a chronic, CD4+ T cell-mediated demyelinating disease with a clinical course and histopathology similar to that of chronic progressive MS (ref. 3). Demyelination in TMEV-infected mice is initiated by a mononuclear inflammatory response mediated by virus-specific CD4+ T cells targeting virus, which chronically persists in the CNS (ref. 4-6). We show that beginning 3-4 weeks after disease onset, T-cell responses to multiple myelin autoepitopes arise in an ordered progression and may play a pathologic role in chronic disease. Kinetic and functional studies show that T-cell responses to the immunodominant myelin proteolipid protein epitope (PLP139-151) did not arise because of cross-reactivity between TMEV and self epitopes (that is, molecular mimicry), but because of de novo priming of self-reactive T cells to sequestered autoantigens released secondary to virus-specific T cell-mediated demyelination (that is, epitope spreading). Epitope spreading is an important alternate mechanism to explain the etiology of virus-induced organ-specific autoimmune diseases.
Miller
S D
SD
Department of Microbiology-Immunology, Northwestern University Medical School, Chicago, Illinois 60611, USA.
Vanderlugt
C L
CL
Begolka
W S
WS
Pao
W
W
Yauch
R L
RL
Neville
K L
KL
Katz-Levy
Y
Y
Carrizosa
A
A
Kim
B S
BS
D000595:Amino Acid Sequence; D000818:Animals; D015551:Autoimmunity; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D003429:Cross Reactions; D003711:Demyelinating Diseases / Q000276:immunology*; D000939:Epitopes / Q000276:immunology*; D005260:Female; D007249:Inflammation; D007700:Kinetics; D051379:Mice; D008815:Mice, Inbred Strains; D008969:Molecular Sequence Data; D009185:Myelin Proteins / Q000737:chemistry / Q000276:immunology*; D018991:Myelin Proteolipid Protein / Q000737:chemistry / Q000276:immunology*; D011051:Poliomyelitis / Q000276:immunology* / Q000503:physiopathology; D017634:Self Tolerance; D013601:T-Lymphocytes / Q000276:immunology*; D017945:Theilovirus
D000939:Epitopes; D009185:Myelin Proteins; D018991:Myelin Proteolipid Protein