A virus-induced molecular mimicry model of multiple sclerosis.
Molecular mimicry is the process by which virus infection activates T cells that are cross-reactive with self antigens. Infection of SJL/J mice with the neurotropic picornavirus Theiler's murine encephalomyelitis virus (TMEV) leads to a progressive CD4(+) T cell-mediated demyelinating disease similar to multiple sclerosis. To study the potential of virus-induced molecular mimicry to initiate autoimmune demyelination, a nonpathogenic TMEV variant was engineered to encode a 30-mer peptide encompassing the immunodominant encephalitogenic myelin proteolipid protein (PLP139-151) epitope. Infection with the PLP139-151-encoding TMEV led within 10-14 days to a rapid-onset paralytic demyelinating disease characterized by PLP139-151-specific CD4(+) Th1 responses; insertion of a non-self ovalbumin sequence led to restoration of the normal late-onset disease. Early-onset disease was also observed in mice infected with a TMEV encoding PLP139-151 with an amino acid substitution at the secondary T cell receptor (TCR) contact residue (H147A), but not in mice infected with TMEV encoding a PLP139-151 substitution at the primary TCR contact (W144A). Most significantly, mice infected with TMEV encoding a Haemophilus influenzae mimic peptide, sharing only 6 of 13 amino acids with PLP139-151, displayed rapid-onset disease and developed cross-reactive PLP139-151-specific CD4(+) Th1 responses. To our knowledge, this is the first study showing that a naturally infectious virus encoding a myelin epitope mimic can directly initiate organ-specific T cell-mediated autoimmunity.
Olson
J K
JK
Department of Microbiology-Immunology and the Interdepartmental Immunobiology Center, Northwestern University Medical School, Chicago, Illinois, USA.
Croxford
J L
JL
Calenoff
M A
MA
Dal Canto
M C
MC
Miller
S D
SD
D000595:Amino Acid Sequence; D000818:Animals; D015551:Autoimmunity; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018188:Cardiovirus Infections / Q000276:immunology / Q000821:virology*; D003429:Cross Reactions; D016207:Cytokines / Q000032:analysis; D020278:Demyelinating Autoimmune Diseases, CNS / Q000276:immunology; D004195:Disease Models, Animal; D018792:Encephalitis, Viral / Q000276:immunology / Q000821:virology*; D000939:Epitopes / Q000737:chemistry; D051379:Mice; D018716:Molecular Mimicry; D008969:Molecular Sequence Data; D009103:Multiple Sclerosis / Q000209:etiology*; D018991:Myelin Proteolipid Protein / Q000096:biosynthesis* / Q000737:chemistry / Q000235:genetics; D010446:Peptide Fragments / Q000096:biosynthesis* / Q000737:chemistry / Q000235:genetics; D011995:Recombination, Genetic; D018417:Th1 Cells / Q000276:immunology; D017945:Theilovirus / Q000235:genetics / Q000378:metabolism*
D016207:Cytokines; D000939:Epitopes; D018991:Myelin Proteolipid Protein; D010446:Peptide Fragments; C435023:myelin proteolipid protein (139-151)