title: Structural requirements for initiation of cross-reactivity and CNS autoimmunity with a PLP139-151 mimic peptide derived from murine hepatitis virus.
abstract: MS is an autoimmune CNS demyelinating disease in which infection appears to be an important pathogenic factor. Molecular mimicry, the cross-activation of autoreactive T cells by mimic peptides from infectious agents, is a possible explanation for infection-induced autoimmunity. Infection of mice with a non-pathogenic strain of Theiler's murine encephalomyelitis virus (TMEV) engineered to express an epitope from Haemophilus influenzae (HI) sharing 6/13 amino acids with the dominant proteolipid protein (PLP) epitope, PLP139-151, can induce CNS autoimmune disease. Here we demonstrate that another PLP139-151 mimic sequence derived from murine hepatitis virus (MHV) which shares only 3/13 amino acids with PLP139-151 can also induce CNS autoimmune disease, but only when delivered by genetically engineered TMEV, not by immunization with the MHV peptide. Further, we demonstrate the importance of proline at the secondary MHC class II contact residue for effective cross-reactivity, as addition of this amino acid to the native MHV sequence increases its ability to cross-activate PLP139-151-specific autoreactive T cells, while substitution of proline in the HI mimic peptide has the opposite effect. This study describes a structural requirement for potential PLP139-151 mimic peptides, and provides further evidence for infection-induced molecular mimicry in the pathogenesis of autoimmune disease.
authors.affiliation: Department of Microbiology-Immunology and the Interdepartmental Immunobiology Center, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
authors.forename: J Ludovic
authors.initials: JL
authors.lastname: Croxford
authors.forename: Anne M
authors.initials: AM
authors.lastname: Ercolini
authors.forename: Mathew
authors.initials: M
authors.lastname: Degutes
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Miller
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D018188:Cardiovirus Infections / Q000150:complications* / Q000276:immunology; D003429:Cross Reactions; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology / Q000821:virology*; D018984:Epitopes, T-Lymphocyte / Q000235:genetics / Q000276:immunology; D005260:Female; D000949:Histocompatibility Antigens Class II / Q000235:genetics; D007150:Immunohistochemistry; D051379:Mice; D018716:Molecular Mimicry / Q000276:immunology*; D018991:Myelin Proteolipid Protein / Q000235:genetics* / Q000276:immunology; D010446:Peptide Fragments / Q000235:genetics* / Q000276:immunology; D017945:Theilovirus / Q000276:immunology*
chemical_list: D018984:Epitopes, T-Lymphocyte; D000949:Histocompatibility Antigens Class II; D018991:Myelin Proteolipid Protein; D010446:Peptide Fragments; C435023:myelin proteolipid protein (139-151)