P0 glycoprotein peptides 56–71 and 180–199 dose-dependently induce acute and chronic experimental autoimmune neuritis in Lewis rats associated with epitope spreading

Abstract

Two synthetic peripheral nerve myelin P0 protein peptides, an immunodominant (amino acids 180–199) and a cryptic (amino acids 56–71) one, induced an acute or chronic course of experimental autoimmune neuritis (EAN) in Lewis rats, when given at low dose (50–100 μg/rat) or high dose (250 μg/rat), respectively. Corresponding to the different clinical course, pathological changes and immune responses were found: (1) Onset of clinical signs of P0 peptide 56–71 (P0 56–71) induced EAN was 1–3 days later than in P0 peptide 180–199 (P0 180–199) induced EAN at all immunizing doses, whereas the peak of the disease occurred at a similar time point post immunization (p.i.), i.e. at days 14–16 p.i. in P0 56–71 induced EAN and at day 16 p.i. in P0 180–199 induced EAN. (2) Intramolecular epitope spreading as assessed by delayed type hypersensitivity response occurred in P0 56–71 induced EAN at both low and high antigen doses and in P0 180–199 induced EAN at high antigen dose (250 μg/rat) only. (3) P0 180–199 stimulated higher levels of interferon-γ production in P0 180–199 induced EAN than in P0 56–71 induced EAN and vice versa. (4) Histopathologic evaluation revealed a similar grade of mononuclear cell infiltration in the sciatic nerves of both types of EAN, but more severe demyelination was found in P0 180–199 induced EAN compared to P0 56–71 induced EAN. The results support the hypothesis that high dose autoantigen immunization induces extensive determinant spreading and chronic course of autoimmune diseases.