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

Two synthetic peripheral nerve myelin PO protein peptides, an immunodominan t (amino acids 180-199) and a cryptic (amino acids 56-71) one, induced an a cute or chronic course of experimental autoimmune neuritis (EAN) in Lewis r ats, when given at low dose (50-100 mug/rat) or high dose (250 mug/rat), re spectively. Corresponding to the different clinical course, pathological ch anges and immune responses were found: (1) Onset of clinical signs of PO pe ptide 56-71 (PO 56-71) induced EAN was 1-3 days later than in PO peptide 18 0-199 (PO 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 PO 56-71 induced EAN and at day 16 p.i. in PO 180-1 99 induced EAN. (2) Intramolecular epitope spreading as assessed by delayed type hypersensitivity response occurred in PO 56-71 induced EAN at both lo w and high antigen doses and in PO 180-199 induced EAN at high antigen dose (250 mug/rat) only. (3) PO 180-199 stimulated higher levels of interferon- gamma production in PO 180-199 induced EAN than in PO 56-71 induced EAN and vice versa. (4) Histopathologic evaluation revealed a similar grade of mon onuclear cell infiltration in the sciatic nerves of both types of EAN, but more severe demyelination was found in PO 180-199 induced EAN compared to P O 56-71 induced EAN. The results support the hypothesis that high dose auto antigen immunization induces extensive determinant spreading and chronic co urse of autoimmune diseases. (C) 2001 Elsevier Science B.V. All rights rese rved.