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 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 microg/rat) or high dose (250 microg/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 microg/rat) only. (3) P0 180-199 stimulated higher levels of interferon-gamma 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.
Division of Geriatric Medicine, Huddinge University Hospital, S-141 86 Huddinge, Stockholm, Sweden. jie.zhu@neurotec.ki.se
J
J
Zhu
S H
SH
Pelidou
G
G
Deretzi
M
M
Levi
E
E
Mix
P
P
van der Meide
B
B
Winblad
L P
LP
Zou
D000208:Acute Disease; D000595:Amino Acid Sequence; D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology; D002908:Chronic Disease; D004195:Disease Models, Animal; D004306:Dose-Response Relationship, Immunologic; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000139:chemically induced / Q000276:immunology*; D020275:Guillain-Barre Syndrome / Q000276:immunology; D016056:Immunodominant Epitopes / Q000276:immunology*; D066298:In Vitro Techniques; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism; D008297:Male; D008969:Molecular Sequence Data; D018993:Myelin P0 Protein / Q000737:chemistry / Q000276:immunology* / Q000494:pharmacology*; D010446:Peptide Fragments / Q000276:immunology / Q000494:pharmacology; D051381:Rats; D011917:Rats, Inbred Lew
D016056:Immunodominant Epitopes; D018993:Myelin P0 Protein; D010446:Peptide Fragments; D007371:Interferon-gamma