T-cell clones specific for myelin basic protein induce chronic relapsing paralysis and demyelination.
Experimental allergic encephalomyelitis (EAE) serves as a model for autoimmune diseases mediated by T lymphocytes. Following sensitization to rat, mouse or guinea pig myelin basic protein (MBP) in complete Freund's adjuvant, inbred mouse strains PL/J (H-2u), SJL/J (H-2s) and (PL/J X SJL/J)F1((PLSJ)F1) develop EAE. Whereas sensitization to the N-terminal 37 amino-acid peptide of rat or guinea pig MBP [MBP(1-37)] induces EAE in PL/J mice, immunization to the C-terminal peptide (89-169) leads to EAE in SJL/J mice. The immune response to MBP in (PLSJ)F1 mice is not co-dominant; sensitization to the N-terminal peptide induces EAE, while sensitization to the C-terminal peptide does not. We have generated MBP-specific T-cell clones restricted to class II (Ia) antigens of the major histocompatibility complex (MHC) from PL/J and (PLSJ)F1 mice following sensitization to rat MBP. Two such I-Au-restricted T-cell clones that proliferate in response to the encephalitogenic N-terminal MBP peptide and recognize a shared determinant with mouse (self) MBP cause paralysis in 100% of (PLSJ)F1 mice tested. Paralysis is induced even when recipients are injected with as few as 1 X 10(5) cloned T cells. Relapsing paralysis followed in two-thirds of the recipients after recovery from acute paralysis, whereas one-third developed chronic persistent paralysis, a form of EAE not usually seen. Histopathology revealed intense perivascular inflammation, demyelination and remyelination within the central nervous system of paralysed mice. The experimental disease induced with these clones shares important features with human demyelinating diseases such as multiple sclerosis. This is the first demonstration that T-cell clones that respond to a defined self-antigen can induce clinical and histological autoimmune disease.
S
S
Zamvil
P
P
Nelson
J
J
Trotter
D
D
Mitchell
R
R
Knobler
R
R
Fritz
L
L
Steinman
D000818:Animals; D001327:Autoimmune Diseases / Q000276:immunology; D002478:Cells, Cultured; D002999:Clone Cells; D003711:Demyelinating Diseases / Q000276:immunology*; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology / Q000473:pathology; D006183:H-2 Antigens / Q000235:genetics; D007116:Immunization, Passive; D008285:Major Histocompatibility Complex; D051379:Mice; D008815:Mice, Inbred Strains; D004676:Myelin Basic Protein / Q000096:biosynthesis*; D010243:Paralysis / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology*
D006183:H-2 Antigens; D004676:Myelin Basic Protein