Class II-restricted T cell responses in Theiler's murine encephalomyelitis virus (TMEV)-induced demyelinating disease. III. Failure of neuroantigen-specific immune tolerance to affect the clinical course of demyelination.
Intracerebral inoculation of Theiler's murine encephalomyelitis virus (TMEV) into susceptible mouse strains produces a chronic demyelinating disease in which mononuclear cell-rich infiltrates in the central nervous system (CNS) are prominent. Current evidence strongly supports an immune-mediated basis for myelin breakdown, with an effector role proposed for TMEV-specific, major histocompatibility complex (MHC) class II-restricted delayed-type hypersensitivity (DTH) responses in which lymphokine-activated macrophages mediate bystander demyelination. The present study examined the possibility that concomitant or later-appearing neuroantigen-specific autoimmune T cell responses, such as those demonstrated in chronic-relapsing experimental allergic encephalomyelitis (R-EAE), may contribute to the demyelinating process following TMEV infection. T cell responses against intact, purified major myelin proteins (myelin basic protein (MBP) and proteolipid protein (PLP], and against altered myelin constituents were readily demonstrable in SJL/J mice with R-EAE, but were not detectable in SJL/J mice with TMEV-induced demyelinating disease. TMEV-infected mice also did not display T cell responses against the peptide fragments of MBP(91-104) and PLP(139-151) recently shown to be encephalitogenic in SJL/J mice. In addition, induction of neuroantigen-specific tolerance to a heterogeneous mixture of CNS antigens, via the i.v. injection of syngeneic SJL/J splenocytes covalently coupled with mouse spinal cord homogenate, resulted in significant suppression of clinical and histologic signs of R-EAE and the accompanying MBP- and PLP-specific DTH responses. In contrast, neuroantigen-specific tolerance failed to alter the development of clinical and histologic signs of TMEV-induced demyelinating disease or the accompanying virus-specific DTH and humoral immune responses. These findings demonstrate that TMEV-induced demyelinating disease can occur in the apparent absence of neuroantigen-specific autoimmune responses. The relationship of the present results to the immunopathology of multiple sclerosis is discussed.
Department of Microbiology-Immunology, Northwestern University Medical School, Chicago, IL 60611.
S D
SD
Miller
S J
SJ
Gerety
M K
MK
Kennedy
J D
JD
Peterson
J L
JL
Trotter
V K
VK
Tuohy
C
C
Waltenbaugh
M C
MC
Dal Canto
H L
HL
Lipton
D000818:Animals; D000917:Antibody Formation; D000918:Antibody Specificity; D003711:Demyelinating Diseases / Q000209:etiology / Q000276:immunology* / Q000473:pathology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000503:physiopathology; D004769:Enterovirus Infections / Q000150:complications / Q000276:immunology*; D000939:Epitopes; D005260:Female; D007108:Immune Tolerance / Q000502:physiology*; D004680:Maus Elberfeld virus; D051379:Mice; D008815:Mice, Inbred Strains; D004676:Myelin Basic Protein / Q000276:immunology; D009186:Myelin Sheath / Q000502:physiology*; D009420:Nervous System / Q000276:immunology*; D011510:Proteolipids / Q000276:immunology; D013116:Spinal Cord / Q000502:physiology; D013601:T-Lymphocytes / Q000502:physiology*
D000939:Epitopes; D004676:Myelin Basic Protein; D011510:Proteolipids