Temporal development of autoreactive Th1 responses and endogenous presentation of self myelin epitopes by central nervous system-resident APCs in Theiler's virus-infected mice.
Theiler's murine encephalomyelitis virus (TMEV)-induced demyelinating disease is a chronic-progressive, immune-mediated CNS demyelinating disease and a relevant model of multiple sclerosis. Myelin destruction is initiated by TMEV-specific CD4(+) T cells targeting persistently infected CNS-resident APCs leading to activation of myelin epitope-specific CD4(+) T cells via epitope spreading. We examined the temporal development of virus- and myelin-specific T cell responses and acquisition of virus and myelin epitopes by CNS-resident APCs during the chronic disease course. CD4(+) T cell responses to virus epitopes arise within 1 wk after infection and persist over a >300-day period. In contrast, myelin-specific T cell responses are first apparent approximately 50-60 days postinfection, appear in an ordered progression associated with their relative encephalitogenic dominance, and also persist. Consistent with disease initiation by virus-specific CD4(+) T cells, CNS mononuclear cells from TMEV-infected SJL mice endogenously process and present virus epitopes throughout the disease course, while myelin epitopes are presented only after initiation of myelin damage (>50-60 days postinfection). Activated F4/80(+) APCs expressing high levels of MHC class II and B7 costimulatory molecules and ingested myelin debris chronically accumulate in the CNS. These results suggest a process of autoimmune induction in which virus-specific T cell-mediated bystander myelin destruction leads to the recruitment and activation of infiltrating and CNS-resident APCs that process and present endogenous myelin epitopes to autoreactive T cells in a hierarchical order.
Katz-Levy
Y
Y
Department of Microbiology-Immunology and Interdepartmental Immunobiology Center, Northwestern University Medical School, Chicago, IL 60611, USA.
Neville
K L
KL
Padilla
J
J
Rahbe
S
S
Begolka
W S
WS
Girvin
A M
AM
Olson
J K
JK
Vanderlugt
C L
CL
Miller
S D
SD
D000595:Amino Acid Sequence; D000818:Animals; D017951:Antigen Presentation; D000938:Antigen-Presenting Cells / Q000276:immunology* / Q000378:metabolism; D001324:Autoantigens / Q000276:immunology* / Q000378:metabolism; D001327:Autoimmune Diseases / Q000276:immunology / Q000473:pathology; D018188:Cardiovirus Infections / Q000276:immunology / Q000473:pathology; D002452:Cell Count; D002478:Cells, Cultured; D002908:Chronic Disease; D018450:Disease Progression; D018984:Epitopes, T-Lymphocyte / Q000276:immunology* / Q000378:metabolism; D005260:Female; D016130:Immunophenotyping; D008213:Lymphocyte Activation; D051379:Mice; D008815:Mice, Inbred Strains; D008969:Molecular Sequence Data; D018991:Myelin Proteolipid Protein / Q000276:immunology* / Q000378:metabolism; D013116:Spinal Cord / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D018417:Th1 Cells / Q000276:immunology*; D017945:Theilovirus / Q000276:immunology*; D013997:Time Factors
D001324:Autoantigens; D018984:Epitopes, T-Lymphocyte; D018991:Myelin Proteolipid Protein