Virus-induced diabetes in a transgenic model: role of cross-reacting viruses and quantitation of effector T cells needed to cause disease.
Virus-specific cytotoxic T lymphocytes (CTL) at frequencies of >1/1, 000 are sufficient to cause insulin-dependent diabetes mellitus (IDDM) in transgenic mice whose pancreatic beta cells express as "self" antigen a protein from a virus later used to initiate infection. The inability to generate sufficient effector CTL for other cross-reacting viruses that fail to cause IDDM could be mapped to point mutations in the CTL epitope or its COO(-) flanking region. These data indicate that IDDM and likely other autoimmune diseases are caused by a quantifiable number of T cells, that neither standard epidemiologic markers nor molecular analysis with nucleic acid probes reliably distinguishes between viruses that do or do not cause diabetes, and that a single-amino-acid change flanking a CTL epitope can interfere with antigen presentation and development of autoimmune disease in vivo.
Sevilla
N
N
Division of Virology, Department of Neuropharmacology, The Scripps Research Institute, La Jolla, California 92037, USA.
Homann
D
D
von Herrath
M
M
Rodriguez
F
F
Harkins
S
S
Whitton
J L
JL
Oldstone
M B
MB
D000595:Amino Acid Sequence; D000818:Animals; D000956:Antigens, Viral / Q000276:immunology; D001483:Base Sequence; D002522:Chlorocebus aethiops; D003429:Cross Reactions; D017931:DNA Primers; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology / Q000821:virology*; D004195:Disease Models, Animal; D008217:Lymphocytic choriomeningitis virus / Q000235:genetics / Q000472:pathogenicity*; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D017386:Sequence Homology, Amino Acid; D013601:T-Lymphocytes / Q000276:immunology*; D014709:Vero Cells
D000956:Antigens, Viral; D017931:DNA Primers