Diabetes induced by Coxsackie virus: initiation by bystander damage and not molecular mimicry.
Viral induction of autoimmunity is thought to occur by either bystander T-cell activation or molecular mimicry. Coxsackie B4 virus is strongly associated with the development of insulin-dependent diabetes mellitus in humans and shares sequence similarity with the islet autoantigen glutamic acid decarboxylase. We infected different strains of mice with Coxsackie B4 virus to discriminate between the two possible induction mechanisms, and found that mice with susceptible MHC alleles had no viral acceleration of diabetes, but mice with a T cell receptor transgene specific for a different islet autoantigen rapidly developed diabetes. These results show that diabetes induced by Coxsackie virus infection is a direct result of local infection leading to inflammation, tissue damage, and the release of sequestered islet antigen resulting in the re-stimulation of resting autoreactive T cells, further indicating that the islet antigen sensitization is an indirect consequence of the viral infection.
Horwitz
M S
MS
Department of Immunology, The Scripps Research Institute, La Jolla, California 92037, USA.
Bradley
L M
LM
Harbertson
J
J
Krahl
T
T
Lee
J
J
Sarvetnick
N
N
D000595:Amino Acid Sequence; D000818:Animals; D002478:Cells, Cultured; D018834:Chaperonin 60 / Q000276:immunology; D003384:Coxsackievirus Infections / Q000276:immunology*; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology* / Q000821:virology*; D004195:Disease Models, Animal; D029822:Enterovirus B, Human / Q000276:immunology*; D005260:Female; D005968:Glutamate Decarboxylase / Q000276:immunology; D006367:HeLa Cells; D006801:Humans; D018960:Hyaluronan Receptors / Q000276:immunology; D019041:L-Selectin / Q000276:immunology; D008216:Lymphocytic Choriomeningitis / Q000276:immunology; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics / Q000276:immunology*; D015375:Receptors, Interleukin-2 / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*
D018834:Chaperonin 60; D018960:Hyaluronan Receptors; D016693:Receptors, Antigen, T-Cell, alpha-beta; D015375:Receptors, Interleukin-2; D019041:L-Selectin; D005968:Glutamate Decarboxylase