Using transgenic mouse models to dissect the pathogenesis of virus-induced autoimmune disorders of the islets of Langerhans and the central nervous system.
Viruses have often been associated with autoimmune diseases. One mechanism by which self-destruction can be triggered is molecular mimicry. Many examples of cross-reactive immune responses between pathogens and self-antigens have been described. This review presents two transgenic models of autoimmune disease induced by a virus through activation of anti-self lymphocytes. Viral antigens are expressed as transgenes either in beta-cells of the pancreas or in the oligodendrocytes of the CNS. Infection by a virus encoding the same gene activated autoreactive T cells that cleared the viral infection, and as a consequence of transgene expression resulted in organ-specific autoimmune disease. In both transgenic mouse models, autoreactive lymphocytes that escaped thymic negative selection were present in the periphery. Several factors are described that play a role in the regulation of the self-reactive process precipitated by a viral infection. These include the quantity of activated autoreactive T cells, the affinity of these T cells, the number of memory T cells generated following primary infection, costimulation by accessory molecules, and the types and locations of cytokines produced. In addition, unique barriers exist in target tissues that prevent or suppress autoreactive responses and define to a large extent the outcome of disease. Restimulation of autoreactive memory lymphocytes may be required to bypass these barriers and enhance autoimmune disease. Therapy directed at modifying these factors can reduce and even prevent autoimmune disease after it has been initiated.
von Herrath
M G
MG
Department of Neuropharmacology, Scripps Research Institute, La Jolla, California 92037, USA.
Evans
C F
CF
Horwitz
M S
MS
Oldstone
M B
MB
D000818:Animals; D001327:Autoimmune Diseases / Q000276:immunology / Q000821:virology; D002490:Central Nervous System / Q000276:immunology*; D002493:Central Nervous System Diseases / Q000276:immunology* / Q000821:virology; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology / Q000821:virology; D004195:Disease Models, Animal; D006801:Humans; D007328:Insulin / Q000235:genetics / Q000276:immunology*; D007515:Islets of Langerhans / Q000276:immunology*; D008217:Lymphocytic choriomeningitis virus / Q000276:immunology* / Q000472:pathogenicity*; D051379:Mice; D008822:Mice, Transgenic; D004676:Myelin Basic Protein / Q000235:genetics / Q000276:immunology*; D017634:Self Tolerance / Q000276:immunology; D014780:Viruses / Q000472:pathogenicity
D007328:Insulin; D004676:Myelin Basic Protein