Cutting edge: inflammatory signals drive organ-specific autoimmunity to normally cross-tolerizing endogenous antigen.
Links have been observed between infections and the development of autoimmunity. Proposed explanations include activation of self-Ag-bearing APC. Using a model system in which transgenic OVA is expressed in enterocytes, we showed that CD8 T cell recognition of cross-presented Ag in gut-associated lymph nodes was tolerogenic. However, concomitant infection with vesicular stomatitis virus encoding OVA abrogated tolerance and induced disease. We now show that following transfer of naive OT-I T cells, the addition of wild-type vesicular stomatitis virus, oral cholera toxin, or CD40 triggering can induce intestinal disease in transgenic mice. Tissue damage accompanied dramatic increases in cytokine release by activated OT-I cells in the intestine. The data indicated that products of antigenically unrelated infections can combine with cross-presented self-Ags on APC to prime autoaggressiveness, independent of additional Ag release. These results help explain how diverse pathogens, lacking any homology to self-proteins, could be causative agents in induction of organ-specific autoimmunity.
Vezys
Vaiva
V
Division of Immunology, University of Connecticut Health Center, Farmington, CT 06030, USA.
Lefrançois
Leo
L
D019264:Adoptive Transfer; D000818:Animals; D001324:Autoantigens / Q000276:immunology*; D001327:Autoimmune Diseases / Q000235:genetics / Q000276:immunology* / Q000473:pathology*; D002772:Cholera Toxin / Q000276:immunology; D007108:Immune Tolerance / Q000235:genetics; D007249:Inflammation / Q000235:genetics / Q000276:immunology; D007413:Intestinal Mucosa / Q000276:immunology* / Q000473:pathology*; D007583:Jejunum / Q000276:immunology / Q000473:pathology; D017710:Lymphocyte Transfusion; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009928:Organ Specificity / Q000235:genetics / Q000276:immunology; D010047:Ovalbumin / Q000276:immunology; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D014721:Vesicular stomatitis Indiana virus / Q000276:immunology
D001324:Autoantigens; D010047:Ovalbumin; D002772:Cholera Toxin