Local expression of TNFalpha in neonatal NOD mice promotes diabetes by enhancing presentation of islet antigens.
The relationship of inflammation to autoimmunity has been long observed, but the underlying mechanisms are unclear. Here, we demonstrate that islet-specific expression of TNFalpha in neonatal nonobese diabetic mice accelerated diabetes. In neonatal transgenic mice, disease was preceded by apoptosis of some beta cells, upregulation of MHC class I molecules on residual islet cells, and influx and activation of both antigen-presenting cells bearing MHC-islet peptide complexes and T cells. Infiltrating dendritic cells/macrophages, but not B cells, from neonatal islets activated islet-specific T cells in vitro. Thus, inflammation can trigger autoimmunity by recruiting and activating dendritic cells/macrophages to present self-antigens to autoreactive T cells.
Green
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EA
Section of Immunobiology, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
Eynon
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EE
Flavell
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RA
D000818:Animals; D017951:Antigen Presentation / Q000276:immunology*; D017209:Apoptosis / Q000502:physiology; D001324:Autoantigens / Q000276:immunology*; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D018450:Disease Progression; D005260:Female; D007515:Islets of Langerhans / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D008213:Lymphocyte Activation; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008822:Mice, Transgenic; D012680:Sensitivity and Specificity; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D019076:Transgenes; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*
D001324:Autoantigens; D014409:Tumor Necrosis Factor-alpha