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Pancreatic lymph node. Islet. CD8 +. En- viron- ment. Perforin?. Co-stimu- latory signals. •. •. •. •. DC. •. •. •. •. •. •. •. •. •. •. •. •. . •. •. •. •. DC. •. •. •. •. IL-1 TNF . O 2. NO. •. •. . •. Th 1. •. •. •. •. •. •. •.
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Pancreatic lymph node Islet CD8+ En-viron-ment Perforin? Co-stimu- latory signals • • • • DC • • • • • • • • • • • • • • • • DC • • • • IL-1 TNF O2 NO • • • Th1 • • • • • • • • • MØ • • Fas FasL IFN T- and B-cell clonal ex- pansion Th1 Mandrup-Poulson
SOD2 NOS2 NFKB BCL2 INS T1DM FASL FAS CTLA4 CD4 IL6 IL12B IL1RN IL1RI IFNG HLA TNFA IL1B Mandrup-Poulson
IFNg IL-1ß Cytokine-signaling Energy generation Defense Repair NO production Mitochondria Apoptosis Insulin production/ß-cell function ß-cell destruction Mandrup-Poulson
Mitogen and stress stimuli Ras Rho TRAF MAPKKK Raf ASK MEKK MLK TAK1 TPL2 ATP ADP MEK1/2 MKK3/6 MKK4/7 MAPKK ATP ADP ERK p38 JNK MAPK Elk-1 ATF2 c-jun Mandrup-Poulson
TNF IL-1 TNF IL-1 p60 IL-1R1 IL-1AcP MyD88 TRADD TRAF2 IRAK TRAF6 FADD NIK IKK IkB NFkB IkB NFkB Gene expression Cellular response Mandrup-Poulson
IFN IFN IFN IFNgR1 IFNgR2 IFNgR2 P STAT1 JAK1 JAK1 JAK1 JAK1 JAK1 JAK2 JAK2 STAT1 P STAT1 Translocation to nucleus Gene expression Mandrup-Poulson
energy generation insulin production/ß-cell function defense NO production +cytokines cytokine-signaling apoptosis repair ß-cell survival ß-cell destruction Mandrup-Poulson