1.   O2O2 NO Co-stimu- latory signals DC CD8 + Perforin? Th 1 IFN  MØ IL-1 TNF  Islet Pancreatic lymph node Th 1 T- and B-cell clonal ex- pansion DC En- viron- ment Fas FasL Mandrup-Poulson

2. T1DM HLA IL1B IFNG TNFA IL1RI IL1RN NOS2 SOD2 NFKB BCL2INS IL6IL12B FASFASL CTLA4CD4 Mandrup-Poulson

3. IL-1ß IFN  Mitochondria  Energy generation  Cytokine-signaling  NO production  Apoptosis  Defense  Repair ß -cell destruction  Insulin production/ß-cell function Mandrup-Poulson

5. Raf ASK MEKK MLK TAK1 TPL2 MEK1/2 MKK3/6 MKK4/7 ERK p38 JNK MAPKKK MAPK MAPKK ATP ADP ATP ADP Ras Rho TRAF Mitogen and stress stimuli Elk-1 ATF2 c-jun Mandrup-Poulson

6. IL-1R1 IL-1AcP IRAK NIK MyD88 TRAF6 IKK NF  B IL-1 IBIB NF  B IBIB Gene expression Cellular response TNF TRADD FADD TRAF2 TNF p60 Mandrup-Poulson

7. IFN JAK1 IFN  R1 JAK1 IFN JAK1 IFN  R2 JAK2 IFN  R2 JAK2 STAT1 Translocation to nucleus Gene expression STAT1 P P Mandrup-Poulson

8. ß-cell destruction ß-cell survival +cytokines  apoptosis  cytokine-signaling  NO production  energy generation  defense  insulin production/ ß -cell function  repair Mandrup-Poulson