Dr. Antonio Condino Neto Professor Associado Livre-Docente Departamento de Imunologia Instituto de Ciências Biomédicas Universidade de São Paulo Imunidade Inata: Mecanismos Efetores Dr. Antonio Condino Neto Professor Associado Livre-Docente

Figure 2-1 Imunidade Inata x Imunidade Adaptativa

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Exemplo de Resposta à Infecção Figure 2-3

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NADPH-Oxidase Gene Cromossomo Frequência (%) gp91-phox Xp21.1 67 5 p47-phox 7q11.23 33 p67-phox 1q25 G6PD Xq28 <0.01 Adaptado de Curnutte et al, 2002

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TLR Ligands - Recognition PAMPS TLR Ligand Source TLR1/2 lipoarabinomanin mycobacteria TLR2±6 Zymosan Fungi TLR3 DS RNA Viruses TLR4 lipopolysaccharide Peptidoglycan RSV fusion protein Gr- bacteria Gr+ bacteria RSV TLR5 Flagellin Flagelated bacteria TLR6/2 Diacyl lipopeptides Mycoplasma TLR7 and 8 SS RNA Imidazoquinolones Synthetic TLR9 CpG Bacteria and DNA viruses TLR10 Unknown

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TLR signal generation to NF-kB after ligation CD14 MD2 Cell membrane TIRAP TIRAP TLR 7/8/9 MyD88 TLR 3 MyD88 Endosome MyD88 IRAK4 TRIF TRAF6 RIP1 MyD88 NEMO Slide 3: TLR pathway image This is a schematic diagram representing the TLR signaling pathway. TLR recognize pathogen associated molecular patterns and can be found on the cell surface or intracellularly. All TLR can function by activation of the IKK complex. Once assembled, IKK directs the phosphorylation and ubiquitination of IkB, targeting it for proteosomal degradation. This in turn allows NF-kB to dimerize and translocate to the nucleus, thus promoting gene transcription. Clearly there are molecules in this pathway that, when defective, can almost completely abrogate TLR function, one example being the human mutation of IRAK4 and another being that of NEMO. (here is boy w/NEMO mut ahving the characteristic syndrome of ED). There are conceivably also more upstream mutations that selectively impair TLR function. This is something that we are interested in investigating further in the future. IKK- IKK- p IkB IkB Cytoplasm NF-B Nucleus New gene transcription NF-B binding motif

TLR induction of other transcription factors CD14 MD2 Cell membrane TIRAP TRAM TIRAP TLR 7/8/9 MyD88 TLR 3 TRIF MyD88 Endosome MyD88 TRIF IRAK4 MyD88 TRAF6 IRAK1/4 IRF5 TRAF6 IRF7 Slide 3: TLR pathway image This is a schematic diagram representing the TLR signaling pathway. TLR recognize pathogen associated molecular patterns and can be found on the cell surface or intracellularly. All TLR can function by activation of the IKK complex. Once assembled, IKK directs the phosphorylation and ubiquitination of IkB, targeting it for proteosomal degradation. This in turn allows NF-kB to dimerize and translocate to the nucleus, thus promoting gene transcription. Clearly there are molecules in this pathway that, when defective, can almost completely abrogate TLR function, one example being the human mutation of IRAK4 and another being that of NEMO. (here is boy w/NEMO mut ahving the characteristic syndrome of ED). There are conceivably also more upstream mutations that selectively impair TLR function. This is something that we are interested in investigating further in the future. TBK1 MAPK AP-1 IRF3 Cytoplasm Nucleus New gene transcription

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Quimiotaxia de Neutrófilos (CD11a/CD18) LAD- II LAD- I E-Selectin Sialyl-Lewis-X Rolagem Adesão Emigração Transendotelial

Lesão Cutânea em Paciente com LAD-I Leucócitos - 40.200 cels/mm3

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