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“cyto”

“kinos”. “cyto”. “cyto”. M228 Biology of HIV: Cytokines and HIV Winter Quarter, 2012 Liz Crabb Breen, Ph.D. From Breen, E.C. 2002. Pro- and anti-inflammatory cytokines in HIV Infection and AIDS. Pharmacology and Therapeutics 95:295-304. STEP 1: CYTOKINES.

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“cyto”

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  1. “kinos” “cyto” “cyto” M228 Biology of HIV: Cytokines and HIV Winter Quarter, 2012 Liz Crabb Breen, Ph.D.

  2. From Breen, E.C. 2002. Pro- and anti-inflammatory cytokines in HIV Infection and AIDS. Pharmacology and Therapeutics 95:295-304.

  3. STEP 1: CYTOKINES

  4. STEP 2: RECEPTORS

  5. STEP 3: SIGNALING

  6. STEP 4: GENE EXPRESSION

  7. cytokines

  8. TABLE 7.1 (from Decker, 2000, Introduction to Immunology, pg 90)

  9. Modified TABLE 7.1 (from Decker) INFLAMMATORY CYTOKINES CYTOKINES IN ADAPTIVE/SPECIFIC RESPONSES REGULATORY CYTOKINES

  10. INFLAMMATORY CYTOKINES Macrophage IL1 TNFa IL6

  11. INFLAMMATORY CYTOKINES Modified Table 7.1 (from Decker)

  12. INFLAMMATORY CYTOKINES Macrophage IL1 TNFa IL17 IL6 17

  13. Adapted from Weaver & Hatton, 9:883-889, 2009

  14. CYTOKINES IN ACQUIRED/SPECIFIC RESPONSES IL2 IL2 IL2

  15. CYTOKINES IN ACQUIRED/SPECIFIC RESPONSES IL1 Co-stim IL2 IL12 IL2 IL2

  16. CYTOKINES IN ACQUIRED/SPECIFIC RESPONSES IL2 IL2 IL2 IL4 IL5 IL6 IL10 IL21

  17. CYTOKINES IN ACQUIRED/SPECIFIC RESPONSES Modified Table 7.1 (from Decker)

  18. NK IFNg REGULATORY CYTOKINES Macrophage Monocyte IL10 IL12

  19. REGULATORY CYTOKINES

  20. IL4 IL6 IL10 IL2 IFNg IL12 B cell activation mactivation cytotoxic T cell activation = cytokine production and/or stimulatory effects = inhibitory effects From Breen, E.C. 2002. Pro- and anti-inflammatory cytokines in HIV Infection and AIDS. Pharmacology and Therapeutics 95:295-304.

  21. Th1/Th2 cells Cell-mediated Humoral Adapted from Weaver et al, Th17: An Effector CD4 T Cell Lineage with Regulatory T Cell Ties, 2006, Immunity 24, 677–688

  22. Cell-mediated Humoral Cross-regulation of Th1/Th2 cells Adapted from Weaver et al, Th17: An Effector CD4 T Cell Lineage with Regulatory T Cell Ties, 2006, Immunity 24, 677–688

  23. Cell-mediated Humoral Inflammatory Diversification of CD4 T Cell Lineages Adapted from Weaver et al, Th17: An Effector CD4 T Cell Lineage with Regulatory T Cell Ties, 2006, Immunity 24, 677–688

  24. Th1/Th2/Th17 cells Cell-mediated Humoral Inflammatory Adapted from Weaver et al, Th17: An Effector CD4 T Cell Lineage with Regulatory T Cell Ties, 2006, Immunity 24, 677–688

  25. Possible contributions by human Th17 cells From Afzali et al, The role of T helper 17 (Th17) and regulatory T cells (Treg) in human organ transplantation and autoimmune disease, 2007, Clinical and Experimental Immunology 148: 32-46

  26. Generation of CD4 T Regulatory Cells Adapted from Weaver et al, Th17: An Effector CD4 T Cell Lineage with Regulatory T Cell Ties, 2006, Immunity 24, 677–688

  27. TREG TREG TREG TREG TREG IL-10 TGF-b

  28. 2008 FEBRUARY 4 Monday Dr. Breen

  29. CYTOKINES IN ACQUIRED/SPECIFIC RESPONSES IL2 IL2 IL2

  30. CYTOKINES IN ACQUIRED/SPECIFIC RESPONSES IL2 IL2 IL2

  31. HIV progression GOOD BAD “Th1 to Th2 Shift” Adapted from Mandell & Mildvan (Eds.). 1997. Atlas of Infectious Diseases, Volume I-AIDS.

  32. From Mosmann, TR, Sad, S. 1996. The expanding universe of T-cell subsets. Immunol Today 17:138-146.

  33. Prediction of Th1/Th2 shift:  GOOD (IFNg) BAD (IL4) From Aziz et al. 1998. Level of Cytokines and Immune Activation Markers in Plasma in HIV Infection: QC Procedures. Clin. Diagn. Lab. Immunol. 5:755-761. HIV- HIV+ HIV+ HIV+ HIV+ >500 350- 200- <200 499 349 HIV- HIV+ HIV+ HIV+ HIV+ >500 350- 200- <200 499 349

  34. INFLAMMATORY CYTOKINES Macrophage IL1 TNFa IL17 IL6 17

  35. From: Viral Immunology 20:66-75, 2007 ↑ TH17 cells in unstimulated peripheral blood cells

  36. From: ELHED and UNUTMAZ, Curr Opin HIV AIDS 5:146-150, 2010

  37. “kinos” “cyto” “cyto” • Possible contributions of cytokines to HIV/AIDS pathogenesis • Immune system dysfunction/activation

  38. HIV infection From Mandell & Mildvan (Eds.). 1997. Atlas of Infectious Diseases, Volume I-AIDS.

  39. STEP 1: CYTOKINES STEP 2: RECEPTORS STEP 3: SIGNALING STEP 4: GENE EXPRESSION

  40. From van der Meijden et al. 1998. IL-6 receptor (CD126’IL-6R’) expression is increased on monocytes and B lymphocytes in HIV Infection. Cell. Immunol. 190:156-166.

  41. From: ELHED and UNUTMAZ, Curr Opin HIV AIDS 5:146-150, 2010

  42. “kinos” “cyto” “cyto” • Possible contributions of cytokines to HIV/AIDS pathogenesis • Immune system dysfunction/activation • Regulation of HIV replication

  43. HIV infection From Mandell & Mildvan (Eds.). 1997. Atlas of Infectious Diseases, Volume I-AIDS.

  44. = increase HIV replication/viral load * * *Can also enhance immune function From G. Poli. 1999. Cytokines and the human immunodeficiency virus: from bench to bedside. Eur. J. Clin. Invest. 29:723-732.

  45. From Mandell & Mildvan (Eds.). 1997. Atlas of Infectious Diseases, Volume I-AIDS.

  46. = decrease HIV replication/viral load = increase and decrease HIV replication/viral load From G. Poli. 1999. Cytokines and the human immunodeficiency virus: from bench to bedside. Eur. J. Clin. Invest. 29:723-732.

  47. = decrease HIV replication/viral load = increase and decrease HIV replication/viral load

  48. Generation of CD4 T Regulatory Cells Adapted from Weaver et al, Th17: An Effector CD4 T Cell Lineage with Regulatory T Cell Ties, 2006, Immunity 24, 677–688

  49. -1082 -851 -592 0 G / A C / T C / A Single Nucleotide Polymorphisms in the promoter region of the human IL10 gene = high IL10 secretor genotype = low IL10 secretor genotype

  50. IL10-5’ -592 genotype • C or A at nucleotide -592 • A allele is dominant for low IL10 secretion C/C = high secretor C/A = intermediate/low secretor A/A = low secretor • Frequency of C/C varies by ethnicity, from ~60% for Caucasians to ~40% for Asians • C/A and A/A alleles reported to be associated with more rapid progression to AIDS (Shin et al, PNAS 97:14467, 2000)

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