Ufp 2011.05.10 imunologia hpv

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  • • 1842: Rigoni-Stern reports that nuns have much lower incidence of cervical cancer than prostitutes • 1951: Successful in vitro culture of “HeLa” cells derived from a lethal cervical cancer (patient Henrietta Lacks) • 1983: Harald zur Hausen discovers new HPV types (types 16 and 18) lurking in HeLa cells and other cervical cancer cells. New cancer-associated types took 89 years to identify because they ’re not associated with overt symptoms like warts • 2008: Harald zur Hausen wins Nobel Prize for his work establishing a causal link between HPVs and cervical cancer
  • Disulfiram, olmesartan and dithiocarbamates can inhibit the nuclear factor-κB (NF-κB) signaling cascade upregulate major histocompatibility complex molecules, MHC I and MHC II, and increase immunoproteasome activity. Higher MHC I expression increases presentation of viral peptides to cytotoxic T cells, while the immunoproteasome processes viral peptides for loading onto the MHC I molecule, thereby increasing the recognition and killing of infected cells by T cells. Higher MHC II expression increases presentation of viral peptides to helper T cells
  • Disulfiram, olmesartan and dithiocarbamates can inhibit the nuclear factor-κB (NF-κB) signaling cascade upregulate major histocompatibility complex molecules, MHC I and MHC II, and increase immunoproteasome activity. Higher MHC I expression increases presentation of viral peptides to cytotoxic T cells, while the immunoproteasome processes viral peptides for loading onto the MHC I molecule, thereby increasing the recognition and killing of infected cells by T cells. Higher MHC II expression increases presentation of viral peptides to helper T cells
  • Disulfiram, olmesartan and dithiocarbamates can inhibit the nuclear factor-κB (NF-κB) signaling cascade upregulate major histocompatibility complex molecules, MHC I and MHC II, and increase immunoproteasome activity. Higher MHC I expression increases presentation of viral peptides to cytotoxic T cells, while the immunoproteasome processes viral peptides for loading onto the MHC I molecule, thereby increasing the recognition and killing of infected cells by T cells. Higher MHC II expression increases presentation of viral peptides to helper T cells
  • Host immune response to early HPV infection. The HPV infects the basal/suprabasal keratinocyte. The infected cell is proliferated and transformed by the E5 protein. This cell is in the premalignant stage. The E5 protein ( ) is presented by MHC class I and class II. CD4+ T-cells recognize the presented E5 antigenic epitope and are activated. The activated CD4+ T-cells activate CD8+ T-cells resulting in differentiation to the E5-specific CTL. This CTL specifically kills the E5 presenting premalignant cells.
  • Ufp 2011.05.10 imunologia hpv

    1. 1. +HPV eRespostaImunológica Hugo Sousa BScH Microbiology, MSc Oncology PhD Student, MD Student _________________________________________ Serviço Virologia – Lab Biologia Molecular Grupo Oncologia Molecular IPO Porto FG EPE hugomls@gmail.com
    2. 2. + Cancro do Colo do Útero
    3. 3. + Cancro do Colo do Útero
    4. 4. + Cancro do Colo do Útero Distribuição Mundial
    5. 5. + Cancro do Colo do Útero Em Portugal  4ª neoplasia na mulher  Neoplasia urogenital  Alta taxas:  Incidência 16 / 100 000  Mortalidade 6 / 100 000
    6. 6. + Cancro do Colo do Útero Etiologia  1842 – A culpa era da profissão…  1901 – A culpa era da religião…  60s – A culpa era da circuncisão…  70s – A culpa era dos Herpes…  80s – Associação com HPV  odds ratio: 60 (95% C.I. 49-73)
    7. 7. + Cancro do Colo do Útero Patologia  Desenvolvimento de Lesões Precursoras que podem evoluir para Cancro Infecção Ca Colo Útero 6 meses 3 anos 6 anos 10 anos
    8. 8. + Cancro do Colo do Útero Patologia  Colo Útero Normal Normal Histologia Citologia
    9. 9. + Cancro do Colo do Útero Patologia  CIN 1 Histologia Citologia
    10. 10. + Cancro do Colo do Útero Patologia  CIN 2 Histologia Citologia
    11. 11. + Cancro do Colo do Útero Patologia  CIN 3 Histologia Citologia
    12. 12. + Cancro do Colo do Útero Patologia  Carcinoma In Situ Histologia Citologia
    13. 13. + Cancro do Colo do Útero Patologia  Carcinoma Invasor Histologia Citologia
    14. 14. + Cancro do Colo do Útero Patologia  Carcinoma Invasor
    15. 15. + Cancro do Colo do Útero Susceptibilidade Genética
    16. 16. + Cancro do Colo do Útero Susceptibilidade Genética
    17. 17. + Vírus do Papiloma Humano (HPV)
    18. 18. + Vírus do Papiloma Humano (HPV) Características Gerais  Vírus com distribuição ubíqua  Independentemente do género, idade, etnia ou localização geográfica  Vírus epitelio-mucosotrópico  Infecta células epiteliais e mucosas
    19. 19. + Vírus do Papiloma Humano (HPV) Características Gerais  Descritos quase 200 tipos de HPV
    20. 20. + Vírus do Papiloma Humano (HPV) Características Gerais  Família Papillomaviridae  Estrutura icosaédrica ( 55nm)  Vírus de DNA cadeia dupla  Genoma com 8000pb  positivo  2 genes estruturais (L1 e L2)  7 ou 8 genes precoces (E1 a E8)
    21. 21. + Vírus do Papiloma Humano (HPV) Características Gerais GENE FUNCTION E1 DNA-dependent ATPase, ATP dependent helicasE; Allow unwinding of the viral genome and act as an elongation factor for DNA replication. E2 Responsible for recognition and binding of origin of replication. Exists in two forms: full length (transcriptional transactivator) and truncated (transcriptional repressor). The ratio of these found in the heterotrimeric complex formed before complexing with E1 regulates transcription of viral genome. E3 ???? E4 Late Expression: C terminal binds intermediate filament, allowing release of virus-like particles. Also involved in transformation of host cell by deregulation of host cell mitogenic signalling pathway. E5 Obstruction of growth suppression mechanisms: e.g EGF receptor; activation of mitogenic signalling pathways via transcription factors: c-Jun and c-Fos (important in ubiquitin pathway degradation of p53 complex by E6). Inactivation of p21 (p53 induced expression halts cell cycle until DNA is proof-read for mutations). E6 Transformation of host cell by binding p53 tumour suppressor protein. E7 Transforming protein, binds to pRB/p107. E8 ?????
    22. 22. + Vírus do Papiloma Humano (HPV) Características Gerais  Baixo-Risco:  HPV6,  11, 13, 40, 42, 43, 44, 54, 61, 70, 72, 81 e 89  Provocam aparecimento de papilomas/verrugas…
    23. 23. + Vírus do Papiloma Humano (HPV) Características Gerais  Alto-Risco  HPV16,  18, 31, 33, 35, 39, 45, 51, 52, 56, 58 e 59  Desenvolvimento de lesões baixo/alto grau e cancro do colo do útero  Desenvolvimento de outras neoplasias
    24. 24. + Vírus do Papiloma Humano (HPV) Infecção
    25. 25. + Vírus do Papiloma Humano (HPV) Infecção
    26. 26. + Vírus do Papiloma Humano (HPV) Infecção  Infecção Queratinócitos Basais  Activação Replicação viral  E1, E2, E4, E5  Amplificação Carga viral  10  1000 cópias/célula  Maturação vírus  1-3 semanas  Desenvolvimento de lesão  Semanas  Meses
    27. 27. + Vírus do Papiloma Humano (HPV) Infecção
    28. 28. + Vírus do Papiloma Humano (HPV) Mecanismo de Carcinogénese
    29. 29. + Vírus do Papiloma Humano (HPV) Mecanismo de Carcinogénese
    30. 30. + Vírus do Papiloma Humano (HPV) Mecanismo de Carcinogénese Major Events Integração DNA viral no DNA do hospedeiro Imortalização celular Instabilidade genómica Escape à Resposta Imunológica
    31. 31. + Vírus do Papiloma Humano (HPV) Mecanismo de Carcinogénese
    32. 32. + Vírus do Papiloma Humano (HPV) Mecanismo de Carcinogénese Integração Viral DNA Episomal: expressão de E2 regula a expressão de E6 e E7 DNA integrado: perda de E2 permite expressão desregulada de E6 e E7 Promove  Inibição replicação viral  Instabilidade genética Confere vantagem selectiva para a proliferação de células Ocorre na maioria dos casos de HSIL Podem co-existir formas episomais com integradas
    33. 33. + Vírus do Papiloma Humano (HPV) Mecanismo de Carcinogénese – E6 Moody and Laimonis, 2010
    34. 34. + Vírus do Papiloma Humano (HPV) Mecanismo de Carcinogénese – E7 Moody and Laimonis, 2010
    35. 35. + Vírus do Papiloma Humano (HPV) Mecanismo de Carcinogénese – E5  Expressa  Retículo endoplasmático  Complexo Golgi  Membrana Pasmática  Papel importante nos eventos precoces da carcinogénese  Presente em lesoes do colo do útero  Ausente após integração  Funções  Ligação à ATPase e danificando a formação de endolisossomas  Downregulating MHC class I and CD1d Moody and Laimonis, 2010
    36. 36. + Vírus do Papiloma Humano (HPV) Mecanismo de Carcinogénese
    37. 37. + Evasão Imunológica do HPV
    38. 38. + Evasão Imunológica do HPV Mecanismo de Infecção
    39. 39. + Evasão Imunológica do HPV Persistência Infecção  Replicate in keratinocytes which are “programmed to die” (squames)  Viral release does not provoke inflammation  Inhibition of Interferon synthesis and signaling  Delayed activation of adaptive immune response  Compromised immune surveillance  (Cell mediated immunity is suppressed in non-regressing cells) MAGARET STANLEY. IMMUNE RESPONSE TO HPV. VACCINE 24s1 (2006)
    40. 40. + Evasão Imunológica do HPV Resposta Imunológica RESPOSTA INATA 1ª linha resposta  Barreira Epitelial  Sistema Fagocitário  Citocinas  Sistema do Complemento Sem memória associada Promove resposta adaptativa por via da interacção com Células Apresentadoras de Antigénios (células dendriticas/langerhans)
    41. 41. + Evasão Imunológica do HPV Resposta Imunológica RESPOSTA ADAPTADA Celular  Células NK  Células CD8 citotóxicas  Macrófagos Humoral  Células B memória  Plasmócitos
    42. 42. + Evasão Imunológica do HPV Resposta Imunológica Anti-viral  NF-Kb  Major transcription factor that regulates genes responsible for both the innate and adaptive immune response  Plays a key role in regulating the immune response to infection by upregulating genes involved in T-cell development, maturation, and proliferation Increases the number of T cells available for immune response
    43. 43. + Evasão Imunológica do HPV Resposta Imunológica Anti-viral  TNFa  Pro-inflammatory ctyokine that promotes a cascade of cytokines which mediate an inflammatory response Inibição da sinalização para as células T Ambiguous functions
    44. 44. + Evasão Imunológica do HPV Resposta Imunológica Anti-viral  Interferon (IFN)  upregulates major histocompatibility complex molecules, MHC I and MHC II, and increase immunoproteasome activity.  Higher MHC II expression increases presentation of viral peptides to helper T cells;  Higher immunoproteasome activity increase viral peptides processing for loading onto the MHC I molecule;  Higher MHC I expression increases presentation of viral peptides to cytotoxic T cells; Increases the recognition and killing of infected cells by T cells.
    45. 45. + Evasão Imunológica do HPV Resposta Imunológica Anti-HPV
    46. 46. + Evasão Imunológica do HPV Resposta Imunológica Anti-HPV
    47. 47. + Evasão Imunológica do HPV Em suma...  HPV replication does not induce:  necrosis  cytolysis  viraemia  Terminally differentiated cells are not part of immune surveillance  HPV E6 and E7 down regulates IFN-gamma  HPV E5 down regulates MHC class I  Despite weak immune response:  Most HPV cleared within 2 years  Cell mediated immunity
    48. 48. +HPV eRespostaImunológica Hugo Sousa BScH Microbiology, MSc Oncology PhD Student, MD Student _________________________________________ Serviço Virologia – Lab Biologia Molecular Grupo Oncologia Molecular IPO Porto FG EPE

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