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Raimonda Grilli
5 anni fa
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6 Infezione da Morbillo Il morbillo è una malattia altamente contagiosa che colpisce i bambini. E causato da infezione da Virus del Morbillo (MV) che causa infezione respiratoria acuta, con un certo di numero di casi di morte o complicazioni neurologiche. L infezione da MV: rimane una delle principali cause di morbilità e di mortalità infantile nei paesi in via di sviluppo focolai di morbillo si verificano regolarmente in paesi industrializzati paesi. induce un'efficace risposta immunitaria in grado di eliminare completamente il virus, Induce una risposta immunitaria duratura che protegge da re-infezioni. dà luogo ad attivazione del sistema immunitario non specifica caratterizzata da: una spontanea proliferazione delle cellule mononucleate del sangue periferico e una up-regolazione dell espressione di marcatori di attivazione delle cellule MV induce una transitoria ma grave immunosoppressione, che aumenta la suscettibilità dei pazienti a contrarre infezioni batteriche e virali secondarie con esito fatale. Le anomalie includono la scomparsa della reazione di ipersensibilità di tipo ritardato, ridotta proliferazione dei linfociti e riduzione della risposta citotossica allospecifica. Il meccanismo immunologico responsabile di questo apparente paradosso che si osserva in corso di infezione da virus del morbillo è oggetto di studio.

9 vaccine Neutral commitment Th1 commitment Th2 commitment

10 Dendritic cells (DCs) represent a major target of MV and could be involved in immunosuppression. In this study, human monocyte-derived DCs were used to demonstrate that DC apoptosis in MV-infected DC T-cell cocultures is Fas mediated, whereas apoptotic T cells could not be rescued by blocking the Fas pathway. Two novel consequences of DC apoptosis after MV infection were demonstrated (i) Fas-mediated apoptosis of DCs facilitates MV release, while CD40 activation enhances MV replication in DCs. Indeed, detailed studies of infectious MV release and intracellular MV nucleoprotein (NP) showed that inhibition of CD40-CD40L ligand interaction blocks NP synthesis. We conclude that the CD40 ligand expressed by activated T cells first enhances MV replication in DCs, and then Fas ligand produced by activated T cells induces Fas-mediated apoptosis of DCs, thus facilitating MV release. (ii) Not only MV-infected DCs but also bystander uninfected DCs undergo a maturation process confirmed by CD1a, CD40, CD80, CD86, CD83, and major histocompatibility complex type II labeling. The bystander maturation effect results from contact and/or engulfment of MV-induced apoptotic DCs by uninfected DCs. A model is proposed to explain how both a specific immune response and immunosuppression can simultaneously occur after MV infection through Fas-mediated apoptosis and CD40 activation of DCs.

because both innate immunity and adaptive immuneresponses play clearly defined roles in the control of this infection, thus providing

12 To better understand the mechanisms involved with MVinduced immunosuppression, the authors used transgenic mice (YAC-CD46) expressing a fulllength human CD46 genomic clone that allows for viral replication and analysis of MV pathogenesis LM was also chosen for this because both innate immunity and adaptive immuneresponses play clearly defined roles in the control of this infection, thus providing an opportunity to simultaneously examine MV-associated effects on both these arms of the immune response to a secondary bacterial infection.

13 Reduced innate immunity cells during MV infection in spleen

14 Which mechanism? Reduction by apoptosis?

15 Which mechanism? Defective proliferation?

16 Which mechanism? Defective cytokine production?

17 The purpose of this study was to investigate the consequences of DC infection by MV, particularly concerning their maturation and their ability to generate CD8 T cell proliferation. MV-infected Langerhans cells or monocyte-derived DCs undergo a maturation process similarly to the one induced by TNF-a or LPS, respectively. CD40 ligand (CD40L) expressed on activated T cells is shown to induce terminal differentiation of DCs into mature effector DCs. In contrast, the CD40L-dependent maturation of DCs is inhibited by MV infection, as demonstrated by CD25, CD69, CD71, CD40, CD80, CD86, and CD83 expression downregulation. Moreover, the CD40L-induced cytokine pattern in DCs is modified by MV infection with inhibition of IL-12 and IL-1a/b and induction of IL-10 mrnas synthesis.

18 CD40-CD40L CD40L The function of CD40 accounts not only for the regulation of T-dependent humoral immune responses, but also for cellular immune responses. Several immune dysfunctions observed in CD40Ldeficient mice and patients could be explained by a failure properly to activate APCs. Recent in vivo studies in mouse demonstrated that CD40 ligation on the DCs can replace CD41 T cells to prime CD8+ cytotoxic responses.

19 Per l attivazione dei linfociti B è richiesto un secondo segnale 19

20 Le cellule T adiuvanti stimolano la proliferazione e poi il differenziamento (switch isotipico) delle cellule B X 20

21 MV replication in immature DCs and PBL High MV replication in immature DCs correlates with CD40 triggering

22 Dendritic cells maturation To become a potent APC, the immature DCs need to be activated by stimuli that promote their maturation and migration to the T cell areas of lymphoid tissues. Living bacteria, microbial products (LPS), or various cytokines (TNF-alfa, GM-CSF, IL-1beta) stimulate DC maturation. Upon maturation, MHC-II molecules are delivered to the plasma membrane and the expression of costimulatory membrane molecules is increased, thus favoring T cell activation. When the mature DCs reach secondary lymphoid organs, they interact with T cells, receiving signals which induce their terminal differentiation into mature effector DCs. CD40-CD40 ligand (CD40L) interaction between DCs and T cells is essential for an optimal cytokine production. The best- known consequence of CD40 ligation is the IL-12 production by DCs

23 Phenotypic maturation of LCs and monocyte-derived DCs is induced by MV replication Thus, CD40-dependent maturation of Mo-DCs is inhibited by MV replication

24 Phenotypic maturation of LCs and monocyte-derived DCs is induced by MV replication Thus, CD40-dependent maturation of Mo-DCs is inhibited by MV replication On the basis of this phenotypic study, authors confirm and further extend to the LCs and Mo-DCs that MV replication induces maturation of immature DCs. CD40 ligation of MV-infected DCs inhibited induction of CD25, CD69, CD71, CD86, and CD83 and up-regulation of CD40 and CD80 expression. Although MV-induced DC maturation was similar to LPS-induced DC maturation, MV-infected DCs are deficient in APC functions in contrast to LPS-activated DCs

25 CD40-induced cytokine pattern in DCs is modified by MV infection Authors then compared cytokine mrna productions of uninfected, LPS-activated, MV-infected, CD40L-activated, and MV-infected + CD40L-activated DCs.

26 MV infection prevents CD40L-dependent CD8+ T lymphocyte proliferation 1) CD40L activation of DCs is required to sustain human CD8+ T cell MV replication could modify the signal transduced by CD40L in DCs. proliferation, invitro, and To investigate this point, PBL from healthy donors or from CD40L-deficient 2) MV infection of DCs prevents this CD40L-dependent CD8+ T cell patients were used proliferation.

MV replication impairs CD40 signaling in DCs To determine CD80 expression whether MV wascould inhibited modify only CD40 when signaling MV-infected into the DCs Mo-DCs, were CD40L the authors studied

27 MV replication impairs CD40 signaling in DCs To determine CD80 expression whether MV wascould inhibited modify only CD40 when signaling MV-infected into the DCs Mo-DCs, were CD40L the authors studied activated the expression either with of CD40L+-PBL membrane or Ags withthat CD40L+-L were cells. induced Thus, or even up-regulated in the by CD40L presence activation of other(s) in DCs. T cell signal(s) able to up-regulate CD80 expression, CD40 triggering of MV-infected DCs did not up-regulate CD80 expression. DC-PBL cocultures were performed using allogeneic PBL either from healthy donors Therefore, both MV replication and CD40 triggering of DCs were needed for or from CD40L-deficient patients. inhibition of CD80 and CD86 expression. CD40L signal was required to increase CD86 expression

Although the nature of the CD40 signaling pathway in DCs has not been elucidated, CD40 signaling in monocytes and B cells has been shown to involve protein tyrosine kinase activity The enhanced

28 Although the nature of the CD40 signaling pathway in DCs has not been elucidated, CD40 signaling in monocytes and B cells has been shown to involve protein tyrosine kinase activity The enhanced effect of CD40 tyrosine stimulation phosphorylation on overall levels wasof evident tyrosinein phosphorylation mock-treated DCs in mock-treated after 10 min or of MV-infected stimulationdcs withwas anti-cd40. examinedbut by MV Western infection blot strongly analysis of inhibited total protein anti-cd40 using anti-phosphotyrosine enhanced tyrosine phosphorylation. Abs.

30 Meccanismi dell immunosoppressione da MV Molteplici sono stati i meccanismi evocati per spiegare l immunosoppressione indotta da MV. PolarizzazioneTH2: citochine risposte si verifica durante la fase tardiva del morbillo si osserva l aumento della produzione di interleuchina 4 (IL-4) e una diminuzione dei livelli di IL-2 e interferonegamma(ifn-γ). La produzione della citochina pro-infiammatoria IL-12 è anche notevolmente soppressa nei azienti con il morbillo e la citochina anti-infiammatoria IL - 10 è aumentata. Alcune proteine di MV sembrano avere un azione immunosoppressiva Le glicoproteine, hemagglutinin (H) e proteina di fusione (F), potrebbero indurre una surface-contact-mediated signaling che porta al blocco dell attivazione della chinasi Akt e all inibizione della proliferazione delle cellule. Inoltre, l'interazione delle nucleoproteine di MV nucleoprotein con Fcγ receptor sulle APC è implicata nella soppressione della risposta cellulomediata, e nell'induzione di linfociti T CD4 regolatorie nei casi di esposizione cronica al virus

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