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Musketeers Course October 20081 The Mucosal Immune System The organization of the mucosal immune systemThe organization of the mucosal immune system The

Jan 16, 2016

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  • Musketeers Course October 2008*The Mucosal Immune System

    The organization of the mucosal immune system

    The mucosal response to infections and regulation of mucosal immune responses

    Musketeers Course October 2008

  • Musketeers Course October 2008*The mucosal response to infection and regulation of mucosal immune responses

    Musketeers Course October 2008

  • Musketeers Course October 2008*The mucosal response to infection and regulation of mucosal immune responsesMany enteric pathogens need to exploit host mechanisms as part of their invasive strategies

    Musketeers Course October 2008

  • Musketeers Course October 2008*Shigella flexneri infects intestinal epithelial cells triggering activation of the NFkB pathwayThe mucosal response to infection and regulation of mucosal immune responses

    Musketeers Course October 2008

  • Musketeers Course October 2008*The mucosal response to infection and regulation of mucosal immune responsesNOD: nucleotide binding oligomerization domain

    Musketeers Course October 2008

  • Musketeers Course October 2008*The mucosal response to infection and regulation of mucosal immune responsesIntestinal pathogensBacteriaVirusesParasites

    induce inflammation

    Musketeers Course October 2008

  • Musketeers Course October 2008*Entry of nonpathogenic antigens e.g. food proteinsMucosal ToleranceThe mucosal response to infection and regulation of mucosal immune responses

    Musketeers Course October 2008

  • Musketeers Course October 2008*The concept of mucosal tolerance. Prolonged mucosally administered antigens induce both systemic and mucosal unresponsivenessto the same Ag when challenged in the presence of adjuvant.

    The mucosal response to infection and regulation of mucosal immune responses2 weeks later

    Musketeers Course October 2008

  • Musketeers Course October 2008*The mucosal response to infection and regulation of mucosal immune responsesProposed dose-dependent mechanisms of oral tolerance.

    Musketeers Course October 2008

  • Musketeers Course October 2008*The healthy intestine contains large quantities of bacteria but does not generate productive immunity against themThe mucosal response to infection and regulation of mucosal immune responsesMetabolism of dietary constituentsDegrading toxinsProduce vitamin K & short chain fatty acidsMaintaining epitheliumCompete the pathogensInhibit pro-inflammatory signals

    Musketeers Course October 2008

  • Musketeers Course October 2008*Clostridium difficile infection after treatment by antibiotics The mucosal response to infection and regulation of mucosal immune responses

    Musketeers Course October 2008

  • Musketeers Course October 2008*The mucosal response to infection and regulation of mucosal immune responsesMucosal DC regulate the induction of tolerance and immunity

    Musketeers Course October 2008

  • Musketeers Course October 2008*Commensal bacteria can prevent inflammatory responsesin the intestineThe mucosal response to infection and regulation of mucosal immune responses

    Musketeers Course October 2008

  • Musketeers Course October 2008*Commensal bacteria recognize by epithelial cells EC secretion of cytokines inhibit the expression of pro-inflammatory cytokines by DC and macrophage

    DC & macrophagessecrete signals for the expansion and/or survival of T cells with regulatory capacities, including regulatory T cells, T regulatory type 1 (TR1) cells, T helper 2 (TH2) cells and TH3 cells. The mucosal response to infection and regulation of mucosal immune responses

    Musketeers Course October 2008

  • Musketeers Course October 2008*The mucosal response to infection and regulation of mucosal immune responsesThe mucosal immune system must maintain a balance between protective immunity and mucosal tolerance to a large number of different antigens

    Musketeers Course October 2008

  • Musketeers Course October 2008*Celiac disease a breakdown of oral toleranceThe mucosal response to infection and regulation of mucosal immune responses

    Musketeers Course October 2008

  • Musketeers Course October 2008*The mucosal response to infection and regulation of mucosal immune responsesParasitesMost helminths can induce both protective (Th2) and pathological (Th1) immune responses

    Musketeers Course October 2008

  • Musketeers Course October 2008*The mucosal response to infection and regulation of mucosal immune responsesGiardia lambliaProduction of antibodiesInfiltration of mucosa by effector cells

    Musketeers Course October 2008

  • Musketeers Course October 2008*The mucosal response to infection and regulation of mucosal immune responsesCryptosporidium parvum & T. gondii

    Intracellular pathogensRequire CD4Th1 and CD8 T cells to clear them

    Musketeers Course October 2008

  • Musketeers Course October 2008*The mucosal response to infection and regulation of mucosal immune responsesChronic infections of intestinal helminthsProduction of mediators that dampen the innate immune responses

    Expression of decoy receptors of cytokines and chemokines

    Downregulation of IL-12 by DC encourage generation of IL-10 producing Treg

    Musketeers Course October 2008

  • Musketeers Course October 2008*The mucosal response to infection and regulation of mucosal immune responsesProtective and pathological responses to intestinal helminths

    Musketeers Course October 2008

  • Musketeers Course October 2008*The mucosal response to infection and regulation of mucosal immune responses

    Musketeers Course October 2008

  • Musketeers Course October 2008*

    Musketeers Course October 2008

    ******Commensalism is a symbiotic relationship where the symbiont benefits but the host is neither harmed nor helped ****Basal recognition of commensal bacteria by intestinal epithelial cells (IECs) may influence the secretion of cytokines, including thymic stromal lymphopoietin (TSLP), transforming growth factor- (TGF ) and interleukin-10 (IL-10), that can directly influence the expression of pro-inflammatory cytokines by dendritic cell (DC) and macrophage populations that resident in the lamina propria and Peyer's patches. Signals derived from commensal bacteria may influence tissue-specific 'licensing' of accessory-cell functions resulting in the expansion and/or survival of T cells with regulatory capacities, including regulatory T cells, T regulatory type 1 (TR1) cells, T helper 2 (TH2) cells and TH3 cells. In addition to TSLP, TGF and IL-10, other IEC-derived factors, including APRIL (a proliferation-inducing ligand), B-cell-activating factor (BAFF), secretory leukocyte peptidase inhibitor (SLPI), prostaglandin E2 (PGE2) and other metabolites have the capacity to directly regulate the functions of both antigen-presenting cells and lymphocytes in the intestinal microenvironment. TLR5, Toll-like receptor 5; SED, subepithelial dome.

    *****The entry of a parasitic helminth leads to the activation of dendritic cells (DCs) in the peripheral tissues; these cells will express co-stimulatory molecules and react to polarizing signals from helminths. It is known that they initially activate naive T cells to become T helper 2 (TH2) cells. It is also possible that crossreactive helminth antigens might stimulate the involvement of natural regulatory T (TReg) cells. The early involvement of TReg cells (natural and/or adaptive) is thought to impede TH2-cell responses, such as interleukin-5 (IL-5)-dependent eosinophil activation, and safeguard against excessive TH2-cell responses. b | With increasing levels of parasite antigens, we postulate that a stronger regulatory network might be established through antigen-specific (adaptive) TReg cells. At this chronic stage of infection, macrophages are known to acquire an alternatively activated phenotype (AAM) that can suppress T-cell proliferation and promote the development of modified TH2 cells. The interactions of DCs and newly differentiating macrophages with T cells in chronic infection are less clear, but the effector arms of the immune system remain in a modified state with, for example, the reduced production of IL-5, and high levels of IL-10 (produced by adaptive TReg cells), which switches B-cell responses to IgG4 and not IgE, and transforming growth factor- (TGF- ), which mediates cellular hyporesponsiveness. **

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