Musketeers Course October 2008 1 The Mucosal Immune System • The organization of The organization of the mucosal immune the mucosal immune system system • The mucosal response The mucosal response to infections and to infections and regulation of regulation of mucosal immune mucosal immune responses responses
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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.
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Musketeers Course October 2008
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The Mucosal Immune System
The Mucosal Immune System
• The organization of the The organization of the mucosal immune mucosal immune systemsystem
• The mucosal response The mucosal response to infections and to infections and regulation of mucosal regulation of mucosal immune responsesimmune responses
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The mucosal response to infection and regulation of mucosal The mucosal response to infection and regulation of mucosal immune responsesimmune responses
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The mucosal response to infection and regulation of mucosal The mucosal response to infection and regulation of mucosal immune responsesimmune responses
Many enteric pathogens need to exploit host mechanisms as part of their invasive strategies
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Shigella flexneri Shigella flexneri infects intestinal epithelial cells infects intestinal epithelial cells triggering activation of the NFkB pathwaytriggering activation of the NFkB pathway
The mucosal response to infection and regulation of mucosal The mucosal response to infection and regulation of mucosal immune responsesimmune responses
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The mucosal response to infection and regulation of mucosal The mucosal response to infection and regulation of mucosal immune responsesimmune responses
NOD: nucleotide binding oligomerization domain
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The mucosal response to infection and regulation of mucosal The mucosal response to infection and regulation of mucosal immune responsesimmune responses
Intestinal pathogensBacteriaVirusesParasites
induce inflammation
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Entry of nonpathogenic antigens Entry of nonpathogenic antigens e.g. food proteinse.g. food proteins
Mucosal ToleranceMucosal Tolerance
The mucosal response to infection and regulation of mucosal The mucosal response to infection and regulation of mucosal immune responsesimmune responses
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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 The mucosal response to infection and regulation of mucosal immune responsesimmune responses
2 weeks later
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The mucosal response to infection and regulation of mucosal The mucosal response to infection and regulation of mucosal immune responsesimmune responses
Proposed dose-dependent
mechanisms of oral tolerance.
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The healthy intestine contains large quantities of bacteria but does not generate productive immunity against them
The mucosal response to infection and regulation of mucosal The mucosal response to infection and regulation of mucosal immune responsesimmune responses
Metabolism of dietary constituents
Degrading toxins
Produce vitamin K & short chain fatty acids
Maintaining epithelium
Compete the pathogens
Inhibit pro-inflammatory signals
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Clostridium difficileClostridium difficile infection after treatment by infection after treatment by antibioticsantibiotics
The mucosal response to infection and regulation of mucosal The mucosal response to infection and regulation of mucosal immune responsesimmune responses
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The mucosal response to infection and regulation of mucosal The mucosal response to infection and regulation of mucosal immune responsesimmune responses
Mucosal DC regulate the induction of tolerance and immunity
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Commensal bacteria can prevent inflammatory responsesCommensal bacteria can prevent inflammatory responsesin the intestinein the intestine
The mucosal response to infection and regulation of mucosal The mucosal response to infection and regulation of mucosal immune responsesimmune responses
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Commensal bacteria
recognize by epithelial cells
EC secretion of cytokines inhibit the expression of pro-inflammatory cytokines by DC and macrophage
DC & macrophages
secrete 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 The mucosal response to infection and regulation of mucosal immune responsesimmune responses
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The mucosal response to infection and regulation of mucosal The mucosal response to infection and regulation of mucosal immune responsesimmune responses
The mucosal immune system must maintain a balance between The mucosal immune system must maintain a balance between protective immunity and mucosal tolerance to a large number of protective immunity and mucosal tolerance to a large number of different antigensdifferent antigens
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Celiac disease a breakdown of Celiac disease a breakdown of oral toleranceoral tolerance
The mucosal response to infection and regulation of mucosal The mucosal response to infection and regulation of mucosal immune responsesimmune responses
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The mucosal response to infection and regulation of mucosal The mucosal response to infection and regulation of mucosal immune responsesimmune responses
Parasites
Most helminths can induce both protective (Th2) and pathological (Th1) immune responses
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The mucosal response to infection and regulation of mucosal The mucosal response to infection and regulation of mucosal immune responsesimmune responses
Giardia lambliaGiardia lamblia
• Production of antibodies
• Infiltration of mucosa by effector cells
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The mucosal response to infection and regulation of mucosal The mucosal response to infection and regulation of mucosal immune responsesimmune responses
Cryptosporidium parvum & T. gondiiCryptosporidium parvum & T. gondii
• Intracellular pathogens• Require CD4Th1 and CD8 T cells to
clear them
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The mucosal response to infection and regulation of mucosal The mucosal response to infection and regulation of mucosal immune responsesimmune responses
Chronic infections of intestinal helminthsChronic infections of intestinal helminths
• Production 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
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The mucosal response to infection and regulation of mucosal The mucosal response to infection and regulation of mucosal immune responsesimmune responses
Protective and pathological responses to intestinal helminthsProtective and pathological responses to intestinal helminths
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The mucosal response to infection and regulation of mucosal The mucosal response to infection and regulation of mucosal immune responsesimmune responses