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• The Mucosal Immune System (Ch. 12)
1. The organization of the mucosal system.
2. The mucosal response to infection and regulation of mucosal immune responses.
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◆ Lymphocytes are originated from BM, but mature in the bone marrow (B) or the thymus (T).
◆ Lymphocyte resides in lymphoidtissues or organs where mature naïve lymphocytes are maintained and adaptive Immune response are initiated.
◆ Lymphoid organs: central (primary) or peripheral (secondary)
Central: bone marrow and ThymusPeripheral: lymph nodes, spleen mucosal lymphoid tissues of the gut, the nasal and respiratory tract and the urogenital tract and other mucosa
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1. The organization of the mucosal immune system
JPEG file adapted fromJaneway’s Immunobiology, 8th Ed.
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Mucosa-associated lymphoid tissue:Lymphocytes, Macrophages and Dendritic cells in the intestine (as an example):1. Scattered throughout the surface epithelium of the mucosa2. Underlying layer of connective tissue (called the lamina propria)3. In organized tissues such as gut-associated lymphoid tissues (GALT).
GALT:i) Peyer’s pathcesii) Isolated lymphoid follicleiii) Appendixiv) Mesenteric lymph node
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Peyer’s patch
- B cell follicles with germinal Center- Subepithelial dome (Area between the surface epithelium and
the follicles): DC, T, B cells- Microfold (M) cell: No digestive enzymes or mucus, No thick
surface glycocalyx, the route by which antigen enters the Peyer’s patch.
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Mucosa-associated lymphoid tissue (MALT):
-GALT-Bronchus-associated lymphoid tissue (BALT): upper respiratory tract-Nasal-Associated lymphoid tissue (NALT)
Tonsils and Adenoids: BALT, NALT
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Waldeyer’s ring:
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Transcytosis by the M cells:
The M cells i) take up antigens by endocytosis or phagocytosisii) transfer antigens to the basal cell membrane iii) and release antigens into extracellular space.
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DCs are also abundant in the wall of the intestine to acquire antigens without the M cells.
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Cells in the mucosal immune system:
- The intestinal mucosa displays many characteristics of a chronic inflammatory response because of the myriad of innocuous antigens.
- But no diseases due to powerful regulatory mechanisms.
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The circulation of lymphocytes within the mucosal immune system is controlled by tissue–specific adhesion molecules and chemokine receptors
Once T cells encounter antigens in the GALT, they become activated and lose expression of CCR7 (receptor for CCL21 and CCL19) and L-selectin.
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GALT DCs specifically induce lymphocytes to express gut-specific homing receptors and integrins.
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Secretory IgA is the class of antibody associated with the mucosal immune system.
IgA: -form dimer (monomer in the blood) -function in secretions -present in intestinal and respiratory tract-Non-inflammatory antibody (tolerance)
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JPEG file adapted fromJaneway’s Immunobiology, 8th Ed.
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Proteolytic clevage of the extracellular domain of the poly-Ig receptor
Transcytosis of IgA:
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Functions of secretory IgA:
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2. The mucosal response to infection and regulation of mucosal immune responses.
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Epithelial cells play a critical role in innate defense against pathogens.
- Epithelial cells have no TLR4 (unable to sense bacteria in the intestinal lumen).
- Epithelial cells have TLR5 which recognizes bacterial flagellin ontheir basal membrane.
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Salmonella tryphimurium
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Innate immune response by intestinal epithelial cells.
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Immune priming vs oral tolerance (mucosal tolearance)
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JPEG file adapted fromJaneway’s Immunobiology, 8th Ed.
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The mechanisms of oral tolerance?
1. anergy?
2. Deletion of antigen-specific T cells?
3. Generation of regulatory T cell (TGFβ)?
4. TGFβ also stimulates B cells to switch to IgA.
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1. Commensal bacteria induce TGFβ, thymic stromal lymphopoietin (TSLP) and prostaglandin E2 (PGE2) expression by gut epithelial cells to keep local DCs in a quienscent state with low level of co-stimulatory molecules.
2. Commensal bacteria cannot penetrate the intact epithelium.
3. Commensal bacteria inhibit NF-κB activation
Commensal bacteria:
- The failure of these regulatory mechanisms induces unrestricted immune response to commensal bacteria: inflammatory bowel diseases such as Crohn’s disease
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JPEG file adapted fromJaneway’s Immunobiology, 8th Ed.
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PPARγ: Proliferator activated receptor-γ
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Side effects of antibiotics:
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