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Mucosal tissues
- Thin barriers protecting the body from invasion
- Defended by innate and adaptive immune mechanisms
- Must recognize pathogens but not respond to:
- – Commensal bacteria
- – Non-microbial antigens, e.g., food proteins
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Mucosal tissues of human body
- GI, urogenital, respiratory tracts
- lachrymal, salivary, mammary glands
- conjunctiva, kidney
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Mucosa-associated lymphoid tissue (MALT)
- Organized lymphoid tissues found in mucosal epithelia and underlying tissue
- Lymphocytes are found in
- - epithelial layers (mostly CD8 T),
- - lamina propria, separated from epithelium by basement membrane (forming discrete compartment, containing CD4, 8 T-cells, Macrophages, DCs (can span this layer), etc.)
- - and in organized lymphoid tissues (e.g., Peyer’s patches and lymphoid follicles) and in the tonsils.
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The tonsils (________) and adenoids form a ring of lymphoid tissues at the entrance of the gut and airway, called ________.
- palatine tonsil and lingual tonsil
- Waldeyer's ring
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Gut-associated lymphoid tissues (GALT) and lymphocyte populations
- Scattered throughout intestine as the effector
- Organized tissue (Peyer's patch) - induce immune response; contains
- – M-cell (microfold) cover, w/ characteristic membrane ruffles; take up Ag by endocytosis and phagocytosis, transport vesicles across, release at the basal surface, to be taken up by DCs, which activate T cells
- – Subepithelial dome (dendritic cells, T and B cells)
- – T-cell dependent areas (TDA)
- – B-cell follicles with germinal centers
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Capture of antigens from the intestinal lumen
- M-cell nonspecific transport across epithelium
- FcRn-dependent transport by enterocytes
- Apoptosis of enterocytes and phagocytosis by DC
- Antigen capture by monocyte, reaching between epithelial cells
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Priming of naive T cells and the redistribution of effector T cells in the intestinal immune system
- Naive T enters Peyer's patch, guided by CCR7 and L-selectin homing receptors
- Exposed to Ag and activated by DC
- Leaves via mesenteric lymph node -> thoracic duct -> bloodstream -> gut
- Guided by CCR9 and a4:b7 integrin, homes to lamina propria and epithelium of small intestine.
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Molecular control of gut-homing lymphocytes
- Endothelium at mucosa expresses MAdCAM-1, which binds to a4:b7 integrin of the gut-homing lymphocytes, activating the adhesion.
- Intestine epithelium expresses chemokine CCL25/28 to bind CCR9/10 of gut-homing lymphocytes in small/large intestine, respectively.
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Secretory IgA
- Associated with mucosal immunity
- In mucosa - dimer linked by a J chain
- Naïve B-cell precursors in Peyer’s patches are activated to become IgA-secreting cells that home to the mucosa
- Binds to poly-Ig receptor, apically transcytosed and released at the mucus layer
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pIgR
polymeric Ig receptor, a specialized transport protein
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Mucosal IgA function
- Neutralizes toxin and pathogen in lumen
- Binds and neutralizes Ag and internalized in endosomes
- Exports pathogens and toxins from lamina propria to lumen when secreted.
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Intraepithelial lymphocytes are
CD8 T cells
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Action of intraepithelial lymphocyte against virus-infected epithelial cell
- When epithelial cell is infected by virus, viral peptide is presented to IEL (CD8 T) via MHC I.
- CD8 T kills the cell by inducing apoptosis via perforin/granzyme and Fas-dependent pathways
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Action of intraepithelial lymphocyte against bacteria-infected or stressed epithelial cell
- [The effector T cell is not a classical CD8 CTL, carries CD8 a:a homodimer]
- Stressed cell express atypical MHC I molecules MIC-A, MIC-B [TL].
- MIC-A/B bind to NKG2D on IEL and activate it to kill the cell by inducing apoptosis via perforin/granzyme pathway
- [The activation may be enhanced by binding of TL-CD8 a:a dimer]
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Epithelial cells have a crucial role in innate defense against pathogens
- TLR and NOD recognize pathogen, activate NFkB, resulting release of cytokine, chemokine, inflammation
- Infection triggers formation of inflammasome, inducing inflammation.
- Bacteria-containing autophagosome forms, fuses w/ lysosome, kill the bacteria.
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Salmonella penetrate the gut epithelial layer via
- killing M-cell and infect
- invading epithelial cell directly
- Ag-sampling monocyte in the lamina propria
- infected macrophage secretes cytokines (activate via TLR5, secrete CXCL8), recruit neutrophil to kill
- Dendritic cell loaded w/ Ag migrate to lymph node to induce adaptive response
- If defense fail, enters bloodstream and causes systemic infection.
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Shigella flexneri causes bacterial dysentery by
- going through M-cell, infecting intestinal epithelial cells by entering from the basal membrane
- activating NFκB pathway via NOD1
- Secretes CXCL8, recruits neutrophil.
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Infection by Clostridium difficile
- happens when commensal flora in colon is wiped out by antibiotic
- toxin of Clostridium damages epithelium
- neutrophil and RBC leak out into gut
- form colitis and pseudomembrane
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Oral tolerance:
How the mucosal immune system distinguishes between pathogens and non-pathogenic organisms and antigens
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Tolerance to antigens can be experimentally generated by oral administration
- mice experiments
- Injection of ovalbumin can induce immune response.
- However, if Ovalbumin has been orally given to the mice for 7d, no response.
- Oral tolerance: tolerance through subs coming through the mouth
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Mucosal dendritic cells regulate the induction of tolerance and immunity in the intestine
- When commensal presented, production of TGF-b, PGE-2, and TSLP inhibit maturation of DC, immature DC weakly stims CD4 T cells in lymph node, diff into TReg
- When infected, DC activated, mature DC strongly stim CD4 T cells in LN, diff into TH1, TH2, TH17
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Commensal bacteria can prevent inflammatory responses in the intestine by
preventing the functioning of NFkB, either blocking the binding, or disabling the entry into the nucleus
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Protective responses to intestinal helminths via
- TH2 effector function
- IL-13 - epithelial repair (leads to shedding) and mucus secretion of goblet cells (prevents adherence)
- IL-4 & IL-13 - recruits M2 macrophage, tissue remodeling
- IL-4 - stim IgE production, ADCC via mast cells
- IL-5 - recruits eosinophil, kills parasite
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Mucosal immunity in the oral cavity
- Two types of dendritic cells
- – Langerhans cells (immature DCs) in epithelial layer
- – Dermal dendritic cells (mature) in lamina propria
- P. gingivalis comes in contact with Langerhans cells
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