- 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
Mucosal tissues of human body
- GI, urogenital, respiratory tracts
- lachrymal, salivary, mammary glands
- conjunctiva, kidney
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.
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
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
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
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.
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.
- 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
polymeric Ig receptor, a specialized transport protein
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.
Intraepithelial lymphocytes are
CD8 T cells
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
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]
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.
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.
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.
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
How the mucosal immune system distinguishes between pathogens and non-pathogenic organisms and antigens
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
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
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
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
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