Mucosal immunity Flashcards
What is the mucosa-associated lymphatic tissue (MALT) divided into?
BALT (bronchus-associated lymphatic tissue)
GALT (gut -associated lymphatic tissue)
Why is the mucosal immune system very important?
Biggest immune compartment of organism
Direct contact with outside environment
Continuous antigen stimulation
Prime site of entry for infectious pathogens + important target site for vaccine-induced protection.
What are the main defence strategies of intestinal mucosa and oropharynx?
Endogenous flora
Epithelium + mucus: mechanical barriers, mucins form viscous barrier, specialised epithelial cells, antimicrobial substances (defensins, lysozyme, lactoferrin, phospholipases).
Regionalised immune system + gut homing of B + T cells:
waldeyer’s ring (tonsils), Peyer´s patches, mesenteric lymph nodes, intraepithelial immune cells, lamina propria immune cells -> sampling dendritic cells (DCs).
Induction sites generated in organised tissues.
Effector sites -> scattered lymphoid cells.
Where are the lymphoid complexes along the GI tract and where is the largest amount of lymphoid tissue?
Waldeyer’s ring, gastric antrum, terminal ileum.
Oropharynx (Waldeyer’s ring) + terminal ileum.
What are the intestinal epithelial cells?
Goblet cells produce mucus (physico-chemical barrier)
Epithelial cells express TLRs e.g. TLR5 is expressed on basolateral surface + activated by invading bacteria.
M cells transport antigens to subepithelial lymphoid structures.
Paneth cells produce human defensin 5 (HD5) precursor, HD6 precursor, trypsin (activates HD5 + HD6 by proteolytic cleavage).
What is the effect of surface TLR ligation?
Tightening of epithelial junctions, increase proliferation, epithelial motility + improve barrier function but not cause inflammation.
What are the features of Peyer´s patches (PPs)?
Located in distal ileum in areas of follicle associated epithelium (FAE).
PPs contain germinal centres for B + T cells.
Inductive site for immune responses.
What are the features of M cells?
Small microvilli
Large cell membrane fenestrations enhance antigen uptake from gut lumen (fluid-phase endocytosis).
Trans-cellular transport of antigen.
Exocytosis at basolateral membrane + delivery to DCs in dome region of underlying lymphatic structures.
Outline the architecture of Peyer’s patches
3 main domains -> follicular area, interfollicular area,
follicle-associated epithelium (FAE).
Follicular + interfollicular areas -> lymphoid follicles with germinal center (GC) containing proliferating B cells, follicular dendritic cells (FDCs) + macrophages. follicle is surrounded by corona or subepithelial dome (SED) containing mixed-cells e.g. B-cells, T-cells, macrophages DCs.
FAE differs from normal epithelium in microvilli regularity, length + presence of infiltrating immune cells.
PPs connected to circulation by endothelial venules + lymphatic vessels.
What is the action of Naive B cells?
Enters PP via specialised high endothelial venules (HEV). If they recognise antigen coming from M-cells at top of PP -> activation + maybe proliferation.
What is the action of naive CD4 T-cells?
Enters PP via specialised high endothelial venules. If they encounter dendritic cell presenting antigen that they recognise -> proliferation. some may then encounter B-cells activated by same antigen.
T-cell/B-cell help -> activate each other, T-cells become mature, B-cells undergo immunoglobulin class-switch -> plasma cells.
Most activated T + B cells leave PP via lymphatic drainage + reach destination via blood stream.
B-cells programmed to produce IgA under influence of NO + TGF-beta from DCs.
What is the location and function of mesenteric lymph nodes (MLN)?
Base of mesentery. collect lymph, cells + antigens from intestinal mucosa. main site for oral tolerance induction.
Drain lymph from intestinal mucosa.
What is oral tolerance?
Avoidance of immune response to foodstuffs
What is oral tolerance induction?
Induce tolerance to allergens e.g. eat honey to treat bee venom allergy
What are the features of intraepithelial lymphocytes (IEL)?
In basolateral part of epithelium, have irregular shape +
long extensions in close contact with neighbouring epithelial cells, occur in variable numbers along gut, up to 12% eosinophils in IEL preparations.
Intraepithelial T-cells can be subdivided into which three main groups?
TCRab+CD8ab+
TCRab+ CD8aa+
TCRab+CD4
MIC-A + MIC-B are ligands for NK cell activating receptor NKG2D, also found on CD8aa+ T-cells.
Thymus leukemia (TL) antigen is MHC-Ib molecule that doesn’t enable peptide binding.
Which cells influence T cell differentiation?
Epithelial cells + DCs
What is the action of T regulatory cells?
Produce IL-10. establishes + maintains food tolerance + class switch, including TGF-β + other mediators.
What is the action of Th1 cells?
Produce IFN-g. kills virally infected epithelial cells.
What is the action of Th2 cells?
May be induced by worm infestation. IL-4 + IL-13 will increase fluid secretion, mucus secretion, bowel motility + smooth muscle contraction.
What is the action of Th17 cells?
Produce IL-17 + IL-22. interact with receptors on epithelial cells to regulate production of mucins or defensins.
What is the location and action of dendritic cells?
Lamina propria. have long extensions reaching through epithelium to ‘sample’ contents of intestinal tube. antigens presented to T-cells.
What is the action of the poly-Ig-receptor (pIgR)?
At basal surface of epithelial cells, can bind to J-chain of IgA + to lesser extent IgM -> enables trans-endothelial transport of dimeric IgA/pentameric IgM. helps enrich immunoglobulins in mucus -> immune exclusion.
What are the actions of IgA?
Main antibody in secretions
IgA against food antigens -> immune exclusion
Activates complement system only weakly
Secretion depends on trans-cellular transport mechanism
What are the gut-homing properties of B and T cells?
The gut-homing properties of effector lymphocytes are imprinted in lymphoid tissues where they’ve undergone differentiation from naive precursors.
DCs in gut-associated lymphoid tissues are induced by thymic stromal lymphopoietin + other factors to express retinaldehyde dehydrogenase -> converts vit A to retinoic acid.
When naive B or T cells are activated -> exposed to retinoic acid produced by DCs -> induces expression of chemokine receptor CCR9 + integrin α4β7 on plasma cells + effector T cells that arise from naive lymphocytes.
Effector lymphocytes enter circulation, into gut lamina propria as chemokine ligand CCL25 + MadCAM (ligand for α4β7) are displayed on lamina propria venular endothelial cells.
What can vitamin A deficiency lead to?
Reduced oral tolerance perhaps due to reduced gut homing of regulatory T-cells
