11. Mucosal immunity Flashcards
what is MALT, BALT AND GALT?
The mucosa-associated lymphatic tissue (MALT) is divided into BALT (bronchial associated lymphatic tissue) and and GALT (gut associated lymphatic tissue)
Why is the mucosal immune system very important?
It is the biggest immune compartment of the organism
estimated surface area of 400 m2
60% of all effector cells
direct contact with the outside environment
continuous antigen stimulation (food, endogenous flora, and pathogens)
mucosal sites are the ports of entry for many infections and an important target site for vaccine-induced protection
Significance of mucosal surfaces in infection
Mucosal surfaces are a prime site of entry for infectious pathogens
Most of the pathogens that cause the deaths of large numbers of people are those of mucosal surfaces or enter the body through these routes.
The genitourinary, rectal and oral mucosa are the mucosal HIV transmission routes.
An effective vaccine that can induce both systemic and local mucosal immunity is generally accepted as an ideal means of protection against mucosal HIV transmission and AIDS.
The main defence strategies of intestinal mucosa and oropharynx
Endogenous flora
Epithelium and Mucus
‘Regionalised’ Immune System & gut homing of B and T cells
Endogenous flora
1014 bacteria, hundreds of different species (10x more than all cells in the human body)
Epithelium and mucus
Mechanical Barriers (cells, tight junctions)
Specialised epithelial cells (goblet cells, absorptive epithelial cells, M cells, Paneth cells)
Antimicrobial substances (defensins, lysozymes, lactoferrin, phospholipases )
Mucins (extensively glycosylated proteins) form a viscous barrier
Regionalised immune system and gut homing of B and T cells
Waldeyer’s ring (lingual and palatine tonsils, nasopharyngeal tonsils)
Peyer´s patches
Mesenteric lymph nodes
Intraepithelial immune cells
Lamina propria immune cells, including sampling DCs
Lymphoid tissue in the GIT
Lymphoid complexes along the gastrointestinal tract.
The largest amount of lymphoid tissue is found in the oropharynx (Waldeyer’s ring) and terminal ileum.
Intestinal Epithelial cells
Specialised epithelial cells have a number of functions improving defence but not inflammation
Goblet cells - mucus
Epithelial cells express TLRs
M cells - transport antigent to subepithelial lymphoid structures
Panneth cells - produce defensins and trypsin
Goblet cells
produce mucus (physio-chemical barrier)
Epithelial cells function in immunity?
express TLRs
TLR2,4,5,6,7,9 depending on region of gut).
Will not cause inflammation but tightening of epithelial junctions, increase proliferation, epithelial motility, enhancing barrier function
What kind of TLRs are expressed in the gut
TLR5 is expressed on the basolateral surface (activated by invading bacteria) and intracytoplasmic NLR for bacterial flagellins are activated only upon access of bacteria to the cytosol (invasion
M cells
M cells transport antigens to subepithelial lymphoid structures
Panneth cells
produce human defensin 5 (HD5) precursor
HD6 precursor
trypsin (activates HD5 and HD6 by proteolytic cleavage)
Peyer’s patches (PPs)
Site of immune induction
PPs contain germinal centres for B- and T cells
Located in the distal ileum infollicle associated epithelium
The foetal human small intestine has ~ 60 PPs before week 30 of gestation and their number steadily increases reaching a maximum of about 240 at puberty
Architecture of Peyer’s patches
3 main domains:
The follicular area
The interfollicular area
Follicle-associated epithelium (FAE)
Follicular and intrafollicular ares of Peyer’s patches
Follicular and interfollicular areas: lymphoid follicles with a germinal center (GC) containing proliferating B-lymphocytes, follicular dendritic cells (FDCs) and macrophages.
The follicle is surrounded by the corona, or subepithelial dome (SED) containing mixed-cells including B-cells, T-cells, macrophages and dendritic cells (DCs).
How does the FAE differ from normal epithelium?
The FAE differs from normal epithelium in regards to microvilli regularity and length, and the presence of infiltrating immune cells
How are PPs connected to circulation?
PPs are connected to the circulation by endothelial venules (from blood to PP) and lymphatic vessels (from PP to mesenteric LN).
How do naive lymphocytes get to Peyer’s patches?
Naive lymphocytes immigrate into the PP via specialized high endothelial venules. Naıve or activated lymphocytes leave the PP via efferent lymphatic vessels at the serosal side of the PPs.
What do M-cells feature?
Small microvilli (microfolds)
Large cell membrane fenestrations - enhance antigen uptake from epithelum (phagocytosis, fluid-phase endocytosis)
Trans-cellular transport of antigen
Exocytosis at the basolateral membrane and delivery to dendritic cells (DCs) in dome region of underlying lymphatic structures
There are approx. 100-150 M-cells/ Peyer´s Patch
What pathogen exploits M cells and how?
Salmonella species exploit this mechanism, they are cytotoxic to M-cells and so cause gaps in the intestinal epithelium.
Mesenteric lymph nodes (MLNs)
These lymph nodes are located at the base of the mesentery and collect lymph, cells and antigens from the intestinal mucosa.
Main site for oral tolerance induction.
What do mesenteric lymph nodes do?
oral tolerance induction but also
Drain lymph from intestinal mucosa
Many food antigens bypass lymphatic tissue and reach the liver through the portal vein
Immune cells in liver sinuses protect against microbes/microbial products in the portal vein e.g. LPS
Main role is tolerance induction, but can raise protective immune responses too
Intraepithelial lymphocyte compartments
IEL are situated in the basolateral part of epithelium
Have an Irregular shape with long extensions in close contact with neighboring epithelial cells
Occur in variable numbers along the gut
Up to 12% Eosinophils in IEL preparations
IEL cell composition
In the small intestine, the great majority of IEL is comprised of:
TCRab+CD8aa+ cells (most)
TCRab+CD8ab+ cells
TCRab+CD4ab+ (least, small fraction)
How are different IEL subsets compartmentalised along intestines?
More TCRab+CD4ab+ in the distal region of the small intestine , can reach 30% of the total IEL population there
Suggests that there is compartmentalisation of different IEL subsets along the intestine to accomplish specific immunological functions
What are MIC-A and MIC-B
MIC-A and MIC-B are ligands for the NK cell activating receptor NKG2D, which is also found on CD8aa+ T-cells
What is TL?
TL=thymus leukemia (TL) antigen is an MHC-Ib molecule that does not enable peptide binding
How do IELs act?
- virus infects mucosal epithelium cell
- infected cell displays viral peptide to CD8 IEL via MHC class I
- Activated IEL kills infected epithelila cell by perforin/granzyme and Fas-dependent pathways
- Epithelial cells undergo stress as a result of infection, damage, or toxic peptides and so express MIC-A and MIC-B
- NKG2D on IEL binds to MIC-A,B and activates the IEL. CD8aa homodimers also bind to TL
- Activated IEL kills the stressed cell via the perforin/granzyme pathway
Mucosal T cells
Treg versus Th1, Th2, and Th17 cells
T cell differentiation is influenced by epithelial cells and DCs
Treg cells
produce IL-10 and TGF-β
establish and maintain food tolerance and class switch
Th1 cells
produce IFN-g and IL2
CD8+ T cells and macrophages
important in cell response e.g. killing virally infected epithelial cells
Th2 cells
may be induced by worm infection
IL-4 and IL-13
increase fluid secretion, mucus secretion, bowel motility and smooth muscle contraction.
Th17 cells
produce IL-17 and IL-22. These cytokines and interact with receptors on epithelial cells to regulate the production of mucins or defensins (antimicrobial peptides)
Dendritic cells in the lamina propria
Dendritic cells (DC) sit in the lamina propria and have long extensions reaching through the epithelium to ‘sample’ contents of the intestinal tube. Such antigens are presented to T-cells.
How can IgA be cross the endothelium?
The ‘secretory component’ (Poly-Ig-receptor) binds to the J-chain and enables the trans-endothelial transport of dimeric IgA. It may have a role in localising secreted IgA in mucus.
What does SIgA do?
Exerts both:
cross-reactive, innate-like (low affinity) and
infection/vaccine-induced specific (high affinity)
protection against epithelial invasion (immune exclusion)
Also important for herd protection
pIgA and pIgM
Exert noninflammatory effects inside and below epithelium
e.g. virus neutralisation and endotoxin. antigen excretion
SIgA antibodies
play no protective role following invasion of infectious agents
(systemic immunity must take over antigen elimination to save life)
IgA
IgA is the main antibody in secretions
IgA against food antigens provides immune exclusion
IgA activates the complement system only weakly
Secretion of IgA (coupled to J chain) depends on a trans-cellular transport mechanism
What does gut homing of B and T cells depend on?
retinoic acid derived from dietary Vitamin A
DCs in gut-associated lymphoid tissues (including PPs and MLNs) are induced by thymic stromal lymphopoietin (TSLP) and other factors to express retinaldehyde dehydrogenase (RALDH).
This enzyme converts dietary vitamin A into retinoic acid.
Gut-homing of B and T cells
The gut-homing properties of effector lymphocytes are imprinted in the lymphoid tissues where they have undergone differentiation from naive precursors.
DCs in GALTs are induced by factors to express RALDH which converts dietary vitamin A into retinoic acid
When naive B or T cells are activated by antigen in GALT, they are exposed to retinoic acid produced by DCs, and this induces the expression of the chemokine receptor CCR9 and the integrin α4β7 on the plasma cells and effector T cells that arise from the naive lymphocytes.
The effector lymphocytes enter the circulation and home back into the gut lamina propria because the chemokine CCL25 (the ligand for CCR9) and the adhesion molecule MadCAM (the ligand for α4β7) are displayed on lamina propria venular endothelial cells.
How do effector cells know where to go?
Different combinations of homing receptors will guide effector cells to different tissues.
At the tissue sites upregulation of the respective ligand molecules will be related to the situation in these tissues.
E.g. , inflammation will lead to increased upregulation.
As T cells migrate through the circulation, integrin and chemokine signals direct their emigration into tissues. In this manner, imprinted T cells have a specific key that allows access to restricted tissues (gates) under normal homeostatic conditions.
How do activated T cells and circulating memory cells return to circulation?
Activated T cells and circulating memory cells exit lymph node via efferent lymphatics and return to circulation through the thoracic duct. They reach target tissues via the blood stream
