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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?

1. virus infects mucosal epithelium cell
2. infected cell displays viral peptide to CD8 IEL via MHC class I
3. Activated IEL kills infected epithelila cell by perforin/granzyme and Fas-dependent pathways
4. Epithelial cells undergo stress as a result of infection, damage, or toxic peptides and so express MIC-A and MIC-B
5. NKG2D on IEL binds to MIC-A,B and activates the IEL. CD8aa homodimers also bind to TL
6. Activated IEL kills the stressed cell via the perforin/granzyme pathway