Flashcards in 11. Mucosal immunity Deck (45)
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
Epithelium and Mucus
‘Regionalised’ Immune System & gut homing of B and T cells
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)
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
produce mucus (physio-chemical barrier)
Epithelial cells function in immunity?
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 transport antigens to subepithelial lymphoid structures
produce human defensin 5 (HD5) 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+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