Theme 5 - 5c (Mucosal immunity) Flashcards
do commensals outnumber host cells
if so by how much
yes
by 10:1
what is the role of commensals
- metabolise and produce vital nutrients
- protect from true pathogens
what is the principle point of entry for pathogens
- mucosal surfaces (eg gut, skin, lung, urinary and genital tracts, eyes)
- main cause of death <5 years old
where are the majority of immune cells located
~80% in the gut
where can antigentic diversity come from
food
what can GALT be broken down into
1) effector sites
2) inductor sites
how is the barrier of mucosa maintained (3 systems)
1) a physical barrier (eg mucus, epithelium)
2) innate immunity eg DCs and macrophages
3) adaptive immunity (ig IgA, Th17 and Tregs)
describe the physical barrier of mucosa
- barrier intestinal mucosa
- mucus provides a semi-permeable barrier made up of COMPACTED GLYCOPROTEINS (eg MUC2), anti-microbial peptides (eg beta defensins) and secretory IgA)
- the intestinal specialised epithelium (enterocytes) expresses tight junciton proteins to MAINTAIN AN INTACT BARRIER to all but the smallest molcules
what is the role of innate immunity in barrier maintenance
- DCs, macrophages, ILCs
- LOCATION: close to epithelium , attracted by MIP3alpha (CHEMOKINE) released by intestinal epithelial cells (enterocytes)
- DCs can CAPTURE antigen direct from lumen by reaching between EPITHELIAL cells whilst maintaining TIGHT-JUNCTIONAL integrity and are highly endocytic with broad range of PRRs
- mucosal DCs preferentially produce IL-10 and TGF beta (tolerogenic) and promote differentiation of Tregs and IgA class switching
- extremely sensitive to epithelial cytokine microenvironment
- activation of DCs leads to recruitment of ILCs
what is the role of adaptive immunity in barrier maintentance
- Peyer’s patches
- are lymphoid aggregates found in the small intestine (not present in colon)
- Antigens enter via specialised epithelial cells called Microfold (M) cells via PRRs (eg TLRs) on surface, through transcytosis, DCs reaching between cells or Ab/FcR transcytosis
- Antigens are collected by sub-epithelial network of APCs
- Germinal centres of lymphoid follicles contain populations of B cells undergoing isotype switching and somatic hypermutation – main function is development of IgA+ B cells in response to infection etc
what is the role of Peyer’s patches in adaptive immunity under TOLERANT (homeostatic) conditions in barrier maintenance
- DCs capture antigens from M cells
- At the same time, TLR-activated epithelial cells release growth factors and TGFb that ‘condition’ the DCs and ILC3 cells (≡ Tregs)
- DCs migrate to the T cell areas of the Peyer’s patches and induce some Th2 and lots of Treg cell differentiation of naïve CD4+ T cells
- Activated CD4+ T cells provide help to activated B cells
- B cells undergo class switching to IgA and somatic hypermutation under the influence of survival factors and cytokines
- B cells differentiate to IgA+ plasma cells in the mucosal lymph nodes and then migrate to the lamina propria•Dimeric IgA is transported to gut lumen via the polymeric Ig receptor on the basal surface of the epithelial cell
what is the role of IgA un adaptive immunity in barrier maintenance
- 75% of Ig in body is IgA – most is secreted at mucosal membranes (~ 3g/day!)
- IgA is produced as a dimer linked by the J chain from plasma B cells beneath the epithelium
- The polymeric IgA receptor (pIgR) on epithelial cells binds the J chain and transports IgA into the lumen
- Proteases cleave the pIgR leaving the ‘secretory component’ attached to the IgA
- sIgA prevents bacterial adhesion to mucosa, aids clearance of pathogens and neutralises pathogens and toxins
- IgA deficiency is most common human immunodeficiency but has v. mild phenotype??? IgM compensation?
- IgA does not fix COMPLEMENT, does not activate granulocyte degranulation, does not induce full DC maturation – activity is homeostatic rather than inflammatory
how does adaptive immunity deal with pathogens in barrier maintenance
- in the presence of adherent or invasive bacteria sustained TLR signals from the epithelium induce a change in the secretion of cytokines by the epithelial cells to more inflammatory factors such as IL-1, IL-6, and TNFα
- This fully activates the gut DCs and ILC1 cells which promote the expansion of Th17 cells (in the presence of TGFb, IL-6, IL-1β) + Th1 cells
- Th17 cells produce high levels of IL-17 & IL-22•IL-17A - enhances neutrophil differentiation, recruitment, and antimicrobial activities
- IL-22 - triggers antimicrobial peptide production from paneth cells and increases epithelial permeability allowing transmigration of immune cells into the lumen - IgA production remains but see some switching to IgG
- If the infection is worms, different TRs are activated and a more Th2-like response develops. ILC2 cells are then involved in recruiting eosinophils etc to the site
which factors affect inflammatory bowel disease
what is it
- it is group of debilitating disorders with mostly unknown aetiologies, not considered to be autoimmune
- 5-20% of IBD patients have family history of IBD
- MZ twins concordance rates (CD ~50%, UC ~20%)
GENETICS:
MHC haplotype, Gene polymorphisms influencing epithelial function and innate / adaptive immunity
MICROORGANISMS:
Altered bacterial populations
ALtered bacterial metabolism
Increased attachment and invasion of mucosa
ENVIRONMENT Western diet Smoking Medications Insufficient nutrients from environments eg Vitamin D
what does Crohn’s disease mainly affect
- Mainly affects small intestine
- Th1 / Th17 cells, neutrophil infiltrate, inflammatory macrophages, granuloma formation, transmural inflammation, IgG to bacterial antigens
