Immunity at mucosal surfaces Flashcards
why are mucosal surfaces more prone to infection
they are thinner (because they have to be semipermeable to exchange molecules)
which regions of the body does the mucosal immune system involve
the urogenital tract
the gastrointestinal tract
the respiratory tract
what are the different types of protective epithelial lining in the mucosal immune system depending on the organ
single columnar epithelium
pseudo stratified columnar epithelium
nonkeritinized stratified squamous epithelium
what are the 4 distinct features of the mucosal immune system
- intimate interactions between mucosal polarized epithelia and lymphoid tissues
- compartments of diffuse lymphoid tissue and more organized structures such as Peyer’s patches, isolated lymphoid follicles and tonsils
- specialized antigen uptake mechanisms (e.g. M cells)
- broad surface area in contact with environmental microbes
true or false mucosal infections are one of the biggest health problems worldwide
true
what is MALT
mucosa-associated lymphoid tissue
GALT = GI tract
NALT = respiratory (nasal)
BALT = respiratory (bronchiole)
what are the induction sites in mucosal immunity
- GALT
- BALT
- NALT
- urogenital tract
- Lacrimal glands
- salivary glands
- mammary glands
what structures make up the GALT
peyer’s patches
ILFs
appendix
induction vs effector sites
induction = where the process of mucosal immune response is initiated
effector = where the mucosal immune response occurs
peyer’s patches vs ILF’s
peyer’s patches they are bigger than ILF’s and have more germinal centres (therefore more B cells)
what are the induction sites (lymphoid tissues) in the intestine
peyer’s patches and isolated lymphoid follicles (ILF)
characteristics of peyers patches and ILF’s in the GALT
- contain M cells
- follicle-associated epithelium that covers peyer’s patch lacks mucus (so antigens can cross)
- the sub epithelial dome is rich in DC’s and lymphocytes
what are M cells
cells between the FAE that are specialized for transcytosis of microbes and antigens into peyer’s patches
what is a cryptopatch
form of GALT - a collection of DCs and LTi cells that is present at birth
in germ-free mice peyer’s patches do not develop normally. what does this say about microbiota influence on mucosal immunity?
- NO ILFs
- decreased IELs
- decreased IgA secreting plasma cells
- decreased AMPs
- decreased immune mediators (cytokines)
what drives maturation of GALT
acquisition of commensal microbiota
what components of GALT are present at birth and which ones will develop after
cryptopatch = present at birth
ILF’s = develop after birth
peyers patch = present at birth, grows after birth
what are the effector sites of GALT
- single layer of the intestinal epithelium
- lamina propria
what does the single layer of the intestinal epithelium consist of
IELs - CD8+ T cells
ILCs
what does the lamina propria consist of
innate cells
CD4+ and CD8+ T cells
B cells
Tregs
ILCs
what are the innate immune defenses of the intestinal immune system
absorptive subsets - enterocytes and M cells
secretory subsets - goblet, paneth, enteroendocrine and tuft cells
what is the function of each absorptive cell in the intestinal immune system
enterocytes: cells of the intestine
M cells: take up the antigen
what is the function of each secretory cell in the intestinal immune system
goblet cells: secrete mucus
paneth cells: secrete AMPs
enteroendocrine cells: secrete hormones and NTs
tuft cells: secrete cytokines and lipid mediators
what are intraepithelial lymphocytes (ILE’s)
- lymphocytes that are positioned within the intestinal lumen
- help in barrier maintenance and defense
- the bigger effector site
- when referring to ILE, ALWAYS talking about mucosal immune system
type A vs type B ILE’s
Type A = function like cytotoxic T cell (TCR activation leads to perforin, granzyme and FasL release)
Type B = function like NK cells (act independently of TCR activation through NKG2D)
how do ILCs act in the GALT
- respond to microbes that breach the epithelium
- abundant in mucosal tissue - predominated by ILC3
2 ways that Gut DCs promote oral tolerance
- induce Tregs
- Ag presentation to CD4 T cells which causes B cells to produce IgA
what are the 6 routes of antigen uptake
- M cells facilitate bulk and receptor-mediated transcytosis
- FcRn-dependent transport via endocytic vesicles
- uptake of soluble antigens via goblet cells
- paracellular transport across tight junctions
- apoptosis-dependent transfer
- antigen capture by TEDs
How do Tregs achieve balance between active immunity and immunological tolerance
protective immunity: promote clearance of infections
mucosal tolerance: limit immune-mediated damage and responses to self
what do IL-10 and CTLA-4 achieve when released from Tregs
they limit inappropriate immune activation in mucosal immunity - anti-inflammatory
how is transcytosis of IgA across epithelia mediated by pIgR receptor
- IgA dimer binds to receptor on basolateral side of epithelial cell
- endocytosis
- transcytosis to apical side of epithelial cell
- release of IgA dimer + secretory component at apical face
what is secretory IgA (sIgA)
IgA dimer + pIgR secretory component
what are the functions of mucosal IgA
- bind and neutralize pathogens and toxins on gut surface
- bind and neutralize pathogens internalized in endosomes
- export toxins and pathogens from the lamina propria while being secreted
- binding of IgA to Dectin-1 on M cell allows transport of antigen to DC-SIGN+ (receptor) dendritic cells
How do intestinal macrophages promote tolerance to harmless foreign antigens
- promote phagocytosis (without inflammation)
- induce Tregs and Th17 T cells
- PGE2 for intestinal repair
- secrete IL-10 (anti-inflammatory cytokine)
- decrease naive T cell activation and pro-inflammatory cytokines
characteristics of mucosal tolerance
antigens = from food or commensal bacteria
primary Ig produced = local IgA, low Ab in serum
Primary T-cell response = Treg cell activation, no local effector T-cell response
response to antigen re-exposure = no memory response and no systemic response
mucus thickness throughout the GI tract
large intestine > ileum > duodenum > jejunum
properties of mucus
- viscous - slippery and sticky
- negatively charged to retain sIgA and AMPs
- substrate for commensals
- contains mucins (MUC2)
what do the different ILCs in the GALT respond to
ILC1: targets pathogens that breach the epithelium
ILC2: targets parasites that breach the epithelium
ILC3: influences gut microbiota on the intestinal epithelium
what are the different outcomes of intestinal exposure to Ag’s
immune priming - harmful pathogens
tolerance - harmless pathogens
characteristic of mucosal tolerance in response to harmless antigens
- harmless antigens = food proteins, commensals
- primary Ig produced = local IgA
- primary T cell response = Treg
- no response to antigen upon re-exposure
characteristics of protective mucosal immunity in response to harmful antigens
- harmful antigens = invasive bacteria, viruses, toxins
- primary Ig produced = intestinal IgA and IgG
- primary T cell response = local and systemic memory and effector T cells
- memory response upon re-exposure
