L13 Flashcards
What are the 2 main ways antigens can be transported by cells across mucosal epithelium?
M cells
Trans-epithelial DCs
When lymphocytes are primed in MALT, what effector sites are they attempting to return to? How?
Effector sites = lamina propria & IEL
How:
- Retinoic acid-dependent expression of a4b7
What are the 2 main division of mucosal associated lymphoid tissue (MALT)? Name subtypes of each.
1. Inductive site BALT = bronchus GALT = gut NALT = nasopharinx 2. Effector site = lymphocytes @ epithelium & lamina propria
How do cells move from the induction –> effector site?
Break/transport across epithelium B/G/NALT Lymph Local lymph nodes Thoracic duct Blood Back to respective epithelium/LP
Describe the 2 types of inductive sites found in the GALT.
- ILF = isolated lymphoid follicle
- No distinct T/B zones in germinal centers–> mostly B cells
- THROUGHOUT GI tract - Peyer’s patch
Describe the characteristics of follicle associated epithelium.
ONLY above lymphoid tissues (Peyer’s patches)
NO goblet cells (little mucous)
YES M cells - for passage to lymph tissue
Since the lamina propria is the major effector site, what cell type dominates here?
B cells!
What are the 2 layer of mucous produced by goblet cells?
Outer layer - contains microbes
Inner layer - sterile with antimicrobials (defensins) & Abs
What junctions hold together epithelial cells?
Tight jxns
What other product, aside from mucous, is produced by goblet cells?
TFF 3 - into mucous, promotes migration of cells and epithelial healing
What are paneth cells? Where do you find them?
@ bottom of intestinal crypts
Make defensins
What are intestinal epithelial stem cells? Where do you find them?
@ bottom of intestinal crypts
Constant replenishment of epithelial cells –> upward migration
What surface receptors do epithelial cells express?
TLR
MHC 1 & 2
What is the fxn of M cells? What receptors do they express?
Transport antigens from lumen –> dendritic cells
No microvilli or lysosomes - no digestions of phagocytosed particles
Express:
- TLR2 & TLR4 - PAMP uptake (non-specific)
- IgA receptors - specific uptake
What are receptors commonly expressed by DCs & macrophages in the intestinal epithelium?
CX3CR1
CD103 - promotes gut specific development of T & Treg cells
CD11b/c
When stimulated/bound to antigen, what do DC produce?
IFN gamma
TNF
NET: helps Th1, increased leakage across epithelium
Which 3 T cell types do DC stimulate the differentiation of when bound to antigen? What do each product? What is the function of each?
- Th1 - IFN gamma & TNF - increased leakage, macrophage inflammation
- Th2 - IL13 - recruit eosinophils, promote IgE from B cells
- Treg - IL10 & TGFbeta - aTENuate the infam response of Th1s
What cytokines do epithelial cells secrete to increase Treg maturation?
TGF beta
Retinoic acid
Explain the function of retinoic acid.
Vitamin A breakdown product
Induces tolerance
- Increases Treg when you’re having Th1 response to something that is relatively non-pathogenic
What are 4 main characteristics of Peyer’s patches?
- Germinal centers with distinct T/B zones –> B cell dominant but also T cell rich
- Center around FDCs - Covered by follicle associated epithelium
- No afferent lymph
- No capsule
Where is IgA secreted by plasma cells?
Lamina propria as the effector site!
- High B cell population!!
What is the difference between IgA1 & IgA2?
IgA1 = monomeric - Found in CIRCULATION - No secretory piece IgA2 = sIgA = dimeric - More resistant to proteolysis - In intestine & female repro - SECRETED @ GI: 2 > 1 @ respiratory tract: 1 > 2
Which cytokine helps B cell switching in the mucosa?
TGF beta
How can you tell mucosal IgA from plasma IgA?
Mucosal has secretory piece from transport with poly-Ig receptor!
Describe the 4 step T dep pathway of IgA induction. Where does this occur?
Where: peyer's patches only 1. Ag+APC 2. APC activated Th cells 3. Th cells stimulate IgM/D B cells via: - CD40L - TGF beta --> push to IgA B cells 4. with retinoic acid in the LP, B cells --> plasma cells IgA = - HIGH affinity - Monoreactive - Vs. pathogens & toxins
Describe the T INdep pathway of IgA induction. Where does this occur?
Where: peyers patches & isolated lymphoid follicles
- DC directly initiates class switch of B cells via:
- TGF beta
- Retinoic acid
- NO, BAFF, APRIL
What kind of IgA is produced by T dep pathway?
- HIGH affinity
- Monoreactive
- Vs. pathogens & toxins
What kind of IgA is produced by T INdep pathway?
Low affinity
Polyreactive
Vs. commensals
Which cytokines are produced by epithelium for B cell differentiation into plasma cells? For B cell switching to IgA?
Into plasma cells: IL 4 5 6 10 IgA class switch = TNF beta
How is IgA transported into the epithelium?
Poly Ig receptor binds J chain on IgA Ab
Secreted IgA has piece of receptor attached to it = secretory component
What is the role of IgA? Can it generate a complement reaction?
Prevent attachment of bacteria & viruses to mucous membranes
Binds intracellular pathogens of epithelium
Anti-inflammatory
NO complement reactions
What is the second most common Ab found in mucous secretions? What receptor moves this Ab?
IgG for neutralization
Via FcRn
What membrane proteins do SI T cells express (what does each bind at the SI target site)? Colon?
SI T cells have a4b7 & CCR9
- a4b7 binds MAdCAM1 @ lamina propria
- CCR9 binds CCL25 @ epithelial cells
Colon T cells have CCR10
Where are intra-epithelial lymphocytes? What is their function?
Between epithelial cells
Mostly CD8 cells –> kill infected cells
Which cytokines drive the development of intra-epithelial lymphocytes?
IL 7 & 15 –> development
How is mucosal tolerance created? Name the 3 major parts.
- Intestinal epithelial cells
- Stimulated by commensals
- Make retinoic acid for TOLERANCE - CD103 DC & CX3CR1 macrophages @ lamina propria
- Stimulated by microbiota
- Make TGF beta, RA & IL10
= anti-inflam - Foxp3+ regulatory T cells
- On when you start making IgA & IL2
- Inhibitory Tregs
How does retinoic acid act on DCs?
Primes them! DCs: - ↑ CD103 - ↑RA production --> Th17 cells - ↑TGF beta --> development of Foxp3 Tregs
What additional cytokine signals are present to create mucosal inflammation?
IL15!
When +IL15, how do dendritic cell cytokine secretions change? What other cell is activated?
CX3CD1 macrophages also activated DCs: - More RA --> ↑Th17 - More IL 12 --> ↑Th1 - No longer making TGF beta NET: inflammation
What is the signal that microbiota create that is critical for healthy mucosa?
IL10
sIgA production via ↑AID
RA –> ↑Treg activity
How is vitamin A as retinoic acid important for get T and B cells?
Imprints T & B cells to be gut specific
↑s B cell IgA specificity
What patient populations (GI auto-immunity) are reported to be vitamin D deficient? What role does vit D play in mucosal immunity?
IBD & colitis patients
Decreases Th1 & Th17
Increases Treg
Inhibits DC differentiation
How to mucosal vaccines work?
Goal = ↑sIgA & local T cells
How deliver polio & cholera vaccines
