Flashcards in L13 Deck (43)
1
What are the 2 main ways antigens can be transported by cells across mucosal epithelium?
M cells
Trans-epithelial DCs
2
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
3
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
4
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
5
Describe the 2 types of inductive sites found in the GALT.
1. ILF = isolated lymphoid follicle
- No distinct T/B zones in germinal centers--> mostly B cells
- THROUGHOUT GI tract
2. Peyer's patch
6
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
7
Since the lamina propria is the major effector site, what cell type dominates here?
B cells!
8
What are the 2 layer of mucous produced by goblet cells?
Outer layer - contains microbes
Inner layer - sterile with antimicrobials (defensins) & Abs
9
What junctions hold together epithelial cells?
Tight jxns
10
What other product, aside from mucous, is produced by goblet cells?
TFF 3 - into mucous, promotes migration of cells and epithelial healing
11
What are paneth cells? Where do you find them?
@ bottom of intestinal crypts
Make defensins
12
What are intestinal epithelial stem cells? Where do you find them?
@ bottom of intestinal crypts
Constant replenishment of epithelial cells --> upward migration
13
What surface receptors do epithelial cells express?
TLR
MHC 1 & 2
14
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
15
What are receptors commonly expressed by DCs & macrophages in the intestinal epithelium?
CX3CR1
CD103 - promotes gut specific development of T & Treg cells
CD11b/c
16
When stimulated/bound to antigen, what do DC produce?
IFN gamma
TNF
NET: helps Th1, increased leakage across epithelium
17
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?
1. Th1 - IFN gamma & TNF - increased leakage, macrophage inflammation
2. Th2 - IL13 - recruit eosinophils, promote IgE from B cells
3. Treg - IL10 & TGFbeta - aTENuate the infam response of Th1s
18
What cytokines do epithelial cells secrete to increase Treg maturation?
TGF beta
Retinoic acid
19
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
20
What are 4 main characteristics of Peyer's patches?
1. Germinal centers with distinct T/B zones --> B cell dominant but also T cell rich
- Center around FDCs
2. Covered by follicle associated epithelium
3. No afferent lymph
4. No capsule
21
Where is IgA secreted by plasma cells?
Lamina propria as the effector site!
- High B cell population!!
22
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
23
Which cytokine helps B cell switching in the mucosa?
TGF beta
24
How can you tell mucosal IgA from plasma IgA?
Mucosal has secretory piece from transport with poly-Ig receptor!
25
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
26
Describe the T INdep pathway of IgA induction. Where does this occur?
Where: peyers patches & isolated lymphoid follicles
1. DC directly initiates class switch of B cells via:
- TGF beta
- Retinoic acid
- NO, BAFF, APRIL
27
What kind of IgA is produced by T dep pathway?
- HIGH affinity
- Monoreactive
- Vs. pathogens & toxins
28
What kind of IgA is produced by T INdep pathway?
Low affinity
Polyreactive
Vs. commensals
29
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
30
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
31
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
32
What is the second most common Ab found in mucous secretions? What receptor moves this Ab?
IgG for neutralization
Via FcRn
33
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
34
Where are intra-epithelial lymphocytes? What is their function?
Between epithelial cells
Mostly CD8 cells --> kill infected cells
35
Which cytokines drive the development of intra-epithelial lymphocytes?
IL 7 & 15 --> development
36
How is mucosal tolerance created? Name the 3 major parts.
1. Intestinal epithelial cells
- Stimulated by commensals
- Make retinoic acid for TOLERANCE
2. CD103 DC & CX3CR1 macrophages @ lamina propria
- Stimulated by microbiota
- Make TGF beta, RA & IL10
= anti-inflam
3. Foxp3+ regulatory T cells
- On when you start making IgA & IL2
- Inhibitory Tregs
37
How does retinoic acid act on DCs?
Primes them!
DCs:
- ↑ CD103
- ↑RA production --> Th17 cells
- ↑TGF beta --> development of Foxp3 Tregs
38
What additional cytokine signals are present to create mucosal inflammation?
IL15!
39
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
40
What is the signal that microbiota create that is critical for healthy mucosa?
IL10
sIgA production via ↑AID
RA --> ↑Treg activity
41
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
42
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
43