Term
| What is the basic anatomical organization of the GALT? |
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Definition
1) Single epithelial layer, arising from basal crypts and composed of differentiated enterocytes, goblet cells, M cells, neuroendocrine cells and paneth cells, with overlying glycocalyx
2) Underlying loose connective tissue lamina propria with vessels and lymphocytes.
**Physical barriers are provided by glycocalyx mucin, epithelial cells and tight junctions between them. |
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Term
| How do M cells function in mucosal immunity? |
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Definition
Epithelial cells overlying GALT tissue.
1) Uptake bacterial and viral antigens (sampling), which are transcytosed and taken up by underlying APCs, which deliver antigens to PPs
2) Cells activated in PPs express a4b7 integrin, which serves as "homing signal" to MadCAM-1 expressing mucosal sites
- B cells in PP receive soluble signal (TGF-b), switching their IG expression from IgG to IgA.
3) Cells leaving PP migrate to mLN and are drained by thoracic duct, ultimately entering the IVC and the right atrium.
4) Once in systemic circulation, cells use a4b7 to find GALT sites, where B cells terminally differentiate into plasma cells and T cells attain activated phenotype. |
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Term
Which of the following characteristics is unique to the GALT (as opposed to the MALT)?
1) M cells
2) Peyer's patches
3) Lamina propria
4) T cells |
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Definition
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Term
| What is meant by the idea of "common mucosal system"? |
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Definition
Gut immunized lymphocytes (GALT) can be found at other sites including the rest of the GI tract and the mammary gland. They travel by "PP-mLN-TD-IVC-lamina P" route.
**MALT is more compartmentalized** |
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Term
| What are the 2 major functions of IgA "secretory component" |
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Definition
Remember, IgG is most abundant IG in serum, but IgA is most abundant in secretions (and serum IgA differs from secreted IgA- monomer vs. dimer joined by J chain in secretions)
Secreted IgA dimers are coated in specialized glycoprotein, "secretory component" which
1) Transports IgA from lamina propria to lumen (vesicle mediated transcytosis)
2) Within lumen, secretory component protects IgA from degradation by proteases and gastric acid by binding the Fc portion and the hinge region of IgA.
IgA DOES NOT BIND Fc RECEPTORS OR ACTIVATE COMPLEMENT (NO INFLAMMATION) |
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Term
True or False:
IgA does not bind Fc receptors or activate complement system |
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Definition
True!
IgA released into intestinal lumen does not mediate inflammatory responses. It blocks microbial binding to epithelium or causes agglutination |
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Term
| What is the major function of IgA secreted into the intestinal lumen? |
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Definition
Prevent bacterial binding to epithelium and causing agglutination of bacterial/viral particles.
Reabsorbed by distal small intestine (ileum) and through enterohepatic circulation can be reutilized. |
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Term
| How is IgA complex with antigen reabsorbed and recycled? |
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Definition
Distal ileum-Liver-Bile duct- Duodenum- Distal Ileum
1) Taken up by distal illeum, traveling via portal vein into liver sinusoids
2) In liver, Kupffer cells take up complex, destroy microbial antigen and release free secretory IgA
3) Bile duct expresses polymeric Ig receptor on basal surface, so IGA is actively transported into bile duct and released into the duodenum to be re-used. |
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Term
| How do B cells become committed to producing IgA? |
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Definition
In Peyer's Patches!
1) IgA switch factor and TGF-b cause class-switching
2) Cells migrate to mLN, enter TD and enter systemic circulation.
3) Terminally differentiate to plasma cells in GALT sites expressing MadCAM1 |
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Term
| What are intestinal epithelial lymphocytes and what is their importance? ** |
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Definition
IELs are CD8+ cells with yd TCRs that express activation markers such as CD45RO+ and aEb7 integrin (long-lived and slowly renewed)
aEb7 binds ligand E-cadherin and is involved in cell signaling and cytoskeletal rearrangements (NOT HOMING) |
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Term
| What transcription factor is activated in the presence of bacerial-activation of TLR-receptors? |
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Definition
| NF-kB leads to transcription of inflammatory factors. |
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Term
| What are the important types of mucosal T cells and what are their functions? |
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Definition
1) Th1- cell-mediated immunity (IL-2 and INF-y)
IL-10 dampens Th1 response (produced by both Th2 and Tregs)
2) Th2- b cell Ab production (IL-4, IL-5, IL-10, IL-13)
3) Tregs make IL-10 |
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Term
| How do intestinal epithelial cells (IECs) respond to invasive pathogens such as Salmonella, Shigella, Yersinia and Listeria? |
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Definition
1) Up-regulate expression and secretion of pro-inflammatory cytokines (CXC and CC family members)
**also release TNF-a, GMCSF, IL-1a and IL-1b**
2) Normal program of gene expression requires commensals |
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Term
| Why is it important that intestinal epithelial cells express MHC-II molecules? |
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Definition
Only non-professional APCs to do so.
1) Important for antigen sampling of soluble proteins that cannot be taken up by M cells
2) Can activate CD8+ T cells (despite expressing MHC-II!)
**May explain oral tolerance and controlled inflammation** |
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Term
| Describe the phenomenon of "Oral Tolerance" |
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Definition
Immunosuppression of GI tract, regulated by nature of antigen, dose and frequency of antigen, genetic background, age and intestinal flora.
1) Oral soluble protein delivery induces antigen specific on-responsiveness (animal will not respond to injection after oral administration)
2) TGF-b produced in response to oral antigen suppresses T and B cells and activates IgA pathway, where higher oral doses can cause cellular anergy. |
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Term
| What is the "bystander effect" and how might it be exploited to treat autoimmune disease? |
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Definition
Remember, induction of oral tolerance is antigen specific, but effector arm (TGF-b) is not.
Give a bunch of a given antigen and then hope that TGF-b will suppress "bystander" auto-antigens in diseases like MS. |
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Term
| How can "pre-biotic" (Fiber, lactulose, ect) use modify bacterial flora and modulate immune responsiveness? |
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Definition
Non-digestible food ingredients that selectively stimulate growth and/r activity of limited umber of bacteria in the colon
Fiber, lactulose and elemental diet. |
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Term
| How might fish oil treat inflammation? |
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Definition
| Partially replace AA in COX pathway, leading to less LTC and prostaglandin production. |
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Term
| Describe the molecular evolution of a food allergy. |
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Definition
1) Undigested fragments are tagged by IgE and fool immune system into thinking it is harmful
2) Mast cells degranulate and inflammation ensues causing some combination of dermatitis, respiratory symptoms and GI symptoms. |
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Term
| Why might you use Nataluzimab to treat IBD? |
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Definition
Antibody against a4b7 integrin (inhibit T cell immune response)
**ASSOCIATED WITH PML** |
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Term
| What are the 3 major mechanisms underlying oral tolerance? |
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Definition
1) Clonal deletion
- Self antigens in the thymus
- Apoptosis after ligation of TcR
2) Clonal anergy
- Self antigens in periphery
- TcR ligation in the absence of co-stimulation
3) Regulatory T cells
- CD4+/CD25+ T cells actively inhibit priming/functions of other naive cells
- Treg cells produce IL-10/TGF-b |
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Term
| What is the clinical significance of oral tolerance? |
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Definition
1) Associated with food allergy and diseases such as celiac disease / IBD
2) May diminish effectiveness of oral vaccines
- Can be overcome with use of Cholera B toxin adjuvant
3) OT may be useful in treating disease |
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