Lecture 20 - Mucosal Immunology Flashcards
Learning Objective 1
Describe a few nonimmunologic surface protective mechanisms for maintaining health.
Skin
- Dessication, normal bacterial flora
GI tract
- Saliva, mucus, low pH, defensins, lysozymes, proteolytic enzymes.
Eyes
- Tears, flushing, lysozyme
Respiratory tract
- Particle size barriers, mucus, cilia, coughing, defensins, lysozyme
Name some of the components of the common mucosal immune system
Tonsils
GALT (Peyer’s patches, lymphoid nodules in GI)
Nasal-associated lymphoid tissue (NALT)
Bronchus-associated lymphoid tissue (BALT)
Eye-associated lymphoid tissue (EALT)
Learning Objective 2
Compare and contrast the common mucosal immune system and the systemic immune system.
Systemic immune system
- Antigens detected in lymphatics
Common mucosal immune system
- Antigens detected on mucosal surface. Lymphocyte drains to lymph node for antigen presentation.
- Lymphocytes home to mucosal sites
- Overall, mucosal system is much larger
- Majority of plasma cells are found at mucosal surfaces
- Primary isotype is IgA. More IgA produced in a day than all other types combined.
What might the consequences of mucosal disruption be (e.g. lack of tear production or breakdown of the skin barrier)?
Examples:
Keratoconjunctivitis, foot rot.
What is the role of commensal bacteria at epithelial surfaces?
Prevent colonization of pathogenic bacteria
Digestion, release of nutrients, etc.
What is MALT?
Mucosal-Associated Lymphoid Tissue
Similar to a lymph node, but not encapsulated. Drains contents entering from luminal surfaces.
Learning Objective 3
Describe what M cells are, where they are found, and their function.
Found between epithelial cells near Peyer’s patches. Interact directly with molecules in the lumen.
Transport luminal molecules into the subepithelial space through transcytosis.
Closely associated with antigen-presenting cells.
Some pathogens can enter through these cells.
Do M cells process antigen?
NO
They transport antigens to the subepithelial space through transcytosis.
Describe how a pathogen might take advantage of an M cell to enter the body.
M cells transport antigens to the subepithelial space, where they are usually picked up by an APC, like a macrophage.
If the pathogen is capable of surviving inside a macrophage, it could use the M cell to gain access into the body and start replicating inside the macrophage.
Examples include Salmonella and Reo virus.
Where are the Peyer’s patches located?
Ileocecal junction
What is the role of TGF beta?
TGF beta is produced by intestinal epithelial cells. It suppresses dendritic cell maturation in the presnece of commensal bacterial organsims (good bacteria).
Also important in influencing B cells to class switch to IgA.
A dendritic cell encounters a food antigen or a commensal organism antigen. How will it interact with a naive T cell?
Will promote the formation of a Treg.
IL10 and TGF beta are important cytokines in this interaction.
A dendritic cell encounters the antigen of a pathogen. How will it interact with a naive T lymphocyte?
Promote the differentiation into Th1, Th17, and Th2 effector cells.
What are the different types of inter-epithelial lymphocytes (IELs)?
CD8 positive
- alpha beta CD8 (classic cytotoxic lymphocyte)
- alpha alpha CD8 (responds to stress proteins)
Gamma Delta T cells
What are the functions of inter-epithelial lymphocytes (IELs)?
Innate and adaptive immunity
Some respond to MHC1 - classic CD8 cytotoxicity
Some respond to stress molecules (MIC-A, MIC-B molecules)
May produce cytokines, cause cytotoxicity, or play a regulatory/suppressive role
Learning Objective 4
Explain the immune response that leads to the production of IgA and the important cells and molecules (cytokines) involved.
- Antigen crosses epithelial barrier and is picked up by a dendritic cell. Antigen is processed via the exogenous pathway and presented on MHC II.
- Processed antigens are recognized by naive T cells. Intact antigens are recognized by B cells.
- B cells class switch to IgA. Occurs through T-dependent (B cell is influenced by T cell) and T-independent (B cell is influenced by local environment) mechanisms.
- B cells activated in the mucosal lymphoid tissues will enter circulation before switching to IgA. May return to the same lymphoid tissue or may enter mucosal lymphoid tissue elsewhere in the body.
Learning Objective 5 Part 1
Draw and label the basic stick figure for an IgA molecule.
- Heavy chain
- Light chain
- J chain
- Secretory component
Learning Objective 5 Part 2
Describe how IgA functions to protect on mucosal surfaces.
- Neutralize toxins
- Block entry of pathogens or commensals
- Provide intestinal immunity to the suckling newborn
How many heavy and light chain components are present on a secretory IgA molecule?
4 light chain, 4 heavy chain
What is the function of the J chain in secretory IgA?
Holds the two IgA molecules together
Where are IgA secretory plasma cells located?
Diffuse mucosal lymphoid tissues.
Note: They are not located on luminal mucosal surfaces. Rather, they are beneath them.
Where is the polyimmunoglobulin (PIg) receptor found and what is its function?
Located on the basolateral surface of mucosal epithelial cells.
Binds to the J chain of IgA molecules. Important in receptor-mediated endocytosis of IgA for eventual secretion.
What is the secretory component on a secretory IgA molecule and what is its function?
Remnant of the PIg receptor that has been cleaved.
Protects IgA from proteases in the lumen.
Binds to mucus to keep IgA from being flushed out.
Some species secrete IgA through the bile duct in addition to secreting directly into the lumen. Which species are these?
Chicken, rabbit, rat
True or False
IgA can totes fix complement.
FALSE
Recall that the Fc portion of an immunoglobulin is responsible for cross-linking complement. In an IgA molecule, the Fc portion is bound to the J chain to make a dimeric molecule.
Learning Objective 6
List the steps to involved in transferring IgA from the basal side of the mucosa across the epithelial cell and the release into the lumen. Include important receptors and molecules
- IgA binds to PIg on the basal surface of the mucosal epithelium (specifically, the J chain binds to PIg).
- Receptor mediated endocytosis into the epithelial cell. PIg remains attached to the IgA.
- IgA transported to apical surface of cell.
- PIg cleaved to form the secretory component.
- IgA (now secretory IgA or sIgA) secreted into the lumen.
Learning Objective 7
Explain what the J-chain is and where the IgA acquires it and what the secretory component is and where the IgA acquires it
The J chain binds two IgA immunoglobulins, forming a dimeric molecule. It is produced by the B cell that secreted the IgA.
The secretory component is the remnant of the PIg receptor on the basal surface of an epithelial cell that has been cleaved before the IgA was secreted onto the mucosal surface.
Learning Objective 8
Explain the function of the secretory component.
- Transportation from basal surface of epithelial cell to the mucosal surface.
- Protection from cleavage by proteases in the lumen.
- Binds to mucus to keep IgA from being flushed out.
Learning Objective 9
Explain how IgA provides protection against pathogens on mucosal surfaces.
IgA binds to pathogens, inactivates them, and prevents them from entering the body.
Recall that IgA cannot fix complement. This is a good thing; complement fixation on mucosal surfaces would result in massive inflammation.
Where will a naive lymphocyte exit the blood stream to reach mucosal associated lymphoid tissue?
High-epithelial venules (HEV)
Where will an activated lymphocyte that has encountered its antigen in lymphoid tissue re-enter the blood stream?
Thoracic duct draining into the vena cava
Learning Objective 10
Explain how sIgA to an intestinal pathogen can be found in the milk of a mare and protects her newborn from the intestinal pathogen.
- M cell takes up pathogen, which is presented intact to a B cell. B cell recognizes antigen, clonally expands, class-switches to IgA.
- B cell drains to lymph node, drains out efferent lymphatics into the thoracic duct, drains into blood stream through the vena cava.
- B cell has changed its addressin molecules to match mammary tissues. Exits blood stream at the mammary gland.
- B cell secretes IgA in the submucosa, which binds to PIg of the mammary epithelium. Excreted into milk.
- The foal suckles the milk. sIgA in the foal’s gut will protect it against the intestinal pathogen.
Which cytokines stimulate B cells to class switch to IgE?
Th2 cytokines IL4 and IL13
What are some advantages to vaccinating at mucosal surfaces (intranasal, oral, etc.)?
No needle required
Induces immunity at site of entry
Better matches natural route of infection
What are some disadvantages to vaccinating at mucosal surfaces?
May be destroyed by GI tract
Can induce tolerance
Must have adequate levels of antigen to induce a response
