L14: Mucosal Immunity Flashcards
Components of the mucosal associated lymphoid tissue (MALT)
Gut associated lymphoid tissue (GALT) Nasal associated lymphoid tissue (MALT) Bronchial associated lymphoid tissue (BALT) Genitourinary tract Lacrimal glands Salivary glands Mammary glands
Does induction of a response via a mucosal site elicit a systemic response as well?
Yes
M cells
Internalize the antigen and transport it across the epithelium where antigen can be taken up by APCs such as dendritic cells
Peyer’s patches
Aggregates of lymphoid cells w/ B cell follicles and smaller T cell areas
Lymphoid follicles
Smaller; many B cells
What do mucosal surfaces do?
Separate the external environment from the internal, sterile environment
What is the major antibody isotype in mucosal secretions?
IgA
What are a major stimulus for development of mucosal immune system?
Commensal bacteria
Crypts
Contain stem cells
Describe uptake and transport of antigens by M cells
M cells take up antigen by endocytosis and phagocytosis → antigen is transported across the M cells in vesicles and released at the basal surface → antigen is bound by dendritic cells, which activate T cells
Lamina propria
Thin layer of connective tissues which lies beneath the epithelium and together w/ the epithelium constitutes the mucosa
In the absence of infection, what guards healthy mucosal tissue?
A variety of effector lymphocytes
What effector cells constitutively exist in the epithelium? In the lamina propria?
Epithelium - intraepithelial lymphocytes; these are mostly CD8+
Lamina propria - A few CD4+ cells, macrophages, dendritic cells, plasma cells (secrete mainly IgA)
Intraepithelial lymphocytes
Lie within the epithelial lining of the gut
Mainly CD8+
Activated appearance
Have intracellular granules (perforin and granzyme)
Restricted use of VDJ gene segments
Expand locally in response to a relatively small # of antigens
Describe priming of naive T cells and the redistribution of effector T cells in the intestinal immune system. How is this different from systemic immune response?
T cells enter Peyer’s patches from blood vessels, directed by homing receptors → T cells in the Peyer’s patch encounter antigen transported across M cells and become activated by dendritic cells → activated T cells drain via mesenteric lymph nodes to the thoracic duct and return to the gut via the bloodstream → activated T cells home back to the lamina propria and inestinal epithelium of the small intestine
Some amount of T cell activaton occurs at site of infection itself rather than in lymph nodes
Describe how the effector functions of intraepithelial lymphocytes (IEL) occur
Virus infects mucosal epithelial cells → infected cell display viral peptide to CD8 IEL via MHC class I → activated IEL kills infected epithelial cell by perforin/granzyme and Fas-dependent pathways
OR
Epithelial cells undergo stress as a result of infection, damage, or toxic peptides, and express MIC-A and MIC-B → NKG2D on IEL binds to MIC-A, B and activates the IEL → activated IEL kills the stressed cell via the perforin/granzyme pathway
What mediates transcytosis of IgA antibody across epithelia?
Polymeric Ig receptor (pIgR), a specialized transport protein
Why is IgA secreted through the epithelial cells and into the gut lumen?
This is where the host is exposed to a lot of extracellular pathogens
What does secretory IgA consist of?
Dimeric
J chain
Secretory component
What are the functions of mucosal IgA in epithelial surfaces?
Secreted IgA on the gut surface can bind and neutralize pathogens and toxins
IgA is able to bind and neutralize antigens internalized in endosomes
IgA can 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+ dendritic cell
What are the crucial functions of epithelial cells in innate defense against pathogens?
Bacteria are recognized by TLRs on cell surface or in intracellular vesicles
Bacteria or their products directly entering the cytosol are recognized by NOD1 and NOD2 → TLRs, NOD1, and NOD2 activate NFκB, inducing cell to express inflammatory cytokines, chemokines, etc. which recruit other immune cells
Intracellular infection triggers formation of inflammasome → activate myeloid cells and increase barrier integrity
Destruction of bacteria in autophagosome → bacteria in cytoplasm or escaping from phagosome are taken into forming autophagosome and destroyed after fusion w/ lysosome
What is the commensal microbiota comprised of?
A number of different phyla of bacteria
How do commensal microorganisms assist the gut in digesting food and maintaining health?
Synthesize essential metabolites (such as vitamin K) → cofactor for synthesis of clotting factors in liver
Break down plant fibers in food → release of small molecules that can be used in metabolism and biosynthesis
Inactivate toxic substances in food or made by pathogens → degradation of toxins into harmless components that can be used by human cells
Prevent pathogens from benefiting from the resources of the human gut → limitation of pathogens to small numbers that are not harmful (takes away resources from pathogen)
Interact w/ epithelium to trigger development of secondary lymphoid tissue → establishment of the GALT
No gut microbiota = no _____
No muscosal immune system
Why are local processes that ensure peaceful coexistence b/w microbiota and host necessary?
These allow the commensal organisms to be recognized by the immune system w/o inducing inflammation or an immune response that would eliminate them
What local processes ensure peaceful coexistence b/w microbiota and the host?
Goblet cells - secrete mucins that endow the mucus w/ the properties to protect from the epithelial barrier; forms a barrier along the epithelial cells and prevent gut microflora from passing the epithelial barrier into the submucosal area and causing infection
Paneth cells - secrete a lot of anti-micobial proteins that keep commensal bacteria in check
IgA antibodies - bind the microflora and prevent it from crossing epithelial barrier
Commensals lack virulence factors - virulence factors are what really make a bacteria pathogenic and would allow them to move across the epithelial layer into the mucosal tissues
Why does the immune system ignore commensals?
Mesenteric lymph nodes form a barrier that prevents commensals from reaching the systemic compartment
DCs present antigen directly to B cells resulting in IgA production
Commensals may used type III or type IV secretion systems to deliver bacterial effector molecules to host cells
Induction of local T regulatory cells
IL-10 producing dendritic cells
Inhibition of inflammation
How does Salmonella enteric enter the gut epithelial layer?
- Salmonellae enter and kill M cells, and then infect macrophages and epithelial cells
- Salmonellae invade the luminal surface of epithelial cells (forms an endosome and enters)
- Salmonellae enter phagocytic cells that are sampling the gut luminal contents (we have phagocytic cells that have long protrusions that sample outside for antigens and salmonella takes advantage of this mechanism)
What are the defense mechanisms we have against salmonella?
What occurs if these fail?
Chemokines and cytokines produced by macrophages recruit neutrophils out of the blood vessels and activate them
Dendritic cells loaded w/ bacterial antigens directly or from macrophages travel to the mesenteric lymph node via afferent lymphatics and provoke an adaptive immune response
If defenses fail, salmonellae can enter the bloodstream and cause a systemic infection
Inflammation of musosal tissue is associated with ____ and not ______
Inflammation of mucosal tissue is associated with causation and not cure of disease
Why is inflammation process minimal in mucosal tissues?
Healthy tissue is protected by mucosal immunity → bacteria gain access to lamina propria by endocytosis, activate macrophages but do not cause inflammation → local effector cells respond to limit infection, dendritic cells travel to mesenteric lymph node to activate adaptive immunity → effector B cells and T cells that are highly specific for the invading bacteria colonize the infected area → infection is terminated with either minor tissue damage or no need for repair
How does antibiotic treatment play a role in infection by Clostridium difficile?
One of the roles of commensal bacteria is to prevent pathogens from binding to epithelial surfaces and gaining access
Antibiotic treatment has gotten rid of the good bacteria so this Clostridium difficile can gain a foothold
Describe infection by Clostridium difficile
The colon is colonized by large #s of commensal bacteria → antibiotics kill many of these commensal bacteria → C. diff gains a foothold and produces toxins that cause mucosal injury → neutrophils and RBCs leak into gut b/w injured epithelial cells → connective tissue degradation leads to colitis and pseudo-membrane formation
What are main things that distinguish muscosal immunity from systemic immunity?
M cells
Antigen presentation can occur in Peyer’s patch itself
Don’t have to wait for the adaptive immune system to be activated in the mesenteric lymph node
Presence of microbiota and how it contributes to mucosal immunity
