L14: Mucosal Immunity

Question 1

Components of the mucosal associated lymphoid tissue (MALT)

Answer 1

Gut associated lymphoid tissue (GALT)
Nasal associated lymphoid tissue (MALT)
Bronchial associated lymphoid tissue (BALT)
Genitourinary tract
Lacrimal glands
Salivary glands
Mammary glands

Question 2

Does induction of a response via a mucosal site elicit a systemic response as well?

Answer 2

Yes

Question 3

M cells

Answer 3

Internalize the antigen and transport it across the epithelium where antigen can be taken up by APCs such as dendritic cells

Question 4

Peyer’s patches

Answer 4

Aggregates of lymphoid cells w/ B cell follicles and smaller T cell areas

Question 5

Lymphoid follicles

Answer 5

Smaller; many B cells

Question 6

What do mucosal surfaces do?

Answer 6

Separate the external environment from the internal, sterile environment

Question 7

What is the major antibody isotype in mucosal secretions?

Answer 7

IgA

Question 8

What are a major stimulus for development of mucosal immune system?

Answer 8

Commensal bacteria

Question 9

Crypts

Answer 9

Contain stem cells

Question 10

Describe uptake and transport of antigens by M cells

Answer 10

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

Question 11

Lamina propria

Answer 11

Thin layer of connective tissues which lies beneath the epithelium and together w/ the epithelium constitutes the mucosa

Question 12

In the absence of infection, what guards healthy mucosal tissue?

Answer 12

A variety of effector lymphocytes

Question 13

What effector cells constitutively exist in the epithelium? In the lamina propria?

Answer 13

Epithelium - intraepithelial lymphocytes; these are mostly CD8+

Lamina propria - A few CD4+ cells, macrophages, dendritic cells, plasma cells (secrete mainly IgA)

Question 14

Intraepithelial lymphocytes

Answer 14

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

Question 15

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?

Answer 15

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

Question 16

Describe how the effector functions of intraepithelial lymphocytes (IEL) occur

Answer 16

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

Question 17

What mediates transcytosis of IgA antibody across epithelia?

Answer 17

Polymeric Ig receptor (pIgR), a specialized transport protein

Question 18

Why is IgA secreted through the epithelial cells and into the gut lumen?

Answer 18

This is where the host is exposed to a lot of extracellular pathogens

Question 19

What does secretory IgA consist of?

Answer 19

Dimeric

J chain

Secretory component

Question 20

What are the functions of mucosal IgA in epithelial surfaces?

Answer 20

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

Question 21

What are the crucial functions of epithelial cells in innate defense against pathogens?

Answer 21

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

Question 22

What is the commensal microbiota comprised of?

Answer 22

A number of different phyla of bacteria

Question 23

How do commensal microorganisms assist the gut in digesting food and maintaining health?

Answer 23

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

Question 24

No gut microbiota = no _____

Answer 24

No muscosal immune system

Question 25

Why are local processes that ensure peaceful coexistence b/w microbiota and host necessary?

Answer 25

These allow the commensal organisms to be recognized by the immune system w/o inducing inflammation or an immune response that would eliminate them

Question 26

What local processes ensure peaceful coexistence b/w microbiota and the host?

Answer 26

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

Question 27

Why does the immune system ignore commensals?

Answer 27

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

Question 28

How does Salmonella enteric enter the gut epithelial layer?

Answer 28

1. Salmonellae enter and kill M cells, and then infect macrophages and epithelial cells 2. Salmonellae invade the luminal surface of epithelial cells (forms an endosome and enters) 3. 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)

Question 29

What are the defense mechanisms we have against salmonella? What occurs if these fail?

Answer 29

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

Question 30

Inflammation of musosal tissue is associated with ____ and not ______

Answer 30

Inflammation of mucosal tissue is associated with causation and not cure of disease

Question 31

Why is inflammation process minimal in mucosal tissues?

Answer 31

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

Question 32

How does antibiotic treatment play a role in infection by Clostridium difficile?

Answer 32

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

Question 33

Describe infection by Clostridium difficile

Answer 33

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

Question 34

What are main things that distinguish muscosal immunity from systemic immunity?

Answer 34

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