Mucosal Immunity Flashcards by Steven Marincel

What are the different immune compartments included in mucosal immunity

peripheral lymph nodes and spleen

peritoneum

skin

MALT

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What is the role of peripheral lymph nodes and spleen in mucosal immunity?

adaptive immune response to foreign Ag in blood or lymph

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How do lymphocytes know where to go?

they have compartment specific homing receptors

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How do we maintain a homeostatic relationship with microbiota?

minimize direct contact between intestinal bacteria and epithelial cells

keep penetrant bacteria in intestinal sites (limit exposure to systemic immune compartment)

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What is the barrier that minimizes direct contact between intestinal bacteria and epithelial cells?

Mucin + 1 layer of epithelial cells

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What are the mucosal tissues of the body?

lachrymal gland

salivary gland

mammary gland

kidney

urogenital tract (uterus, bladder, vagina)

conjunctiva

GI tract (oral cavity, esophagus, stomach, intestine)

respiratory tract (sinus, trachea, lung)

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What are the different MALTs?

GI tract (GALT)

respiratory tract (BALT)

nasal mucosa (NALT)

salivary glands

lacrimal glands

mammary glands

genitourinary glands

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Where are mucosal lymphoid tissues found?

under the epithelial cells

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What is the main Ig in mucosal lymphoid tissue?

IgA

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70-80% of Ig producing cells are located where, and what type of cell are they predominantly?

mucosal areas, most of them are IgA plasma cells

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What cells of the mucosal immune system are found in the epithelial compartment?

IEL (alpha-E:beta7 integrins) and dendritic cells

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What cells of the mucosal immune system are found in the lamina propria compartment?

lots of different kinds of cells including cells expressing alpha4:beta7 integrins

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What does alpha4:beta7 do?

addressin that tells the cell to go to the gut

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What do M cells do?

antigens entering the digestive tract are taken up by specialized mucosal cells called M cells via phagocytosis and endocytosis

M cells internalize the Ag and transport it across the epithelium in vesicles where it can be taken up by APCs

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How are M cells formed?

formed in mucosal epithelium in response to signals from lymphocytes

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What is Ag capture?

Ag can be taken up by a DC that has a dendrite extending through the epithelial tight junction into the lumen

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What is the third step of the induction process?

Ag are then presented to lymphocytes (in the intestine this occurs in Peyer’s patches)

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Do M cells have villi/microvilli?

No –> they take up Ag

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Where are M cells found?

Tonsils, Adenoids, PP

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What is FcRn-dependent transport?

if an Ag is already coated in Ab, cells can recognize he Fc receptor and transport it

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What is apoptosis-dependent transfer?

If a M cell is killed, the pathogens can invade and be taken up

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What are the ways that Ag can be taken up?

nonspecific M cell transfer

FcRn-dependent transfer

Apoptosis-dependent transfer

Ag capture

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How are T cells directed to PP, and where are they coming from?

T lymphocytes enter PP from the blood vessels, directed by the homing receptors CCR7 and L-selectin

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After T cells in PP encounter Ag presented by dendritic cells, where do they go?

Activated T cells drain via the mesenteric lymph nodes to the thoracic duct, and return to the gut via the blood stream

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Where do activated T cells in the bloodstream go, and how are they homed?

Activated T cells will express alpha4-beta7 integrin and CCR9 and will home to the lamina propria and intestinal epithelium of the small intestine

What do gut homing effector T cells bind on the blood vessel epithelium?

alpha4:beta7 and L-selectin bind MAdCAM-1 on the blood vessel endothelium, which allows the cell to extravasate into the lamina propria

What do gut epithelial cells express to help home T cells, and what do they bind on the T cells?

gut epithelial cells express chemokines specific for gut homing T cells CCL25 on small intestine epithelium binds CCR9 on T cells CCL28 on large intestine epithelium binds CCR10 on T cells E-cadherin on gut epithelium (both) binds alphaE:beta7 on T cells

is an M cell an APC?

No - just takes up Ag to allow APC to take it up

What does the administration of Ag at one mucosal site result in?

specific Ab production at distant mucosal sites, but with regional preference

What do B cells in the mucosa preferentially produce?

dimeric IgA

What is the selective switch of B cells to IgA mediated by?

specific cytokines produced by T cells in the inductive sites

Conventional T cells are important in the mucosal immune response. What T cell population is particularly important?

CTLs

A mucosal encounter produces B and T cells that home to the mucosal sites. What else occurs?

a systemic immune response is also induced, and serum antibodies can be detected. This indicates that B and T cells are also migrating to the lymph nodes and spleen

What type of cells are intraepithelial lymphocytes?

CD8+ T cells (will recognize particles presented via MHC class I)

What do IELs do?

Kill infected cells via perforin and granzyme and FasL pathways

What is the first line of mucosal defense?

Epithelial cells provide innate defense against most pathogens

How do epithelial cells provide defense against invading pathogens?

endocytosed bacteria are recognized by TLR bacteria or bacterial products entering cytosol direclty are recognized by NOD1 or NOD2 TLRs and NODs activate NFkB which induces the epithelial cell to produce inflammatory cytokines, chemokines, and other mediators which activated neutrophils, macrophages, and DCs

How does salmonellae bypass the first line of defense?

can enter and kill M cells, invade the luminal epithelium of M cells, enter dendritic cells that are sampling the gut lumen

What is the effect on the immune system for a patient with IgA deficiency?

Pts with low or absent IgA have normal cell mediated immunity and serum Ab responses

What conditions would lead you to suspect IgA deficiency?

family history of IgA deficiency or agammaglobulinemia high incidence of oral infection frequent respiratory infections chronic diarrhea

What can happen if you give immunoglobulin treatment to a patient with IgA deficiency?

the pts immune system can develop anti-IgA Abs leading to shock or allergy

What is the predominant Ig in mucosal secretions?

IgA

What are the relative amounts of IgA in serum and secretions, and what forms are they in?

serum Ig: 12% IgA, monomeric secreted Ig: 96% IgA, dimeric

What does the production of secretory IgA require?

requires both plasma cells in the lamina propria and epithelial cells of the mucosa

What does dimeric IgA consist of?

two monomeric IgA molecules joined by a J chain

What produces dimeric IgA?

plasma cells in the mucosal lamina propria

once formed, where and what does dimeric IgA bind?

dimeric IgA binds the polymeric immunoglobulin receptor (pIGR) on the basal surface of mucosal epithelial cells

once bound, what happens to the IgA:pIGR complex?

endocytosed across the the epithelial cell to the luminal surface and released

What occurs during transport of the IgA:pIGR complex?

cleavage of the pIGR molecule - a small part is lost, the remainder remains attached to the dimeric IgA

What kind of Ig can be transported by pIGR?

only polymeric Igs (dimeric IgA, pentameric IgM)

What are the functions of IgA at mucosal surfaces?

barrier intraepithelial viral neutralization excretory immunity passive immunity (eg breast milk)

How does IgA mediate barrier functions at mucosal surfaces?

IgA can bind to bacteria and viruses and prevent them from adhering to and invading mucosal tissues. IgA can also neutralize bacterial toxins

What is excretory immunity?

viral particles that complex with IgA in the lamina propria can be endocytosed and transported out via pIGR

What are the advantages of oral vaccination?

ease of administration generates both mucosal and systemic immunity

What are the disadvantages of oral vaccination?

difficulty in eliciting robust response (because of tolerance) response may not be long lasting

What is a key feature that distinguishes between the induction of a response and the induction of tolerance?

inflammation

What do Ag encounters that occur alongside inflammation induce?

an immune response

What do Ag encounters in the absence of inflammation induce?

tolerance

Does systemic vaccination provide mucosal immunity?

no!

does mucosal vaccination provide systemic immunity?

yes - both mucosal and systemic immunity

how do you induce mucosal immunity in the tolerogenic environment?

induce inflammation

What is mucosal tolerance mediated by?

mucosal DCs

in the presence of commensals, what happens to the DCs?

PGE2, TGF-beta, and TSLP inhibit DC maturation

What do immature DCs do?

provide a weak costimulatory signals to CD4 T cells, inducing the T cell to differentiate into regulatory Th3 or Tregs

What is the largest organ of the immune system?

mucosa!

how do most pathogens enter the body?

via the mucosa

What mediates the induction of immunity in the mucosa?

M cells

What do you need to develop mucosal vaccines?

mucosal adjuvants