Mucosal Immunity Flashcards
What are the different immune compartments included in mucosal immunity
peripheral lymph nodes and spleen
peritoneum
skin
MALT
What is the role of peripheral lymph nodes and spleen in mucosal immunity?
adaptive immune response to foreign Ag in blood or lymph
How do lymphocytes know where to go?
they have compartment specific homing receptors
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)
What is the barrier that minimizes direct contact between intestinal bacteria and epithelial cells?
Mucin + 1 layer of epithelial cells
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)
What are the different MALTs?
GI tract (GALT)
respiratory tract (BALT)
nasal mucosa (NALT)
salivary glands
lacrimal glands
mammary glands
genitourinary glands
Where are mucosal lymphoid tissues found?
under the epithelial cells
What is the main Ig in mucosal lymphoid tissue?
IgA
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
What cells of the mucosal immune system are found in the epithelial compartment?
IEL (alpha-E:beta7 integrins) and dendritic cells
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
What does alpha4:beta7 do?
addressin that tells the cell to go to the gut
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
How are M cells formed?
formed in mucosal epithelium in response to signals from lymphocytes
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
What is the third step of the induction process?
Ag are then presented to lymphocytes (in the intestine this occurs in Peyer’s patches)
Do M cells have villi/microvilli?
No –> they take up Ag
Where are M cells found?
Tonsils, Adenoids, PP
What is FcRn-dependent transport?
if an Ag is already coated in Ab, cells can recognize he Fc receptor and transport it
What is apoptosis-dependent transfer?
If a M cell is killed, the pathogens can invade and be taken up
What are the ways that Ag can be taken up?
nonspecific M cell transfer
FcRn-dependent transfer
Apoptosis-dependent transfer
Ag capture
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
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
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
