Lecture 19 (11A) - Mucosal Immunity Flashcards Preview

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Flashcards in Lecture 19 (11A) - Mucosal Immunity Deck (50):

Mucosal surfaces

• respiratory tract - lungs and airways
• reproductive tract
• eye and lachyrmal glands
• lactating breast


Mucosal infections - a major health problem

• acute respiratory infections
• diarrheal
• TB
• measles
• hepatitis
• whooping cough
• roundworm and hookworm


The gut presents particular problems for the immune system

1. function (absorption of nutrients and fluid) requiers
• very large surface area
• minimal barrier (simple epithelium 1 cell thick ~ 30micrometers)


The gut presents particular problems for the immune system
2. colonize by

2. colonized by diverse major pathogens
• many pathogens infect through the gut


The gut presents particular problems for the immune system
3. large exposure to

3. large exposure to harmless (or even beneficial) antigens
• food proteins ~100Kg/year (peptide + MHC presented)
• commensal bacteria (colon, do useful things)


The immune system must

• discriminate self from non-self
• respond vigorously to pathogens whist limiting responses to food and commensals: homeostasis
• non-responsiveness is actively maintaned


Oral tolerance

feeding with a protein antigen induces a state of antigen-specific systemic non-responsiveness
• eg immunize with antigen (ovalbumin) + adjuvant
• then paint skin with ovalbumin
--> swelling due to T cell mediated immune response

if fed with ovalbumin prior to immunization
• immunize with alternate antigen (eg KLH) + adjuvant
• paint skin with KLH
• swelling due to T cell mediated immune response

• mechanisms are complex - T cell deletion, T cell anergy, regulatory T cell induction (iTreg, Tr2, Th3)


Immune cells in the intestine

• gut associated lymphod tissue (GALT)
• Peyer's pathces
• mesenteric lymph nodes
• sites of Ag presentation to T and B cells

• more lymphoid tissue in gut than the rest of the body combined


Peyer's patches

described by Johann Conrad Peyer in 1677
• like lymph node by no afferent lymphatics
• FAE = follicle-associated epitlium


M (microfold) cells

in Peyer's patches, M cells transport antigen to underlying immune cells
• transport antigen from lumen across epithelium to DC
• sample antigen from lumen of intestine
• some cells target M cell to get in


DC sample antigen from the lumen of the small intestine via multiple different pathways

1. via M cells (reach through to Peyers patch)
- transport across
- trans-celllular tubules
2. via goblet cells
3. via Cx3CR1 + APC (monocytes)
4. via FcRn mediated transport


Lymphocytes activated in the gut home back to the intestinal mucosa

1. enter via peyer's patch
2. allow T cell proliferation
3. activated lymphocytes "imprinted" with homing properties enter circulation
4. gut tropic lymphocytes home back to the mucosa

1. migration to mesenteric/draining lymph nodes in systemic circulation
2. allow T cell proliferation
3. activated lymphocytes imprinted with gut homing properties enter circulation
4. gut tropic lymphocytes home back to the mucosa


Tissue specific homing of lymphocytes

naive T cells recirculate through the secondary lymphoid tissue, through body


Multi-step paradigm of leukocyte extravasation

1. tethering (to endothelium)
2. rolling and activation
3. arrest
4. diapedesis and migration

• selectins high in 1, almost nonexistant in 2
• chemokines equally high in 2-4
• activated integrins increase 2-4


Naive T cells recirculate through secondary lymphoid tissue

• extravasation in lymph nodes occurs in specialized regions - high endothelial venules
• ~1.4x10^4 lymphocytes per second extravasate at a single node
• loss of L-selectin and CCR7 upon activation changes migration pattern


Naive T cell interaction with HEV

1. L selectin on T cell
--> Cd34, GlyCAM-1 on HEV

2. CCR7 on T cell
--> CCL21, CCL19 on HEV

3. LFA-1 on T cell
--> ICAM-1 on HEV


Tissue specific homing of lymphocytes

• activated T cells acquire the ability to traffic to peripheral tissues
• T cells activated in gut draining nodes home to the gut
• T cells activated in skin draining nodes home to the skin


α4β7 and CCR9 mediate

lymphocyte homing to the mucosa of the small intestine

• α4β7 on T cell
--> MAdCAM-1 on intestinal lamina propria endothelium
• α4β7 integrin on lymphocytes binds MaDCAM-1 on wall of blood vessels in the gut

• CCR9 on T cell + CCL25 = gut homing effector T and B cells
• binding of CCL25 - a chemokine - to CCR9 strengthens binding and allows lymphocyte to enter tissue

chemokines activate MAdCAM


Retinoic acid produced by gut DC induces

lymphocytes to express α4β7 and CCR9
(switches on expression of gut homing receptors α4β7 and CCR9)
• DC from other tissues don't produce retinoic acid - lack the required enzymes


The intestine is a highly active immune organ

large numbers of effector T and B cells are scattered in the mucosa in the normal, healthy intestine
• B cells are plasma cells, mostly making IgA


T cells in the normal small intestine

• mainly CD4+ T cells in the lamina propria (connective tissue between the epithelium)
• intra-epithelial lymphocytes (IEL)
- mainly CD8+ T cells
- significiant proportion of γδ T cells
• loss of gut T cells (eg in HIV infection) increases susceptibility to low grade intestinal pathogens



• B cells initially make IgM
• under influence from eg cytokines, they switch producing different isotypes (classes)
• mostly IgA in the mucosa (T cell derived TGFβ enhances class switching to IgA)



when on the surface, not pentameter
• pentameter when secreted


IgA is the major

immunoglobulin at mucosal sites (80%)


IgA structure

• monomer in blood
• dimer in mucosal tissues
• J chain links 2 IgA molecules in dimeric IgA
• 2 subtypes - IgA1 and IgA2
• mostly IgA2 in gut - more resistant to proteases
• ~5g/day secreted into gut lumen - transported across epithelium


IgA - transport into gut lumen

1. binding of IgA to receptor on basolateral face of epithelial cell (poly-Ig receptor)
2. endocytosis
3. transcytosis to apical face of epithelial cell
4. release of IgA dimer at apical face of epithelial cell (+ secretory component)
• secretory component - retains IgA near epithelial surface and protects against degradation by proteases


Secretory component

retains IgA near epithelial surface and protect against degradation by proteases


IgA - what does it do?

limits access of pathogens without risking inflammatory damage


IgA doesn't

• activate complement
• recruit inflammatory cells
• opsonize for phagocytosis


IgA does

• exclude
• agglutinate


IgA deficiency

• doesn't increase gut infections
- IgM can compensate
- low infectious pressure in developed countries?
• influences host's interaction with commensal bacteria?


A common mucosal immune system?

no - some crosstalk between different mucosal sites
• put in different places --> response in different places
• links in tissues
• eg protect against STD via nasal


Oral immunization

induces responses in breasts as well as gut
(cheeks and throat)


Nasal immunization

induces local responses and responses in the reproductive tract
(nose, lungs, junk)


Link between gut and breast allows

IgA specific for gut pathogens to be secreted into breast milk for protection of newborns
(passive immunity to baby)


Commensal gut bacteria and the immune system

• numbers increase dramatically distally
• 1Kg = 10^14 bacteria in large intestine (10^11 - 10^12 per ml)
• super-organism - 90% of our cells are microbial
• approximately 2 million genes (20,000 protein encoding genes in man)
• 90% belongs to 2 phyla - Firmicutes and Bacteriodetes - highly variable at species level
• beneficial - digestion of complex carbs, compete with pathogens (bugs in gut good at extracting calories)


The resident microbiota shape development in the intestinal immune system

germ-free mouse must feed 30% more calories
• rudimentary peyer's patch without microbiota
• newborn babies have no IgA (child populated by IgA producing cells, but newborn has few IgA producing B cells)


Different organisms have

distinct immunological effects


Why don't we all get inflammatory gut disease?

likely that we would
• resident bacteria express PAMPS (danger)
• M cells and DC sample these bacteria
• adaptive immune system responds
• many effector cells in mucosa
(make IgA response to bacteria in blood)

but we don't
• because of specialized mechanisms that operate in the gut
- physiological inflammation
• not fully understood but multiple pathways contribute


In the steady-state gut

CD103+ DC generate gut tropic inducible T reg
• CD103+ DC make retinoic acid
• made in inactive form , cleaved to active form by αVβ8
• upregulates homing receptors
• favors T reg induction (at the expense of Th17 cells)
• increases gut tropic regulatory regulatory T cells


What give gut DC their special properties?

conditioning of DC by factors from epithelial cells
• DC in gut different because epithelial barrier delivers signals - changes properties of DC (conditioning), activates T cells (downstream effect on T cell responses)


Conditioning of intestinal DC
• worm infections

• need Th2 response to get rid of worms
• epithelium makes factors that affect the DC to make sure it makes Th2

• engineer epithelium so signalling in epithelium can't respond to worm, didn't make TSLP, IL-25, or IL-3 --> no signal to DC --> made Il-12 --> Th1 and worms not cleared


Conditioning of intestinal dendritic cells
• steady-state

TSLP (thymic stromal lymphoprotein), RA, etc
--> induction of CD103, TGFβ and RA regeneration
--> generation of inducible Treg


Mucosal tissues (the gut) are exposed to

both pathogens and harmless antigens
• need balancing out


Highly immunologically active

specialized features enable protective responses to pathogens while limiting responses to harmless antigens


Responses characterized by

secretory dimeric IgA and effector T cells


m cells and specialized DC

sample antigen from the lumen


During activation

lymphocytes are imprinted with gut homing properties by DC


In healthy intestine

CD103+ DC generate regulatory T cells to control effector cells


Signals from ... influence gut DC

epithelial cells
signals from epithelial cells influence gut DC