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Basic Immunology > Lecture 19 (11A) - Mucosal Immunity > Flashcards

Lecture 19 (11A) - Mucosal Immunity Flashcards

1
Q

Mucosal surfaces

A
  • GASTROINTESTINAL (GI) TRACT - THE GUT
  • respiratory tract - lungs and airways
  • reproductive tract
  • eye and lachyrmal glands
  • lactating breast
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2
Q

Mucosal infections - a major health problem

A
  • acute respiratory infections
  • diarrheal
  • TB
  • HIV
  • measles
  • hepatitis
  • whooping cough
  • roundworm and hookworm
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3
Q

The gut presents particular problems for the immune system

A
  1. function (absorption of nutrients and fluid) requiers
    • very large surface area
    • minimal barrier (simple epithelium 1 cell thick ~ 30micrometers)
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4
Q

The gut presents particular problems for the immune system

2. colonize by

A
  1. colonized by diverse major pathogens

• many pathogens infect through the gut

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5
Q

The gut presents particular problems for the immune system

3. large exposure to

A
  1. large exposure to harmless (or even beneficial) antigens
    • food proteins ~100Kg/year (peptide + MHC presented)
    • commensal bacteria (colon, do useful things)
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6
Q

The immune system must

A
  • discriminate self from non-self
  • respond vigorously to pathogens whist limiting responses to food and commensals: homeostasis
  • non-responsiveness is actively maintaned
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7
Q

Oral tolerance

A

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)

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8
Q

Immune cells in the intestine

A
  • 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

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9
Q

Peyer’s patches

A

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

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10
Q

M (microfold) cells

A

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

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11
Q

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

A
  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
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12
Q

Lymphocytes activated in the gut home back to the intestinal mucosa

A
  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
  5. migration to mesenteric/draining lymph nodes in systemic circulation
  6. allow T cell proliferation
  7. activated lymphocytes imprinted with gut homing properties enter circulation
  8. gut tropic lymphocytes home back to the mucosa
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13
Q

Tissue specific homing of lymphocytes

A

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

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14
Q

Multi-step paradigm of leukocyte extravasation

A
  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
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15
Q

Naive T cells recirculate through secondary lymphoid tissue

A
  • 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
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16
Q

Naive T cell interaction with HEV

A
  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
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17
Q

Tissue specific homing of lymphocytes

A
  • 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
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18
Q

α4β7 and CCR9 mediate

A

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

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19
Q

Retinoic acid produced by gut DC induces

A

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

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20
Q

The intestine is a highly active immune organ

A

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

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21
Q

T cells in the normal small intestine

A

• 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

22
Q

IgA

A
  • 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)
23
Q

IgM

A

when on the surface, not pentameter

• pentameter when secreted

24
Q

IgA is the major

A

immunoglobulin at mucosal sites (80%)

25
Q

IgA structure

A
  • 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
26
Q

IgA - transport into gut lumen

A
  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
27
Q

Secretory component

A

retains IgA near epithelial surface and protect against degradation by proteases

28
Q

IgA - what does it do?

A

limits access of pathogens without risking inflammatory damage

29
Q

IgA doesn’t

A
  • activate complement
  • recruit inflammatory cells
  • opsonize for phagocytosis
30
Q

IgA does

A
  • exclude

* agglutinate

31
Q

IgA deficiency

A

~1:500
• doesn’t increase gut infections
- IgM can compensate
- low infectious pressure in developed countries?
• influences host’s interaction with commensal bacteria?

32
Q

A common mucosal immune system?

A

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

33
Q

Oral immunization

A

induces responses in breasts as well as gut

cheeks and throat

34
Q

Nasal immunization

A

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

35
Q

Link between gut and breast allows

A

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

36
Q

Commensal gut bacteria and the immune system

A
  • 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)
37
Q

The resident microbiota shape development in the intestinal immune system

A

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)

38
Q

Different organisms have

A

distinct immunological effects

39
Q

Why don’t we all get inflammatory gut disease?

A 
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
GENERATION OF T REG BY GUT DC IS PROBABLY IMPORTANT

40
Q

In the steady-state gut

A

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

41
Q

What give gut DC their special properties?

A

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)

42
Q

Conditioning of intestinal DC

• worm infections

A
  • 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

43
Q

Conditioning of intestinal dendritic cells

• steady-state

A

TSLP (thymic stromal lymphoprotein), RA, etc

  • -> induction of CD103, TGFβ and RA regeneration
  • -> generation of inducible Treg
44
Q

Mucosal tissues (the gut) are exposed to

A

both pathogens and harmless antigens

• need balancing out

45
Q

Highly immunologically active

A

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

46
Q

Responses characterized by

A

secretory dimeric IgA and effector T cells

47
Q

m cells and specialized DC

A

sample antigen from the lumen

48
Q

During activation

A

lymphocytes are imprinted with gut homing properties by DC

49
Q

In healthy intestine

A

CD103+ DC generate regulatory T cells to control effector cells

50
Q

Signals from … influence gut DC

A

epithelial cells

signals from epithelial cells influence gut DC

Basic Immunology (15 decks)

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