Mucosal Immunology - Lee 4/13/16 Flashcards Preview

Immunity > Mucosal Immunology - Lee 4/13/16 > Flashcards

Flashcards in Mucosal Immunology - Lee 4/13/16 Deck (21):
1

mucosal associated lymphoid tissues

NALT - nasopharyngeal

BALT - bronchial

GALT - gastroint

2

antigen sampling in aerodigestive tract

M cells in follicle-assoc epithelium → overlays organized lymphoid tissue in GALT, NALT → production of mucosal IgA (acquired)

M cells in epithelium → overlays diffuse lymphoid tissue → production of systemic IgG (acquired) [and maybe mucosal IgA?]

DCs in epithelium →overlays diffuse lymphoid tissue → production of systemic IgG [maybe mucosal IgA]

 

common signaling features

*Wnt signaling : tells all intestinal stem cells (from basal crypts) where to go 

*Notch signaling : determines cell lineage specification (what they produce, etc)

3

mucosal barrier components

mucus

paracellular pathway

antimicrobial peptides

4

mucus

highly hydrated, viscous secretion with complex macromolecular profile

  • viscosity due to olymeric mucin glycoproteins
  • mucin : permeable to macromolecules (like antimicrobial peptides, Ig) but also serves as a barrier to undesirable mols

5

intercellular jx

1. tight junctions : transmembrane proteins located at lateral surface of epi cells made of claudin and occludins

2. adherent junctions : made of cadherins

3. desmosomes

6

antimicrobial peptides

1. cathelicidins

  • chemotactic for neutrophils, monocytes, mast cells, T cells
  • induces mast cell degranulation
  • alters macrophage transcriptional responses

2. defensins

  • microbicidal against bacteria, fungi, spirochetes, protozoa, viruses
  • present in various cell types

7

cellular constituents

in layers:

epithelial cells

intraepithelial cells

lamina propria lymphocytes

  • mucosal B cells, dendritic cells, intestinal macrophages, mucosal basophils/eosinophils/mast cells, M cells

8

secretory cells in mucosal epithelium

1. goblet cells : mucus producing cells, abundant in GI epi

2. specialized cells producing antimicrobial peptides, found throughout GI tract

*nonspecialized cells show high plasticity → secretory phenotype of lineage can be modified in response to infection or inflammation

9

intraepithelial lymphocytes

wedged between epithelial cells (on basal ends)

balance protective immunity & barrier fx

can be natural (innate) or induced (acquired via exposure to pathogens)

  • at start, natural > inducible → over time, natural (stays constant) < inducible

features:

  • small mononuclear cells
  • mostly CD4-/CD8+ or CD4-/CD8-
  • express NK cell receptors
  • express integrins : interact with epi cells' Ecadherins

 

IELs send signals to thymus where T cells are maturing → inform selection → selected T cells home to lymph nodes or to where theyre going to fx

10

T cells in lamina propria

  • predominantly CD4 cells
  • receive signals from epi cells, IELs, stromal cells, integrin receptors
  • interact with microbiota : diff biota induce diff cytokine responses in mucosal T cells

 

11

mucosal B cells

evidence for mucosal B cells: all mucosal secretions (tears, nasal secretion, saliva, int juice, breastmilk) contain antibodies!

  • abs are produced by mucosal B cells = plasmablasts in lamina propria
  • IgA, IgM are dominant mucosal Igs

12

epithelial transcytosis of secretory Ig

 

how do antibodies get from lamina propria to the lumen?

can't make it past tight jx...need to find another way through

 

transcytosis is mediated by polymeric immunoglobulin receptors (pIgR) found on basolateral surface of epithelial cells

  • pIgA and pIgM bind to pIgRs → receptor-mediated endocytosis of pIg-pIgR complex into epi cell → transcytosis to apical surface of epi cell → cleavage of complex, release of secretory Ig at apical face
    • expression of pIgR is affected by microbial factors, cytokines, hormones
  • sIgA and sIgM anchor to mucin, provide immunological barrier to infection

 

13

dendritic cells

immature DCs capture, process, and present antigens via MHC

  • pick up self-antigens (apoptotic bodies), soluble exogenous antigen (ex. food proteins), commensal bacterial from skin/mucosa

once stimulated, DCs mature

  • elongate dendrite
  • increase antigen presentation
  • enhance co-stim molecules

mature DCs migrate from nonlymphoid tissue to T cell zone of draining lymph nodes → select/activate naïve T cells

  • induce peripheral tolerance via clonal deletion or anergy; potential pathways include...
    • antigen-specific T cell deletion
    • induction of Treg differentiation
    • production of IgA that prevents antigen/microbial uptake

14

how do intestinal dendritic cells effect a response to an antigen?

 

also: role in T cell response

  • drive Treg cells involved in tolerance to oral antigen and commensal bacteria
  • provide differentiation signals for IgA-producing B cells
  • once stimulated, migrate to lymph nodes and thymus → cause maturation of T cells and imprint lymphocytes with homing signals back to int tissues

 

role in T cell response

intestinal DCs pick up an antigen, mature, and travel to thymus or lymph nodes → stimulate naive T cell maturation → mature T cells then home to the site of antigen-pickup to go aid in the immune response

 

fx of intestinal dentrici cells

15

macrophage

derived from stem cells in bone marrow → continuously populate healthy int mucosa

  • foot soldiers that serve as first-line of immune resp: kill invaders and activate other aspects of response 

 

specialize in scavenging dead/dying cells, repairing damaged tissues, killing intracellular microbes

  • has endocytic properties; has lysozymes and cathepsins that degrade antigens

do not present antigens

  • no dendrite, yes HLA-DR expression, but no expression of costim molecules

16

M cells and FAE

M cells = microfold cells

  • diff cells are tucked in to microfold: antigens that are taken up get presented to DCs → present to B cells, T cells, etc → local production of cytokines and infl markers that either ramp up or dampen an immune response

FAE = follicle-assoc epithelium

  • FAE mediates crosstalk between int flora and mucosal immune system

17

3 mechanisms for antigen uptake and presentation

1. M cells

2. dendritic cells : with costim (pathogens=bad!) or without costim (self=ok)

3. transcytotic pIg pathway (pIg-pIgR complex effecting transcytosis out to lumen and back in once antigen is bound)

18

cell trafficking and homing

INDUCTIVE SITE:

1. M cells deliver antigen to DCs

2. DCs activate lymphocytes and hook them up with gut homing receptors (CCR9, alpha4beta7 → interact with epi cell proteins)

3. lymphocytes migrate to lymph nodes, where systemic homing receptor is downregulated (L selectin/CD62L)

summary: M cells → DC → lymphocyte (turn on specific homing, turn off systemic homing)

 

HOMING TO EFFECTOR SITE:

1. lymphocytes (now homing only to int) move into bloodstream via thoracic duct and travel to mucosa

  • head to lamina propria, IELs

 

19

commensal microbiota

  • metagenome
  • germ free mice

metagenome: aggregate of genes found in microbiome that can be organized in to functional metabolic repertoires

microbiota is acquired after birth ( through food, skin flora of breast when suckling, etc)

  • have to survive GI tract to make it to int, where they might become part of microbiome

 

commensal bacteria are IMPORTANT: germ free mice have all sorts of abnormalities

  • enlarged cecum
  • longer intestines with abnormal villi
  • poorly developed mesenteric lymph nodes
  • poorly developed Peyer's patches
  • lower numbers of isolated lymphoid follicles
  • small spleen

20

segmented filamentous bacteria

able to stimulate immune fx

  • expose normal mice to antigens → immune response
  • expose germ free mice to antigens → NO immune response
  • expose germ free mice to antigens conjugated with SFB → immune response!

implication: there is something out there (in environment) than can stimulate immune response

21

microbiota and metabolic syndrome

regular mice droppings fed to germ free mice → regular size

obese mice droppings fed to germ free mice → obese!