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Flashcards in Mucosal Immune System Deck (23)
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1

Mucosal immune system

Situated at ‘____ mucosal surfaces of body

e.g., ___, _____, ____, ___, _____

___ from systemic immune system

 

Mucosal immune system

Situated at ‘exposed’ mucosal surfaces of body

e.g., eyes, gastrointestinal tract, oral cavity, lungs, genitourinary tract

Distinct from systemic immune system

 

2

Challenges at mucosal surfaces

  • Sites of important interaction between the _____ and the_____
    • Lung epithelium: ___ ____
    • Gastrointestinal epithelium: ___ ___
  • Represent a vast ___ ___
    • ____ and most important area exposed to the external environment
    • GI surface is over____
  • Most ____ site of infection by pathogens
    • Heaviest ____ load
    • Vulnerable to ___ and invasion
  • Skin is exposed to the external environment but is____
  • The mucosa is an extension of the skin and lines the digestive track from mouth to anus

 

Challenges at mucosal surfaces

Sites of important interaction between the organism/body and the external environment

Lung epithelium: gas exchange

Gastrointestinal epithelium: nutrient absorption

Represent a vast surface area

Largest and most important area exposed to the external environment

GI surface is over 200 m2

Most frequent site of infection by pathogens

Heaviest antigenic load

Vulnerable to colonization and invasion

Skin is exposed to the external environment but is sealed.

The mucosa is an extension of the skin and lines the digestive track from mouth to anus

3

Surface area exposed to the external environment

SA of Skin is very___ compared to lungs and GI.

This is due to ___ in lungs and___ in GI

Surface area exposed to the external environment

SA of Skin is very small compared to lungs and GI.

This is due to alveoli in lungs and villi in GI

4

___ ___ ___ ___ (MALT)

  • ___-associated lymphoid tissues (GALT)
    • ___ ____
    • ___  lymph nodes
    • ____
    • ___ lymph nodes
  • ____-associated lymphoid tissues (NALT) Oral Cavity
    • ____ Ring: palatine, nasopharyngeal (adenoids), tubal, and lingual tonsils
  • ____ tract
  • ____-associated lymphoid tissue (BALT)
  • ____ (or ___)-associated lymphoid tissue (CALT or EALT)
  • ____ ____-associated lymphatic tissue (O-MALT)

Mucosa-associated lymphoid tissue (MALT)

Gut-associated lymphoid tissues (GALT)

Peyer’s patches (PP)

Mesenteric  lymph nodes

Appendix

Solitary lymph nodes

Nasopharyngeal-associated lymphoid tissues (NALT) Oral Cavity

Waldeyer’s Ring: palatine, nasopharyngeal (adenoids), tubal, and lingual tonsils

Genitourinary tract

Bronchus-associated lymphoid tissue (BALT)

Conjunctiva (or Eye)-associated lymphoid tissue (CALT or EALT)

Organized mucosa-associated lymphatic tissue (O-MALT)

 

5

Fundamental objectives of the mucosal immune system

  • Containment of the vast onslaught of environmental ____ without compromising the integrity of mucosal ___
    • Protect ___ ___ from pathogens (while still allowing for efficient ___ ___ ___ from external environ into host)
      • ____  infectious agents and prevent (pathogenic) microbial _____
    • Barrier function
      • Transport ____ across the ___ ___ (____ Sampling)
        • So that immune sys can recognize and respond to pathogens
      • Epithelial barrier separates the ___ immune tissue from the ____
  • Prevent ___ _____of the ___ compartment
    • Compartmentalization of ____ functions
    • Tolerate ____ and____antigens (___ ___)
      • Do not respond to ____ environmental antigens (like gluten)
      • Do not ____ the mucosal surface
    • Maintenance of mucosal homeostasis
  • ____ influence on ____ immunity
    • Focus of much vaccine work

Fundamental objectives of the mucosal immune system

Containment of the vast onslaught of environmental antigens without compromising the integrity of mucosal barriers

Protect mucous membranes from pathogens (while still allowing for efficient transfer of nutrients from external environ into host)

Clear infectious agents and prevent (pathogenic) microbial colonization

Barrier functionTransport antigens across the mucosal surface (Antigenic Sampling)

So that immune sys can recognize and respond to pathogens

Epithelial barrier separates the mucosal immune tissue from the lumen

Prevent over-stimulation of the systemic compartment

Compartmentalization of effector functions

Tolerate commensals and food antigens (Oral Tolerance)

Do not respond to harmless environmental antigens (like gluten)

Do not damage the mucosal surface

Maintenance of mucosal homeostasis

Regulatory influence on systemic immunity

Focus of much vaccine work

 

 

6

Mucosal Defense:

  • Non-immunologic barriers
    • Physical
      • ____ barriers
      • ______ ____
      • ____ of epithelium
      • ____
    • Physiological/Chemical
      • Gastric___ and ____
      • _____ secretions
  • Commensal bacteria
  • Immune system- innate and adaptive
    • Cellular
      • ___/___-___ response
      • ____
    • _____
    • ____ factors
      • C
      • C
      • S
      • D
      • P
      • L
      • L

Mucosal Defense:

Non-immunologic barriers

Physical

Epithelial barriers

Mucociliary escalator

Shedding of epithelium

Peristalsis

Physiological/Chemical

Gastric acid and bile

Mucous secretions

Commensal bacteria

Immune system- innate and adaptiveCellular

Cytotoxic/Cell-mediated response

Phagocytosis

Immunoglobulins

Soluble factors

Cytokines

Complement

Surfactant proteins

Defensins

Proteases

Lactoferrin

Lysozyme

 

 

 

7

Mucosal Defense: Epithelium as a Physical Barrier

Epithelial ___ junctions, ___ junctions, and_____ form a _____ (structural) barrier to prevent _____ passage

Don’t want free flow of stuff from external environment to underside of mucosa

Mucosal Defense: Epithelium as a Physical Barrier

Epithelial tight junctions, adherens junctions, and desmosomes form a paracellular (structural) barrier to prevent macromolecule passage

Don’t want free flow of stuff from external environment to underside of mucosa

8

Mucosal Defense: Physiological/Chemical Barriers

  • ____
    •  Low __ of ____ and ___
  • Molecular defenses
    • ____/____ secretions
      • ____, ____ enzymes, ____
    • C____
    • C___
    • M____

Mucosal Defense: Physiological/Chemical Barriers

Biochemical

 Low pH of stomach and vagina

Molecular defensesAntibacterial/antimicrobial secretions

Defensins, Hydrolytic enzymes, Lysozyme

Complement

Cytokines

Mucus

 

9

Mucosal Defense: Secretions

  • Mucins- form a ___ layer to ____ pathogens; ___of mucosal surface for passage of nutrients
    • Secreted from ____ cells in the epithelial layer
  • ____ peptides- promote epithelial ____
  • Antimicrobials (___, ___, & ____)- ____ effects on bacteria and fungi
    • Excreted into the ___
  • Cytokines- immune _____ effects
  • Antibodies/Immunoglobulins: _____and ___ foreign objects

Mucosal Defense: Secretions

Mucins- form a mucus layer to trap pathogens; lubrication of mucosal surface for passage of nutrients

Secreted from goblet cells in the epithelial layer

Trefoil peptides- promote epithelial healing 

Antimicrobials (defensins, cathelicidins, & RegIII)- microbicidal effects on bacteria and fungi

Excreted into the lumen

Cytokines- immune modulatory effects

Antibodies/Immunoglobulins- identify and neutralize foreign objects

 

10

Mucosal Defense: Microbiota

  • They outnumber human cells at least 10-100:1 (“you are only ____% human”)
  • Weight ~_ kg
  • Normal commensal flora maintain ____
    • Help ___ ____, etc.
    • Fill niches to prevent pathogenic bacteria from___
      • Secret ___ substances
      • ____ with pathogenic bacteria for nutrients or attachment to cell surfaces
    • Required for immune____ 
      • Germ-free rodents have reduced lymphoid __, low __, reduced immune ____ of all types
    • Help maintain ____

Mucosal Defense: Microbiota

They outnumber human cells at least 10-100:1 (“you are only 1-10% human”)

Weight ~1 kg

Normal commensal flora maintain health

Help metabolize cellulose, etc.

Fill niches to prevent pathogenic bacteria from colonizing

Secret toxic substances

Compete with pathogenic bacteria for nutrients or attachment to cell surfaces

Required for immune development

Germ-free rodents have reduced lymphoid organs, low Ig, reduced immune responses of all types

Help maintain tolerance

 

11

Detox: If we eat xenobiotic, they can convert it to ___ ___

Biosynthesis: secrete into the lumen for uptake by host ___ ___ or ____ that host can’t make

Immune maturation

Metabolic: Help digest ___ into __ __ ___, which have ___ and ____(_______) activities for the host

Protective: compete with pathogenic bacteria to exclude them 

Detox: If we eat xenobiotic, they can convert it to harmless metabolite

Biosynthesis: secrete into the lumen for uptake by host essential aa or vitamins that host can’t make

Immune maturation

Metabolic: Help digest fiber into short chain fa, which have catabolic and immunological (anti-inflammatory) activities for the host

Protective: compete with pathogenic bacteria to exclude them 

12

Mice with knocked out genes have changes in the ____

Genes influence___ and microbiota influence the ___

Mice with knocked out genes have changes in the microbiota

Genes influence microbiota and microbiota influence the host

13

Mucosal Defense: Cellular Barriers

Primary Functions:

  • Phagocytosis:
    • ____ and _____
    • Goble it up and destroy it
    • Macrophages also ____ it to adaptive immune cells
  • Cytokines
    • ____ cells and _____ secrete cytokines that will ____/____ immune response
  • Mucus
    • _____ cells secrete ___ that form ____ layer to prevent pathogens from ____ the host
  • Antigen Presentation
    • APC= ___ ___ involved in processing Ag from pathogens and presenting them to the immune system for identification and possible response
  • Antimicrobials
    • ____ Cells
  • Antibodies
    • B cells, plasma cells
  • Cytotoxic effects
    • ____ the ___ ___ itself
    • _____ ___ (mainly CD_)

Mucosal Defense: Cellular Barriers

Primary Functions:

Phagocytosis:

Neutrophils and macrophages

Goble it up and destroy it

Macrophages also present it to adaptive immune cells

Cytokines

CD4 T cells and macrophages secrete cytokines that will enhance/suppress immune response

Mucus

Goblet cells secrete mucins that form mucous layer to prevent pathogens from colonizing the host

Antigen Presentation

APC= Dendritic Cell involved in processing Ag from pathogens and presenting them to the immune system for identification and possible response

Antimicrobials

Paneth Cells

Antibodies

B cells, plasma cells

Cytotoxic effects

Within the epithelial layer itself

Interepithelial lymphocyte (mainly CD8)

 

 

14

Nomenclature of immune cells

 

Green mediates cross talk bw the two 

___
___ ____ 
____ ___ __

Nomenclature of immune cells

 

Green mediates cross talk bw the two 

NK

Gamma delta T cells

Innate Lymphoid Cells

15

Mucosal Defense: Epithelium as Orchestrators of Immune Response

In addition to the physical ____ function, the epithelial cells interact with innate and adaptive cells, via ___ ___ (i.e., cytokines, TSLP) and ___ ____, to regulate __ ___ and ___ ___

Epithelium provides the barrier fcn so you keep out pathogens

In addition, when epithelium encounters a pathogen, it can ___ ___ itself that will interact with underlying innate and adaptive immune cells to regulate the barrier fcn and initiate an immune response

Mucosal Defense: Epithelium as Orchestrators of Immune Response

In addition to the physical barrier function, the epithelial cells interact with innate and adaptive cells, via chemical messengers (i.e., cytokines, TSLP) and antigen presentation, to regulate barrier function and immune response.

Epithelium provides the barrier fcn so you keep out pathogens

In addition, when epithelium encounters a pathogen, it can secrete cytokines itself that will interact with underlying innate and adaptive immune cells to regulate the barrier fcn and initiate an immune response

16

Detection of Microbiota by Epithelial Cells through Cell-Surface Receptors

Epithelial cells use __ __ ____

Detection of Microbiota by Epithelial Cells through Cell-Surface Receptors

Epithelial cells use Toll like Receptors

17

TLR Expression in Intestinal Epithelial Cells

TLRs _ _ _ _ are expressed ____ in the ___ ____

TLRs have various specificities

TLR Expression in Intestinal Epithelial Cells

TLRs 2, 4, 5, and 9 are expressed apically in the small intestine.

TLRs have various specificities

18

Mucosal Defense: Epithelial Cell Types

Epithelium is rapidly __ ___and ___ regularly

4 unique cell types derived from common stem cell

  • ____ (____ epithelial)
    • ____nutrients
  • _____
    • Produce ___ __ & other _____ for ____ digestion
  • Goblet
    • Secretion of ____
  • Paneth
    • Secretion of _____
    • Disruption of function implicated in ileal ____ disease

Mucosal Defense: Epithelial Cell Types

Epithelium is rapidly self-renewing and shed regularly

4 unique cell types derived from common stem cellEnterocyte (absorptive epithelial)

Absorbs nutrients

Enteroendocrine

Produce Substance P & other neurohormones for regulating digestion

Goblet

Secretion of mucins

Paneth

Secretion of antimicrobials

Disruption of function implicated in ileal Crohn’s disease

 

19

Subpopulations of macrophages
Before, we just had a macrophage and it was thought to be proinflammatory.

In last few years we discovered there are subsets of macrophages, M1 and M2.

These can be further subdivided in M2A, M2B, M2C...

 

M1 are the ____ activated. Resting macrophage encounter pathogen in environment and in context of _____ stimuli (____, ____ ,____) they ____ into M1 cells that promote immune response and____

 

M2 are the ____ activated. Resting macrophage Come in contact with ______ stimuli (___) They will differentiate into M2 macrophages and promote ____regulation of the immune response

Subpopulations of macrophages
Before, we just had a macrophage and it was thought to be proinflammatory.

In last few years we discovered there are subsets of macrophages, M1 and M2.

These can be further subdivided in M2A, M2B, M2C...

 

M1 are the classically activated. Resting macrophage encounter pathogen in environment and in context of proinflammatory stimuli (TNF alpha, IFN gamma, LPS) they differentiate into M1 cells that promote immune response and inflammation.

 

M2 are the alternatively activated. Resting macrophage Come in contact with anti-inflammatory stimuli (IL-10) They will differentiate into M2 macrophages and promote down regulation of the immune response

20

Phagocytosis

Neutrophil take up pathogen. Merge with ___ ____ and degraded

Phagocytosis

Neutrophil take up pathogen. Merge with phagocytic lysosome and degraded

21

Neutrophil Killing Mechanism

Besides phagocytosis, neutrophils are___ line defenders, first line responders for most infections.

Neutrophils have other key effects.

Intracellular: Phagocytosis

Extracellular:

  • ___ ___ ___: They release granules and produce ROS to attack any sort of microbes
  • ___ ___ ___: Basically another form of ___ ___ that the neutrophils use to combat infection. It____ its ____ Chromatin becomes saturated with ____. It ____ that DNA into the environment. This forms a ___with antimicrobials on the net
  •  

Neutrophil Killing Mechanism

Besides phagocytosis, neutrophils are first line defenders, first line responders for most infections.

Neutrophils have other key effects.

Intracellular: Phagocytosis

Extracellular:

Reactive oxygen species: They release granules and produce ROS to attack any sort of microbes

Neutrophil extracellular traps (NETs): Basically another form of cell death that the neutrophils use to combat infection. It decondenses its chromatin. Chromatin becomes saturated with antimicrobials. It secretes that DNA into the environment. This forms a net with antimicrobials on the net

 

22

Human neutrophils form neutrophil extracellular traps (NETs) in response to signals from ___ ___ in addition to other stimuli.

 

Its for ___ ____ and unfortunately as you are excreting toxic things into the host, it can also lead to ___ and ___ ___

NET provides a capsule to prevent microbe from ___ ___ and localize it here. It is also meant to _____ antimicrobial peptides into an isolated area, so that they ___ ____ and cause further tissue damage. 

Human neutrophils form neutrophil extracellular traps (NETs) in response to signals from activated platelets in addition to other stimuli.

 

Its for antimicrobial defense and unfortunately as you are excreting toxic things into the host, it can also lead to vascular and tissue injury

 

NET provides a capsule to prevent microbe from spreading further and localize it here. It is also meant to concentrate antimicrobial peptides into an isolated area, so that they don’t spread and cause further tissue damage. 

23

Neutrophils lay ____ trails

As the first responders they can ___ the ____ immune cells to the ___ of ___

Neutrophils lay chemokine trails

As the first responders they can attract the adaptive immune cells to the area of infection