1-22 Mucosal Immunity Flashcards Preview

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Flashcards in 1-22 Mucosal Immunity Deck (55):
1

What is the largest immune tissue?

Mucosal Tissues
Surface area: 200 X skin
Largest immune tissue:
¾ all lymphocytes
Majority of Igs
Function(s): thin & permeable
Vulnerable

2

What are 2 strategies of mucosal immunity?

Exclusion
Immunosuppression

3

What is the primary function of mucosal immunity?

Provide defense at all mucosal surfaces

4

What is a secondary function of mucosal immunity?

Prevent antigens from entering into the circulation

Prevent a systemic immune response to an inappropriate antigen exposure

5

What is unique about mucosal immunity?

Unique population of immune cells that undergo alternative development

Unique mucosal immunoglobulin (sIgA)

Distinct antigenic environment

Use different homing signals

6

What is GALT? What does it consist of?

Gut-Associated Lymphoid tissue – GALT
Consist of mucosal follicles: Peyer’s patches

7

What is an “afferent” lymphoid area?

Antigen is entering at these sites

8

How does GALT differ from systemic immune system tissues?

Antigen influx occurs across a mucosal epithelium

Not through blood or lymph

9

What are the cellular components of a mucosal barrier?

Enterocytes (IEC), basement membrane, tight junctions, normal flora

10

What are the acellular components of a mucosal barrier?

Digestive activity:
- pepsin, papain, trypsin, chymotrypsin, pancreatic proteases (unfavorable living environment)
- lactoferrin, lactoperoxidase, lysozyme (inhibit microbe growth)

Defensins

Peristalsis

Mucin: Protective reservoir for sIgA

11

What are commensals?

Normal flora

Physical barrier limiting colonization by pathogens

Must distinguish between beneficial & pathogenic

12

How do commensals protect against infection?

By colonizing a surface so that it resembles rush hour on a Tokyo subway.

Out-competes most invading pathogens for space, resources.

Sheer numbers keep potentially pathogenic normal flora in check.

13

What 2 compartments make up the mucosal immune system?

epithelium
lamina propria

14

How do intestinal epithelial cells contribute to mucosal immunity?

Joined by tight junctions apically and basally
- Prevent passage of macromolecules

Nonprofessional antigen presentation and inducible cell surface molecules
- Selective activation of CD8+T

Constant translocation of sIgA

Inducible FcER (IL-4)
cross-linking leads to fluid & electrolyte secretion

15

What are M cells?

Microfold cells

Flattened epithelial cells

16

What do M cells do? Are they APCs? Specific?

Distinguished by ability to pinocytose material

Transport material in an un-degraded form

Express HLA class II but DO NOT act as antigen presenting cells

Possibly some specificity involved - normal flora not transported

17

What is the mechanism for M cells?

M cells take up antigen by endocytosis and phagocytosis

Ag is transported across the M cells in vesicles and released at the basal surface

Ag is bound by DCs, which then activates T cells

18

What are Dome cells?

Mucosal dendritic cells
- a type of APC

19

Where are Dome cells located prior to migration? Why are they located here?

Dense band of dendritic cells
just below the epithelium & through it
- bacteria induced homing

Dome cells can extend processes across the epithelial layer to capture Ag from the gut

Can uptake antigen emerging from M-cells

20

Where do Dome cells migrate to? What do they do?

Migrate to the inter-follicular areas

Present antigen to T-cells
InduceTreg proliferation
IL-10

21

How are Dome cells important for digestion/absorption?

Retinoic acid synthesis

Only DCs in the gut express retinal dehydrogenases (RALDH) which is necessary for the synthesis of retinoic acid from vitamin A.

22

What are Intraepithelial lymphocyte (IELs)?

Mature differentiated T-cells
- Most are CD8+ T-cells (80%)
- Significant population express a / TCR
- 10-40% - normal <5%

23

What are some important features of the cellular processes of IELs?

Proliferate POORLY

Produce large amounts of cytokines: IL-10, TGFb

Have normal CTL activity after activation

24

What is the defensive process mediated by IELs?

Virus infects mucosal epithelium cell

Infected cell displays viral peptide to CD8+ IEL via MHC I

Activated IEL kills infected epithelial cell by perforin/granzyme release and Fas-dep pathways

25

What is the efferent lymphoid area of the mucosal tissue?

Lamina propria

26

What are the immune cells associated with the lamina propria?

Chief APCs - are DCs
MOs - alternatively activated
NK cells
Mast cells
Polys only in inflammation

27

What is the T-cell population of the lamina propria like?

Mainly CD4+ (few CD8+ 3:1)
/ TCR
CD4+ similar to peripheral Treg cells
- Except they express CD45RO

Proliferate poorly

Produce large amounts of cytokines
- IFNγ, IL-5, IL-10

28

What other T-cells are in the gut? Why? What are their characteristic cytokines?

Th17
Murine models indicate that Th17 cells play a role in colonization and protection of the gut
IL-17 and IL-22 characteristic cytokines


Th2
Th2 cells protect against helminthic infections
IL-4 and IL-13 characteristic cytokines

29

Are B cells in the lamina propria? Where are they located?

B-1 cells present

Follicular areas
Contained in the germinal centers

30

What happens when B-1 cells are activated?

When activated, proliferate & class-switch to IgA

Mostly IgA expressing plasma cells or IgA surface expressing cells

IgG and IgM plasma cells are also found infrequently & increase in during inflammation

Self-renewing

Reservoir of “natural antibodies”

31

Where do most of the body's activated B cells reside? What does this make the gut?

Plasma cells and Memory Cells
80% of the body’s activated B cells reside in the gut lamina propria

1010 IgA PC/meter bowel
The gut is the largest Ab producing “organ”

Very little migration to bone marrow

32

What is the role of secretory IgA?

Protective role of secretory-IgA (sIgA):
Neutralize biologically active antigens
- viruses, toxins and enzymes

Prevent uptake of antigens by the intestinal tract

Inhibit adherence of bacteria to epithelial surfaces

Enhance innate immune factors

33

What are some limitations of sIgA?

Does not fix complement
Allows for clearance of immune complexes without inducing inflammation

34

What is the most common primary immunodeficiency in world?

Selective IgA

35

What is the structure and function of sIgA?

External secretions contain polymeric forms of IgA

IgA dimer associated with additional peptides
- J-chain (joining)
- secretory component (SC)

SC is derived from various epithelial cells

Assembled molecule of sIgA is a product of two entirely different cells types

sIgA molecule is much less susceptible to proteolytic cleavage

36

How is sIgA transported?

IgA bound to receptor on basolateral face of epithelial cell

Endocytosis

Transcytosis to apical face of epithelial cell, via vesicles

Release of IgA dimer at apical face of epithelial cell

37

What ensures that SC isn't limited during an immune response?

SC is constitutively made by enterocytes (IECs)
- cycles from the basal to apical membrane regardless of whether IgA is present or not

ensures SC is not limiting during an immune response

38

What binds IgA heavy chains?

J-chain

39

What happens to SC after sIgA is released?

During release of sIgA SC is cleaved and is degraded
- SC is not recycled

40

What is immune exclusion in the context of gut mucosa?

Process by which sIgA/mucin provides a barrier to macromolecular absorption

Primary: binding of Ag at the mucosal surface by sIgA

Can bind Ag during transport or prior to transport

41

How can IgA neutralize threats?

Secreted IgA on gut surface can bind and neutralize pathogens and toxins

IgA is able to being and neutralize antigens internalized in endosomes

IgA can export toxins and pathogens from the lamina propria while being secreted

42

What is mucosal homing?

Immune cells developing in one mucosal site migrate as effector cells to the lamina propria of other distal mucosal sites.

Gut-specific homing signals imprinted on naïve lymphocytes by DCs

43

What is oral tolerance?

State of immunological unresponsiveness to Ag induced by feeding.

44

What properties of immune cells in the gut does oral tolerance depend on?

Most lymphocytes in the mucosal tissues have markers/secretion patterns associated with activation
Display many characteristics of a chronic inflammatory response
Overt disease is rare

Robust Suppressive Mechanisms
Exclusion (Tight junctions, IgA & commensals)
Polarized PRRs (TLRs)
Th regulatory cells
Tolerance-inducing DCs
Ag dosing

45

What happens to T-cell populations with oral tolerance?

Anergy (high dose)
Deletion of Ag-specific T cells (high dose)
Generation of regulatory Ts (low dose)

46

What is the role of Th reg cells in oral tolerance?

Th reg:
Produce IL-4, 10 and TGF-β

Mucosal origin & activated by mucosal presentation of Ag.

Function is to control/suppress immune responses in the mucosa.

Oral tolerance leads to expansion of Th reg population(s)

47

How does malnutrition/starvation affect gut mucosal immunity?

Mucosal atrophy
Increase of intestinal permeability
Decrease in IL-4 & IL-10
CD4+:CD8+ ratio changes (1:1)
Decrease sIgA

48

What does TPN and EN imply about gut immunity?

TPN: significant changes in the
lymphocyte population

Higher rate of sepsis than EN

Need for physical stimulus?

49

What is the pathology of leaky gut?

Irritants to gut

breakdown of mucosa IgA and tight jxn proteins

increased permeability

intestinal barrier dysfxn

food allergy and intolerance

immune system abnormalities

autoimmunity

Influence on the BBB and neuroautoimmunity

50

What is the etiology and associated symptoms of leaky gut?

Hyper-permeability of the gut mucosal layer

Tight junctions loosen

Caused by inflammatory reactions

Pro-inflammatory cytokines
Alcohol, toxins, antibiotics, infections, foods, etc.

Inappropriate immune response to Ags

Cramping, diarrhea, gas, bloating, constipation
IBD?

51

What are the symptoms of an IgE mediated food allergy?

Rapid onset (minutes to hours)

Acute or chronic cutaneous symptoms or generalized anaphylaxis

Gastrointestinal anaphylaxis: nausea, vomiting, cramping (minutes) diarrhea (hours)

Oral allergy syndrome: pollen

Most prevalent in young children

52

What are the symptoms of a non-IgE mediated food allergy?

Non-IgE mediated: Th2-cell mediated

Chronic skin and/or GI symptoms

Food protein-induced enterocolitis

Food protein-induced proctitis

Eosinophilic gastroenteritis

53

What is the theory and symptoms of childhood food allergies?

Very Common: milk, eggs, etc.

Theory: mucosal barrier not complete until around 4 years of age. (Leaky Gut)

Symptoms: GI, skin
Atopic dermatitis: early infancy (40%)
Extreme pruritis (chronic)
Associated with asthma/rhinitis (30%)

Most are “outgrown”

Anaphylactic responses: not outgrown

54

What are some symptoms of adult food allergies?

Mainly GI: gas, bloating, diarrhea, constipation
Cutaneous presentations: urticaria
Mimic many other GI disorders
Rhinoconjunctivitis
Oral allergy: contact allergy
Sensitivities: migraines

55

What is oral immunotherapy? How does it work - what immune cells does it change?

Ingest the food antigen

Little chance of systemic reaction

Once at maintenance, can continue at home

Promotes blocking s-IgA production

Low dose Ag to promote Treg

Must continue ingestion for continued tolerance
Milk, egg, peanut