1-22 Mucosal Immunity Flashcards
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
What are 2 strategies of mucosal immunity?
Exclusion
Immunosuppression
What is the primary function of mucosal immunity?
Provide defense at all mucosal surfaces
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
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
What is GALT? What does it consist of?
Gut-Associated Lymphoid tissue – GALT
Consist of mucosal follicles: Peyer’s patches
What is an “afferent” lymphoid area?
Antigen is entering at these sites
How does GALT differ from systemic immune system tissues?
Antigen influx occurs across a mucosal epithelium
Not through blood or lymph
What are the cellular components of a mucosal barrier?
Enterocytes (IEC), basement membrane, tight junctions, normal flora
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
What are commensals?
Normal flora
Physical barrier limiting colonization by pathogens
Must distinguish between beneficial & pathogenic
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.
What 2 compartments make up the mucosal immune system?
epithelium
lamina propria
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
What are M cells?
Microfold cells
Flattened epithelial cells
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
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
What are Dome cells?
Mucosal dendritic cells
- a type of APC
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
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
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.
What are Intraepithelial lymphocyte (IELs)?
Mature differentiated T-cells
- Most are CD8+ T-cells (80%)
- Significant population express a / TCR
- 10-40% - normal <5%
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
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
What is the efferent lymphoid area of the mucosal tissue?
Lamina propria
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
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
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
Are B cells in the lamina propria? Where are they located?
B-1 cells present
Follicular areas
Contained in the germinal centers
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”
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
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
What are some limitations of sIgA?
Does not fix complement
Allows for clearance of immune complexes without inducing inflammation
What is the most common primary immunodeficiency in world?
Selective IgA
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
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
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
What binds IgA heavy chains?
J-chain
What happens to SC after sIgA is released?
During release of sIgA SC is cleaved and is degraded
- SC is not recycled
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
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
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
What is oral tolerance?
State of immunological unresponsiveness to Ag induced by feeding.
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
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)
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)
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
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?
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
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?
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
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
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
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
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
