Mucosal Immunity Flashcards
What is the primary function of mucosal immunity?
Provide defense at ALL mucosal surfaces: GI, respiratory, and urogenital
What are the 2 secondary functions of mucosal immunity?
Prevent Ags from entering into circulation
Prevent a systemic immune response to an inappropriate Ag exposure
What is the major difference between mucosal immunity and systemic immunity?
Mucosal immunity = tolerant
Systemic immunity = active
What effect does low dose oral administration of Ag have on GALT?
Induction of Th2 and TGF-beta secreting regulatory cells
Active suppression and immunologic hyporesponsiveness
What effect does high dose oral administration of Ag have on GALT?
Deletion or anergy of Th1 and Th2 cells
Clonal anergy and clonal depletion leading to immunologic hyporesponsiveness
___________ is a mechanism of mucosal immune regulation that minimizes direct contact between bacteria and epithelial surface
Stratification
What components of mucosal immunity participate in stratification, that is minimization of direct contact between bacteria and epithelial surfaces?
Mucins
Anti-bacterial proteins
IgA
______ is a mechanism of mucosal immune regulation that confines bacteria to intestinal sites and limiting systemic exposure
Compartmentalization
What components of mucosal immunity participate in compartmentalization, which confines bacteria to intestinal sites and limits systemic exposure?
Action of phagocytes in lamina propria
Homing of activated lymphocytes to mucosal surfaces
Immunity in mucosal tissues:
Cell types undergo _______ development
Cells respond differently to Ag in that B cells are skewed toward _____ production
Mucosa encounters very different antigens and uses different ______ signals
Alternative
IgA
Homing
T/F: there is regional preference in mucosal immunity (intestine to intestine, lung to lung, etc.)
True
_________ ________ is the process by which s-IgA/mucin provides a barrier to macromolecular absorption
Immune exclusion
During immune exclusion, which is the process by which sIgA/mucin provides a barrier to macromolecular absorption, binding of antigen at the mucosal surface by s-IgA leads to ________ of the Ag in the mucous layer, subjecting it to __________
Entrapment; degradation
IgA is _________ and __________, which is what allows it to trap Ag effectively in mucous layers
Hydrophilic; mucophilic
What aspect of innate mucosal immunity has mucus secreting barrier function and antibacterial?
Goblet cells
What aspect of innate mucosal immunity has barrier and antibacterial functions?
Epithelial cells
What aspect of innate mucosal immunity are the antibacterial secreting cells?
Paneth cells
What aspect of innate mucosal immunity participate in antigen sampling?
M cells
What 2 cell types participate in barrier function in mucosal immunity?
Enterocytes
Normal flora
What non-cellular aspects of mucosal immunity have barrier function?
Digestive activity - pepsin, papain, trypsin, chymotrypsin, pancreatic proteases, lactoferrin, lactoperoxidase, lysozyme
Mucin - protective barrier between a pathogen and the mucosal epithelium, reservoir for sIgA
Intestinal epithelial cells, or enterocytes, participate in absorption of nutrients via the _____ border.
They are joined by _______ ________ apically and basally which prevents the passage of macromolecules
Brush
Tight junctions
What type of antigen presentation is performed at intestinal epithelial cells?
Nonprofessional
Nonprofessional antigen presentation and inducible cell surface molecules result in selective activaiton of _____ and ______ T cells at intestinal epithelial cells
CD8; regulatory
There is constant translocation of ____ at intestinal epithelial cells, as well as inducible ______, which may result in cross-linking –> fluid and electrolyte secretion
sIgA
FceR
Where are the innate receptors for bacterial PAMPs expressed in mucosal immunity?
In the cytoplasm and basolateral membrane, NOT on luminal surfaces
DCs in lamina propria also express low levels of TLRs
The functional response in mucosal immunity is biased towards an ________________ response
Anti-inflammatory
[this limits inflammation in GI tract]
The first susceptibility gene identified for Crohn’s disease was a _______ family member, a receptor for the muramyl dipeptide structural unit of bacterial peptidoglycan
NOD (NOD2)
IgA transport requires ________ ________, which cycles from basal to apical membrane regardless of whether IgA is present or not
Secretory component
What ensures that SC is not a limiting factor during an immune response?
It is constitutively made by epithelial cells and cycles regardless of whether IgA is present or not
What binds to IgA heavy chains and facilitates its transport?
J-chain
What happens to SC when s-IgA is released from its vesicle into the lumen?
SC is cleaved and is degraded (it is not recycled, only used once)
________ cells are Peyer’s patch dome cells that are modified at both apical and basolateral surfaces
Microfold (M) cells
What is the purpose of Microfold (M) cells?
Found at dome of peyer’s patch; promote uptake and transport of luminal contents - “sampling” mechanism
T/F: Microfold (M) cells transfer processed Ags only, because they must fit through the cell itself
False! Microfold cells transfer whole Ags only, NO processing takes place
What CD marker is found on the specialized intestinal DCs in the GALT?
CD103+
[these are regulatory DCs]
Where are CD103 DCs found?
In GALT: under basolateral membrane of IECs and M cells so that they can extend dendrites directly to sample
What do CD103+ intestinal DCs produce in terms of mediators and cytokines?
Where do they travel to present to T cells?
Produce retinoic acid (RA) and produce primarily anti-inflammatory cytokines: TGF-beta, IL-10, and IL-2
Travel to mesenteric LNs to present to T cells
What are the two primary functions of mucosal humoral immunity and IgA?
Neutralization
Enhancement of innate immune factors
What is the primary function of mucosal cell-mediated immunity?
Suppression!
There is a high percentage of Treg cells, regulatory CD103+ DCs, and TGF-beta, IL-10, and IL-2
What type of B cell is abundant in GALT?
B-1 cells
Mostly IgA expressing plasma cells or IgA surface expressing cells
[IgG and IgM plasma cells are found infrequently]
GALT is considered a reservoir for __________ antibodies
Natural
[during times of inflammation, these cells can increase IgG and IgM expressing cell populations, which are not usually as common]
What is the physiologic role of serum IgA?
Unknown/unclear
Serum IgA in humans is mostly __________
In terms of its physiological role (which is unclear), mucosal Ag that gets into circulation will not induce a systemic _________ response
Monomeric
Inflammatory
What form of IgA functions as a neutralizing Ab, serum or secretory?
Secretory
Does secretory IgA fix complement?
NO
Thus it will not induce an inflammatory response. It prevents colonization without inflammation
What GI movement allows for clearance of IgA-Ag immune complexes without inducing inflammation?
Peristalsis
Most intraepithelial lymphocytes are ______ cells
CD8+ T cells
The majority of intraepithelial lymphocytes (IELs) are CD8+ T cells. What other cells are present?
CD4+ gamma/delta T cells
Large population of Tregs (produce large amounts of anti-inflammatory cytokines)
Where do gamma/delta T cells typically “live”
In epithelial/mucosal compartments (make up 10-40% of the T cell pop)
Gamma/delta T cells can be differentiated from alpha/beta T cells in that:
They recognize _____ Ags
They can be directly activated by ______ and ________
They do not seem to be ______-restricted
Lipid
PAMPs; DAMPs
HLA
Th17 cells in the gut are protective against _________ and __________
They are influenced by ______ cells
Extracellular bacteria; fungi
Dendritic
________ cells’ inflammatory activity in the gut is balanced by Tregs and anti-inflammatory cytokines
Th17
What cytokine is needed for induction of tolerance in the mucosa?
TGF-beta
Retinoic acid produced by DCs in the gut
What are some host factors associated with oral tolerance?
Digestion, physical barriers, GALT, immune cells, immune regulation
What are some environmental factors associated with oral tolerance?
Breastfeeding
Time of introduction of solid food
Intestinal flora
What are some management factors associated with oral tolerance?
AIT
Probiotics
What are some immune regulation mechanisms associated with oral tolerance?
Tregs Effector T's DCs TLRs IL-10 TGF-beta IgA IgG4
What is the most common primary antibody deficiency?
Selective Ig-A deficiency
[genetic, most are never diagnosed, usually found incidentally or by recurrent sinus infections]
Why are most selective Ig-A deficiencies never diagnosed?
IgM also has a J chain and is able to cross the mucosa
What are the 3 categories of diseases related to inappropriate mucosal immune responses?
- Inflammatory bowel disease (crohns and UC)
- Food allergies
- Celiac disease
How would you differentiate between the two types of inflammatory bowel diseases: Crohn’s disease and Ulcerative Colitis
Crohn’s: affects entire thickness of bowel wall
Ulcerative colitis: restricted to colonic mucosa
In what part of the intestine does Crohn’s disease most frequently affect?
Terminal ileum
What are the 2 dysregulated aspects of the innate immune system in IBD?
Defective defensin expression
Inadequate negative immune regulation to commensal organisms
What are the 2 abnormal aspects of cell-mediated immunity in IBD?
Overactive Th17 response
Granulomatous inflammation by IFN-y producing Th1 cells
IBD may result from defective _________ T cell function, due to FOXP3 and IL-2 or IL-2R deficiencies
Regulatory
Aside from dysregulated innate immune responses, abnormal cell-mediated immunity, and defective regulatory T cell function, another immunologic abnormality in IBD may be defective __________, which is an intracellular degradation system that usually delivers cytoplasmic constituents to the lysosome
Autophagy
Conditions of malnutrition and starvation result in:
Mucosal ________
Increase in intestinal __________
Decrease in cytokines ____ and _____
Change in the ___:____ ratio (1:1)
Decrease in antibody ______
Atrophy
Permeability
IL-4; IL-10
CD4+:CD8+
sIgA
In conditions of malnutrition and starvation, what are the two methods of restoring nutrition?
TPN: Total parenteral nutrition
EN: enteral nutrition
TPN vs. EN has trauma and surgical implications due to shock cytokines TNF, IL-1, and IL-6, as well as ACTH and cortisol risks.
What are the potential biological complications?
Sepsis, multi-organ failure, hypermetabolism
TPN vs. EN has trauma and surgical implications due to shock cytokines TNF, IL-1, and IL-6, as well as ACTH and cortisol risks.
Which nutrition restoration method causes significant changes in the lymphocyte population and carries a high rate of sepsis?
TPN
What are the three general types of food allergies in terms of immunological classification?
IgE mediated
Non-IgE mediated (Th2 mediated)
Mixed (both IgE and Th2)
Which type of food allergy is most common in young children and results in acute or chronic cutaneous symptoms or anaphylaxis?
IgE mediated (food-specific IgE is made)
What type of food allergy results in chronic skin and/or GI symptoms as well as eosinophilic disorders?
Non-IgE mediated (Th2 mediated)
