Lecture 13: GI Immunology (Grosche) Flashcards
fxs of the mucosal immune system
1) maintains immunological homeostasis along the epithelial surface in oral/nasal/respiratory/GI/urogenital cavities and tracts
2) mediates symbiotic relationship b/w host and endogenous microorganism
3) first line of physical and immunological defense against invading pathogens
MALT
mucosa-associated lymphoid tissue
NALT
nasopharynx-assoc. lymphoid tissue
BALT
bronchus-assoc. lymphoid tissue
GALT
gut-associated lymphoid tissue
inductive site
regional MALT and follicle-associated epithelium containing microfold (M) cells. (M cells transport organisms and particles from the gut lumen to immune cells across the epithelial barrier, and thus are important in stimulating mucosal immunity)
3 examples of antigen-presenting cells. What do they do?
dendritic cells, macrophages, B cells. Prime naive B and T cells to become effector cells
what is the largest lymphoid organ in the body?
the gut
major fxs of the GI tract
1) digestion/absorption of nutrients
2) barrier function
3) immune response
Components of mucosal defense mechs.
- extramucosal components
- intact mucus epithelium
- subepithelial/submucosal microcirculation and nervous system
- mucosal immune system
- ability of mucosa to undergo repair
extramucosal components of mucosal defense mechanisms
- saliva
- HCl
- digestive enzymes
- water and electrolytes
- mucus
- immunoglobins
- normal peristalsis
- normal commensal microflora
indigenous gut flora include 2 groups:
autochthonous (those with an evolutionary symbiotic relationship) and allochthonous flora (those with some pathogenic potential)
non-indigenous gut flora include:
environmental flora (non-gut organisms acquired from the environment)
what part of the gut are gram neg. and anaerobic bacteria more commonly found?
distal GI tract (past ileum)
protective fxs of normal gut flora
- pathogen displacement
- nutrient competition
- production of anti-microbial factors to attack pathogens
metabolic fxs of normal gut flora
- control of epithelial cell differentiation and proliferation
- synthesis of vitamins
- fermentation of non-digestible digestible dietary residues and mucus
- ion absorption
- salvage of energy
- production of by-products
structural fxs of normal gut flora
- barrier fortification
- induction of IgA
- tightening of tight junctions
- immune system development
Where are Peyer’s patches located?
small intestine
where are lymphoid follicles located?
throughout entire gut
Describe the structure and function of a Peyer’s patch
Domes of tissue covered by an epithelial layer and M cells. M cells come into contact with luminal antigens and transport them to antigen-presenting cells. T cells, B-cells and memory cells are stimulated upon encountering antigen. These cells then pass to the mesenteric lymph nodes where the immune response is amplified. Activated lymphocytes pass into the blood stream and travel to the gut where they carry out their final effector functions.
describe structure of the mucosal epithelium
- monolayer of intestinal epithelial cells
- apical junction complex
- overlaying mucus layer
what do goblet cells produce? What is its function?
mucus. Acts as physical barrier/bacterial adhesion/antibacterial substance
main regulators of adaptive immunity
epithelial cells
How do intestinal epi. cells effect innate immunity?
they maintain the density of apical microorganisms (antimicrobial peptides, neutrophils)
3 components of the intestinal epithelial cell physical barrier
- microvilli of brush border
- tight junctions
- glycocalyx and thick mucus layer
compare the responsiveness to bacteria at the luminal surface of intestinal epithelial cells to the crypts in the epithelium
Low responsiveness at the luminal surface to commensal bacteria. However, the crypts must be kept sterile to protect the stem cells that reside there. The crypts have special receptors (paneth cells) that recognize microbes and activate a pro-inflammatory mechanism if bacteria invade
transcellular vs. paracellular pathways through the intestinal epithelial barrier
transcellular: pathway for molecules to move directly across the epithelial cells; mediated with receptors and channels. (90%)
paracellular: substances move across barrier BETWEEN cells through tight junctions and adherens junctions. (10%)
ileal transport of IgG in neonates
used for uptake of immunoglobulins from collostrum during the first 24hrs of life. IgG binds to Fc receptors on apical membrane and is transported to basolateral membrane via endocytosis
What is the apical junction complex?
controls paracellular pathway via tight junctions and adherens junctions. Regulates permeability of the GI tract
fxs of adherens junctions
maintains cellular proximity and intercellular communication. Required for assembly of tight junctions
fxs of tight junctions
- hold cell together
- maintain cell polarity
- regulate paracellular permeability
immune cells of the lamina propria of the mucosal immune system
- plasma cells
- T and B cells
- Dendritic cells
- Macrophages
- mast cells
immune cells of the epithelium of the mucosal immune system
effector T cells
the main immunoglobulin of the GI tract
IgA
functions of secretory IgA
- binds pathogens/toxins
- neutralizes intracellular LPS
- exports pathogens/toxins to apical surface
- limits access of pathogens to mucosal surfaces w/o risking inflammatory damage
how does the nervous system regulate mucosal immunity?
modulation via sympathetic, parasympathetic, and local peripheral nervous system. Transmitters, hormones, and receptors all help modulate a normal immune response (i.e. neuroendocrine hormones regulate cytokine balance)
Mechanisms of intestinal tolerance to commensal bacteria
- bacteria have impaired ability to escape mucus/invade epithelial barrier, low endotoxicity, and they inhibit the inflammatory pathway
- mucosal epithelium has reduced expression of receptors and permanent activation of anti-inflammatory response
- lamina propria has tolerogenic dendritic cells macrophages, and T cells, and produces anti-inflammatory cytokines
Response of mucosal immune system to pathogens
- recognition by complement, NK cells
- inflammatory response
- activation of adaptive immune system
- destruction of pathogens + immunity
failure to eradiate pathogens or to discriminate self from non-self leads to:
pathogen proliferation (sepsis), autoimmunity and allergy
How is inflammation resolved?
- neutrophil infiltration stopped
- uptake and clearance of apoptotic cells and microorganisms
- antimicrobial activity of mucosal epithelial cells stimulated
- switch to biosynthesis of anti-inflammatory and pro-resolution lipid mediators (lipoxins, resolvins, protectins)
Process of mucosal restitution and repair
- villus contraction
- restitution (migration of epithelial cells to seal exposed membrane)
- closure of leaky intercellular spaces (tight junctions)
- initiated by mediators released from nerves, immune effector cells, myofibroblasts, endothelial cells, extracellular matrix
- “repair” occurs after “restitution”
