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The Mucosal Immune System
The epithelial surfaces of the body are exposed to many pathogens and antigens
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Thus a
sophisticated, continual immune response is required in order to keep invasions under control
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The thin epithelial layer is related to the function of these systems: gas exchange in the lungs, food
absorption in the gut, sensory activities in the mouth, nose, eyes, skin and throat, reproduction in the
uterus and the vagina
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Some non-pathogenic antigens enter the immune system via the epithelial layer
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An estimated 10-15kg of protein is consumed on average per year
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They are known as the commensal
microorganisms as they live in complete harmony with our bodies
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However, responding to this would be a
waste and not beneficial for the host
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g
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The diversity of commensal bacteria found in
each area of the mucosal tissues
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As a result the mucosal
immune system plays a crucial role in preventing and fighting infection
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When compared to the lymph nodes and spleen (the systematic immune system) it has many unusual
features
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They prevent immune response to food and other nonharmful antigens (e
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gut flora, pollen)
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IgA is the most common antibody used in the mucosal immune system because it can cross epithelia
easily
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Immunoregulatory environment- we are eating a lot of stuff which comes through the gut but most of it
does not trigger an immune response this is due to tolerance
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The mucosal immune system may have been the first immune response to develop
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Organised lymphoid tissues have
been found in the gut of primitive cartilaginous fishes (vertebrates)
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The lymph nodes and the spleen are thought to have
specialised and evolved later
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Under the epithelium layer, lies the lamina propria layer (the connective tissue holding these structures
together)
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The epithelium is renewed regularly to replace damaged epithelial cells
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There are about 100-200 Peyer’s patches in the
human intestine
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They have a distinctive domelike appearance because of the aggregation of
lymphoid cells in the intestinal lumen
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The sub-epithelial dome is rich
in dendritic cells, T cells and B cells
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The vili are closely associated with Peyer’s patches
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Overlaying the epithelial tissues and separating them from the gut lumen is a layer of follicle- associated
epithelium
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2) M cells- associated with the mucosal immune system- no microvilli, folded membrane; they are
more submerged than enterocytes and have completely different structure
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Next to the Peyer’s patches you see the isolated lymphoid follicles; they are present both in the small
intestine and the colon
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Distinct from Peyer’s
patches which are present in fetus, but the isolated lymphoid follicles are thought to appear in response
to the commensal microbiota after birth
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Antigens must cross the epithelium before they can stimulate an immune response
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The M cells in the follicle associated epithelium are the front line of the
mucosal immune system
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It is all taken up to the other side of the epithelial
layer not exposed to the lumen where there are a lot of immune cells waiting
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The dendritic cells undergo the
process of antigen presentation and then present the
antigen to the T lymphocytes
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g
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The antigen loaded
dendritic cells migrate from the dome region to the T
cell areas of Peyer’s patch or via the draining lymphatics to the mesenteric lymph node
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The dendritic cells can extend processes between the cells of the epithelium without
disturbing the integrity of the layer to pick up antigens and bacteria from the gut lumen
without the help of M cell
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In the intestine these effector cells are found in two compartments: the epithelial layer and
the lamina propria
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The vast majority of the lymphocytes in the epithelial layer are CD8+ T cells
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The lamina propria contains CD4+ and CD8+ T cells, plasma cells, macrophages, dendritic cells,
eosinophils and mast cells
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The total number of lymphocytes in the epithelium and the lamina propria
probably exceeds that of most other parts in the body
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Naïve T and B cells circulating in the blood stream are not
predetermined as to which compartment of the immune system they will end up in
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CCL21 and CCL19 are released from the peripheral lymphoid tissues and bind to the CCR7 receptor on
the naïve lymphocytes
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If they do not
encounter an antigen the lymphocytes will leave the area via the efferent lymphatics and will return to
the blood stream
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However, dendritic cells upon encounter with naïve T cells
imprint them to express CRR9 (specific to the intestine) which is recognized by the CCL25 and integrin
α4β7
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g
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After activation but before differentiation the T cells exit
the Peyer’s patches via the draining lymphatics, passing the mesenteric lymph node, and end up in the
thoratic duct
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They are specifically attracted by the chemokines to enter the lamina propria of the vili
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This triggers it to
enter the lamina propria of the intestine
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Cells which need to enter the epithelial later stop expressing α4β7 and start
expressing αEβ7 which is recognized by E-cahedrin on the surface of epithelial cells
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The MAdCAM-1 receptor is expressed in other mucosal surfaces, which means that cells with a coreceptor that can be recognized by MAdCAM-1 can enter these tissues
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This is referred to as common mucosal
immune system
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E
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antigens in breast milk which pass through to the
intestine of the baby
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It is produced locally by
plasma cells located in the mucosal wall
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IgA1 is produced in the bone marrow and found as a monomer
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The IgA1:IgA2 ratio in the blood is 10:1
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The ratio of IgA1:IgA2 in the mucosa is 3:2
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Class switching is mediated by cytokine transforming growth factor TGF-β
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Selective pressure against individuals with low IgA2
might have led to higher expression of IgA2 in the mucosal layers
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IgA is produced in the lamina propria but has to be transported to the lumen to pursue its function
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They express a polymeric immunoglobulin receptor which has a
high affinity for J-chain linked immunoglobulins
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Part of the cleaved receptor remains on the IgA; it is referred to as
secretory component and the antibody is known as secretory antibody
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The IgA which hasn’t been taken up by the epithelial
cells is transported to the liver via the hepatic portal vein
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This
has no significance in humans as our hepatocytes do not have poly-Ig receptor
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Its main function is to protect the mucosa without triggering
inflammation which may damage the epithelial cells
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This prevents pathogens from
binding to the gut and neutralizes their toxins
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IgA can also enter epithelial cells and neutralize lipopolysaccharides that have entered the cells
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IgA deficiency is common in Caucasian populations
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IgM is good at replacing IgA (because it is also dimeric) and higher IgM
numbers are found in IgA deficient patients
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The mucosal immune system contains unusual T lymphocytes
In the intestine the T lymphocytes are found in two distinct layers: the lamina propria and the
epithelium
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Most of these cells have markers associated with memory cells
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These cells proliferate poorly in response to antigens and mitogens
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The function of the CD4 cells
in a healthy gut is unknown (they may help plasma cells produce IgA or be regulatory T cells which help
prevent hypersensitivity to food and commensal microbiota), but they are known to cause tissue
damage to the epithelium during inflammation
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The intraepithelial lymphocytes are quite distinct
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More than 90% of the lymphocytes in the epithelial layer are Tcells and around 80% of those are
CD8 T cells (in contrast to the lamina propria)
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There is a
restricted used of V(D)J recombination suggesting local expansion in response to a small number of
antigens
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There are two types of intraepithelial antigens: type a and type b
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They have an α:β T cell receptor and an CD8α:β
heterodimer
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They function
as CD8+ cytotoxic MHCI T cells and kill virus infected cells
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Type b lymphocytes also release cytokines and act as cytotoxic T cells
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They have either an α:β or γ:δ T cell receptor
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These cells do not undergo negative selection in the thymus and appear to be autoimmune but
there is no expression of CD8 α:β so they cannot self-react as they don’t bind to conventional
antigen:MHC complexes
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They are
probably involved in a process called agonist selection where late double negative/ early double positive
T cells are positively selected in the thymus by relatively high affinity ligands
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In the intestine they undergo further
positive selection by non-classical MHC ligands
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NKG2D binds to two MHClike molecules MICA and MICB which are expressed in the intestinal epithelial cells in response to
cellular injury and stress
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These lymphocytes appear to be important in the repair process after the damaged cells are
destroyed
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MICA-dependent
cytotoxic activity is enhanced in celiac disease which is associated with tissue damage and increased
number of epithelial lymphocytes
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Epithelial cells
The epithelial cells do not express TLRs or CD14 (an essential part of TRL-4 which detects
lipopolysaccharides) so they cannot detect bacteria in the lumen, however, they do express TLR5 which
is able to recognise flagellin
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There are also the NOD1 and NOD2 proteins (related to TLRs) internally
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This
results in activation of NFkB pathway in the epithelial cells and the subsequent release of cytokines ,
chemokines and defensins
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This leads to the influx of lymphocytes which induce the innate immune response and activate the
adaptive immune response if needed
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Injury and stress to enterocytes stimulates the activation of MICA and MICB which are recognised by
NKG2D receptor on NK cells
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Many pathogens use M cells for invasion e
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salmonella, HIV, Yersinia
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Once delivered to the subepithelial space, these pathogens can cause way more damage
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Once in the lumen the pathogens
interact with TLRs of the immune cells and once engulfed cause caspase-dependent apoptosis of that
cell
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Tolerance to commensal microbiota and beneficial antigens
Oral tolerance- state specific peripheral unresponsiveness develops to oral administration of protein
antigen
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g
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If the same protein antigen is then injected there is
still no immune response
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Mucosal tolerance- respiratory system, tests show results as above^
The immune responses suppressed by oral tolerance are those which induce the inflammatory response
(T cell, IgE more than IgG)
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Oral tolerance is likely to include anergy and the deletion of antigen-specific T cells and the production
of T regulatory cells which produce IL-10 (it plays an important role in mucosal tolerance)
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TGF-β helps B cells
switch to IgA production which is a non-inflammatory antibody
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It may be used like a vaccine to prevent certain diseases
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Reproducing this success in clinical trials has shown little success
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In small amounts they are eliminated and do
no harm as they lack virulence
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Response to the commensals leads to inflammatory bowel diseases
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Abnormal responsiveness to these commensals may
drive this response e
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NOD2 mutation found in 30% Crohn’s disease patients
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Yet they seem to suppress T effector cell
responses and stimulate local IgA production
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DC:commensal directly activate B cells to differentiate into noninflammatory IgA secreting plasma cells
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When these DC present antigens to T cells, the T cells differentiate into antiinflammatory Treg rather than Th1 or Th2
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Responses to helminth infection
Th2 response is mounted against worms (helminths)
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The Th2 response produces IL-3, IL-4, IL5, IL9 and
IL13 in large amounts which triggers the production of IgE by B cells
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IL-5 recruits andactivates eosinophils which induce cytotoxicity via MBP or ADCC against IgG coated
worms
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IL-3 and IL-9 recruit mucosal mast cells which bear IgE produced by the B cells
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g
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This can
remodel the gut structure by destroying the basal membrane between the epithelium and the lamina
propria
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These mast cells also attratc leukocytes and stimulate
goblet cells to produce mucus
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Helminth responses to infection
- Produce mediators to dampen the innate immune response
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- Skew differentiation of T cells into Tregs
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- Produce a state of persistent infection without damage to the host
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