Download 5 dent inflammation and mucosal immunity

5. Inflammation, mucosal immunity
1. Cell migration during the immune response
During the immune response not only the activity of individual cells, but their localization is
tightly regulated. Three families of molecules selectins, integrins and chemokines are
responsible for directing cell migration. The appearance and the concentration of these
molecules are spatially and/or temporally regulated. An example of spatial control is how the
migration of naïve lymphocytes to the secondary lymphatic organs is regulated. Only the
endothelial cells of secondary immune organs (high endothelial venule) are characterized by
the expression of a special selectin ligand (sialyl Lewis X / PNAd). Lymphocytes bearing L
selectin recognize this ligand and can exit from the circulation, but only in these areas. The
appearance of E and P selectins are regulated temporally. These molecules are expressed on
the endothelial surfaces around inflamed tissues only after the detection of pathogen or danger
signals. Thus, the extravasation of neutrophil granulocytes is restricted into the period of
inflammatory processes.
2. Acute inflammatory processes
2.1 The initial steps of inflammation
The inflammatory processes can be generated by pathogens or danger signals (tissue necrosis,
foreign body). Pathogen patterns (PAMP) induce same processes as the danger signals
(DAMP), so all the pathogen generated processes of inflammation corresponds to the
mechanisms developed during sterile inflammation. The recognition of PAMP or DAMP
signals induces rapid response, during which leukocytes, plasma proteins and fluid move into
the site of inflammation.
Beside macrophages, neutrophil granulocytes, IL -12 activated NK cells, and monocytes (exit
from the circulation and differentiate to tissue macrophages) are the most important cellular
components of inflammation. Memory T cells can also be critical contributors upon reinfection. At the same time, different plasma proteins, such as antibodies or the components
of different cascade systems might also get into the tissues form the vessels.
Firstly, pattern recognition receptors of macrophages (or mast cells) sense the PAMPs or
DAMPs and following it inflammatory cytokines are produced such as TNF, IL-1, IL-6, IL-12
and IL-8. (Mast cell additionally also release histamine and serotonin) The produced
cytokines (TNF, IL-1, IL-6) react in an autocrine manner and activate macrophages. On the
other hand by paracrine manner these cytokines regulate the function of vascular smooth
muscle cells and the endothelial layer. As a results of paracrine effects of inflammatory
cytokines selectins and integrins appear on endothelial cells and activated endothelial cell
start to produce more inflammatory factors together with the activated macrophages.
2.2 The migration of immune components during inflammation
(1.) Selectins: E and P selectins appear on the surface of activated endothelial cells and these
molecules are connected selectin ligands expressed constitutively on neutrophils and
monocytes. These interactions significantly slow down the movement of circulating cells, thus
these cells are held on the endothelial surface. At the same time chemokines are produced at
the site of inflammation and accumulate on the apical surface of endothelia, these chemokines
become also available for the leukocytes.
(2.) Chemokines, these special cytokines, regulate the movement of the cells. The cells are
directed toward the higher chemokine concentration using specific cell surface chemokine
receptor. IL-8 has been described as the major chemokine appearing during inflammation.
The selectin-selectin ligands fix the appropriate cells of circulation on the endothelial surface.
Chemokines are available here and the developed chemokine/chemokine receptor interactions
determine the direction of further movement of the cells and on the other hand on leukocytes,
chemokine receptor signals induce the change of integrins from inactive conformation to
active one.
(3) Inflammatory cytokines induce the appearance of integrins on endothelia and integrins
are activated on leukocytes (due to the effect of chemokines) resulting in integrin/integrin
interactions. These relationships affect on both cell function. The endothelial cells shrink and
the tight junction between the cells temporarily and reversibly terminated. At the same time
the integrin activated immune cells transmigrated through the endothelial cells. The
expression of different integrins may vary in time, thus the exit of different cell types from the
blood are determined in time. For example Lymphocyte function-associated antigen 1 (LFA1) molecule on neutrophil granulocytes instantly connect to Intercellular Adhesion Molecule 1
(ICAM-1), in contrary the Very Late Antigen-4 (VLA4) appears on monocytes and binds to
vascular cell adhesion molecule 1 (VCAM1) on the endothelium only 3-4 days after the onset
of inflammation. The further movement of the cells are determined by the concentration
gradient of chemokines in the inflamed tissues.
2.2 Symptoms of inflammation
Mainly the factors produced by macrophages and activated endothelial cells, and the products
of cascade systems (getting out form the blood) are responsible for the classical the symptoms
of inflammation: redness (rubor), swelling (tumor), warmth (calor), pain (dolor) loss of
function (function lesa) such components are platelet activating factor (PAF), prostaglandins,
NO, leukotrienes (which is produced also by mast cells and leukocytes). These factors are
continuously released, but at the site of the inflammation their production is significantly
enhanced, due to the effect of inflammatory cytokines.
NO and prostaglandins result in the relaxation of smooth muscle surrounding to blood vessels,
thereby causing vasodilation. The expansion of vessel diameter leads to increased blood flow
around the site of inflammation, which explains the symptoms of redness and warmth. In
addition to the integrin signaling, the permeability of the vessel wall is regulated by
leukotrienes, PAF and by histamine and serotonin.
The serum cascade systems (coagulation, complement, quinine and fibrinolytic systems) can
exit from the blood based on the increased permeability of vessel wall, which leads to their
activation.
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The coagulation system: the tissue factor localized in subendothelial layer activates the
extrinsic pathway of blood coagulation, thus clots are formed around inflammation.
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Activation of the kinin system results in bradykinin synthesis. Bradykinin increases
vascular permeability and it is important for the development of pain.
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Activation of the complement system leads to the destruction of pathogens directly
and indirectly via opsonization. In addition, it results in the production of
anaphylatoxins (C3a and C5a). These factors also increase the vascular permeability
and as chemotactic substances attract further leukocytes to the site of inflammation.
The increased vascular permeability cause swelling because the plasma and the cellular
components equally get into the tissues. Bradykinin and prostaglandins are primarily
responsible for the appearance of pain. Neutrophils are activated by leaving the blood vessel
where the PAMP and DAMP signals and the detection of opsonized pathogens cause further
activation. The activated neutrophils and macrophages produce soluble mediators to kill
pathogens. Over a range these lysosomal enzymes, oxygen metabolites, nitric oxide is also
harmful to the human cells, leading to cell death and thus resulting in loss of function.
Pus is the typical product of inflammatory processes, primarily composed of dead pathogens
and neutrophils. Since the detection of pathogens and danger signals trigger the same
response, the above mechanisms, such as tissue damage may develop in the absence of
pathogens.
2.3 The endocrine effects of inflammation
Beside the local functions, the inflammatory cytokines have endocrine effects.
The inflammatory cytokines
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in the brain influence on the Circumventricular Organ System (CVOS) which
ultimately results in prostaglandin synthesis in the hypothalamus. The whole process
leading up to the development of fever.
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in the liver results in a significant increase in the production of acute phase proteins.
These factors get into the inflamed tissue by the circulation. The C-reactive protein,
mannose binding lectin, serum amyloid protein binds directly to the pathogens
(actually may be considered as soluble pattern recognition receptors) and as opsonins
thereby promote phagocytosis and activate the complement system. The production of
several complement proteins and coagulation factors (fibrinogen, plasminogen) are
also drastically elevated.
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in the bone marrow facilitate the egress of neutrophils that are stored in the bone and
promote progenitor cells to produce further leukocytes.
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If a large amount of TNF is produced by reason of hyper intense inflammation,
systemic inflammatory response syndrome (SIRS) sepsis may develop. This can be
seen, for example due to the endotoxins released into the blood. The high
concentration of TNF inhibits myocardial contractility and vascular smooth muscle
tone, and in the same time increases the permeability of capillaries, which processes
cause significantly lower blood pressure, and finally block the functions of vital
organs that are essential for survival (multiorgan failure). Excessive activity of the
coagulation system results in disseminated intravascular coagulation, following it the
system is exhausted and severe bleeding can occur from various sites.
2.4 Tissue regeneration
Tissue regeneration begins in the final stage of inflammation. The process is controlled by M2
macrophages and fibroblasts. The type M2 macrophages differentiate primarily in the
presence of glucocorticoids, IL-10, TGF-β and IL-4. These cells produce immune suppressive
cytokines such as IL-10 and TGF-β. Releasing angiogenic and growth factors, M2
macrophages and fibroblast play a role in wound healing, tissue regeneration, angiogenesis
and regulate the rearrangement of extracellular matrix. As a result of the aforementioned
features, M2 macrophages significantly promote the development of tumors.
3. Chronic inflammation
Chronic inflammation differs from acute inflammation in certain processes and also in
cellular components. During the elongated inflammatory responses tissue destruction and
regeneration are simultaneously observed in addition to inflammatory processes. The
continuously produced cytokines and growth factors progressively modify the structure of the
affected tissue. Chronic inflammation can develop due to recurring or prolonged acute
inflammation, persistent infections (such as tuberculosis), allergens (such as hay fever),
autoimmune diseases (eg rheumatoid arthritis), toxic agents (lipids), foreign substance
(silicosis) or chronic irritation. (such as smoking)
Macrophages are essential participants in the chronic inflammation as well. At the site of
inflammation monocytes continuously exit from the vessels, followed by the activation of
macrophages. This activation may be a direct effect of pathogens or various danger signals or
a consequence of IFNy production by T cells and NK cells. Elastase, collagenase, NO is
produced by activated macrophages damaging the surrounding tissue. Activated macrophages
(mainly M2 macrophages) and the appearance of plasmin result in TGF-ß secretion, which
increases the activation of fibroblasts. Both the activated macrophages and fibroblasts release
various growth factors. (PDGF, FGF, VEGF, etc.) Depending on the tissue types, cells are
able to divide (hepatocytes, the cells of endocrine glans) or not (cardiomyocytes, neuron)
inducing tissue regeneration or fibrosis (for example in atherosclerosis).
Chronic inflammation is characterized by the appearance of additional cells beside
macrophage. Mast cells, granulocytes and because of the longer reaction, lymphocytes
migrate into the site of inflammation. The dominant cytokine production of helper T cells
(IFNy, IL-17, IL-6) determine the direction of further reactions, generating Th1, Th2 and
Th17 responses.
Granuloma is a special case of chronic inflammation serve to prevent spread of microbes. It
can appear as a results of foreign body (suture) infection (syphilis, tuberculosis, leprosy), but
it can be generated by non-infectious origin (eg Crohn's disease). The lack of phagocytosis
induces the fusion of macrophages to multinucleated giant cells, which are usually surrounded
by the layer of activated helper T cells.
MUCOSAL IMMUNITY
1. Mucosal immunity presents distinct features compared to the systemic immunity
It has been suggested that the mucosal immunity, as an ancient immune system is the original
vertebrate immune system and the spleen or other lymph nodes of the body are later
specializations. It is further supported by the fact that the central lymphoid organs, namely the
thymus and the bone marrow are derived from the embryonic intestine.
The thin epithelial (physical) barrier can be disrupted relatively easily and so its barrier
function needs to be supported by defenses provided by the cells and molecules of the
mucosal immune system. The tissues of the mucosal immune system are the lymphoid organs
associated with the intestine, respiratory tract and urogenital tract, as well as the oral cavity
and pharynx and the glands associated with these tissues, such as the salivary glands and
lachrymal glands. The mucosal lymphoid organs of the nose, mouth, skin, stomach, intestinal
tract, vagina and lungs belong together to the mucosa-associated lymphoid tissues (MALT).
These mucosal surfaces of the human body also serve as a habitat for a large amount of
microbes living together with the host. It has been proposed that the evolution of mucosal
surfaces could be linked to the need to deal with the vast populations of commensal bacteria,
Fungi, protozoa, Archaea, viruses which are called ‘microbiota’ and co-evolved with the
vertebrates. Several microbes use distinct parts of the human body as a habitat and live in with
it. This relationship can be mutual for both partners (symbionts) or neutral for the host
(commensal microbes). Some types of bacteria are opportunistic pathogens and these
microbes can invade the host when the abundance of mutual bacteria is decreased.
Enormous diversity of commensal bacteria determines individual functions acting on the
development and activities of the human mucosal immune system and indirectly the systemic
immunity. These involve specialized macrophage and dendritic cell (DC) subsets, expression
of unique pattern recognition receptor (PRR)-combinations coupled to evolutionally
conserved signaling pathways, induction of co-stimulatory molecules, secretion of cytokines,
chemokines and type I interferons. This complexity can directly be translated to Tlymphocyte polarization to support tolerance induction or inflammation locally. Collectively,
immune homeostasis in the human mucosa is maintained by both self and non-self factors
such as the microbiota, the epithelium and cells of innate and adaptive immunity that involve
T- and B-lymphocyte subsets and their secreted products and metabolites.
As the commensal microbiota contains several bacterial and fungal strains with unique
immunomodulatory and probiotic features, the immune system in the mucosa has to
distinguish between potential pathogens and harmless antigens, generating strong effector
responses to pathogens but remaining tolerogenic against food proteins and commensal
microbes. This mechanism is generated by DCs and tolerance against commensal microbiota
is maintained by the adaptive immune system, especially by regulatory cells (regulatory Tlymphocyte, Treg) and cytokines (interleukin-10/IL-10, transforming growth factor-ß/TGF-ß)
of the mucosa. In contrast to this, pathogens provoke T helper 1 (Th1) and Th17 immune
responses which normally result in the elimination of the infection. It should be noted that
commensal microbes leaving the mucosal surface and entering into the rest of the human
body via the blood circulation also induce a strong and specific, effector, systemic immune
response leading the elimination of the microbe.
Compared to the systemic immunity, the mucosal immune system develops several distinct
ways to protect the body from microbial invasion and environmental hurt:
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Anatomical features: (1) Intimate interactions between mucosal epithelium and
lymphoid tissue; (2) the circulation of lymphocytes within the mucosal immune system is
controlled by tissue-specific adhesion molecules and chemokine receptors; (3) discrete and
more organized lymphoid organs; (4) specialized antigen uptake.
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Effector mechanism: (5) The predominance of activated/memory lymphocytes even in
the absence of infection (physiological inflammation induced by the microbiota); (6) Multiple
activated ‚neutral’ effector and regulatory T cells present; (7) The production of dimeric IgA
as the predominant antibody.
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Immunoregulatory environment: (8) Active down regulation of immune responses to
innocuous antigens such as food antigens and commensals; (9) Inhibitory macrophages and
tolerogenic DCs.
2. Some subsets of immune and non-immunocompetent human cells are uniquely
abundant in the mucosa
In the human gastrointestinal tract multiple cell types become to intimate contact with a huge
load of commensal and potentially pathogenic microbes (pathobionts). Common and
specialized epithelial cells, macrophages, resident DCs together with lymphocytes act in
concert to maintain the balance between the host’s immune system and the microbial flora. In
the mucosal surfaces, effector cells are found in two main compartments: the epithelium and
the lamina propria (LP). These tissues are quite distinct in immunological terms, despite being
separated by only a thin layer of basement membrane. Moreover, the total number of
lymphocytes in the epithelium and LP probably exceeds that of most other parts of the body.
Intestinal epithelial cells lining the small and large bowel are an integral part of the
gastrointestinal innate immune system, involved in responses to pathogens, tolerance to
commensal organisms, and antigen sampling for delivery to the adaptive immune system in
the gut. The epithelium contains mainly intraepithelial lymphocytes, which cells play role in
innate immunity in the small intestine. The intraepithelial T cells do not have antigen
receptors but they produce cytokines followed by the non-specific recognition of the microbe.
These cytokines stimulate the epithelium, DCs and macrophages and recruit the antigen
specific memory and effector T cells.
Microfold (M) cells, Goblet cells and Paneth cells are specialized epithelial cells with
different functions. M cells, as it is described below have a role in luminal antigen transport to
the LP in the gut and respiratory tract. In the crypts of intestinal villi, Goblet cells
continuously produce glycosylated proteins, called mucins playing role in chemical defense
against microbes. Several different mucins form a viscous physical barrier that prevents
microbes from contacting the cells of the gastrointestinal tract. Moreover, the mucus-layer
serves as a surface for penetration of symbiotic bacteria. The secretory function of Goblet
cells is mediated by environmental factors such as cytokines and chemokines produced by
myeloid cells and microbiota specific effector T cells. Paneth cells secrete anti-microbial
peptides such as defensins which play role in inhibiting the invasion of bacteria.
The LP is much more heterogeneous compared to the epithelium, with large numbers of CD4+
and CD8+ T cells, as well as plasma cells, macrophages, DCs and occasional eosinophils and
mast cells to maintain gut and respiratory homeostasis. These cells are continuously exposed
to foreign antigens derived from diet and the resident microflora. Under physiological
conditions the LP is conditioned by all-trans retinoic acid (ATRA) produced by epithelial
cells, DCs, macrophages and stromal cells. ATRA acts as an immunomodulator of DC and
induces the expression of mucosa-specific homing receptors in T-lymphocytes and supports
regulatory T-cell differentiation. The effector lymphocytes that are generated in the draining
lymph nodes or MALT of a particular regional immune system (skin, small bowel) will enter
the blood and preferentially home back to the same organ (dermis, LP).
The special environment of LP makes B cells to switch the isotype of their antigen-specific
BCR from IgM and IgD to IgA in both T-dependent and independent manner. These B cells
may differentiate to secretory IgA producing plasma cells or memory B-cells.
Innate lymphoid cells that produce IL-17 and IL-22 are found mainly in the mucosa and
contribute to immune defense against some bacteria as well as to mucosal epithelial barrier
function.
Natural B-1 cells are also abundant in the mucosal surfaces and together with intraepithelial T
lymphocytes without antigen receptor serve as a first line of defense against microbial
presence. These natural B-1 cells may deliver the process of isotype switching from IgM to
IgA in the presence of TGF-ß but they do not perform the T-cell dependent affinity
maturation on their B cell receptor.
3. Specialized luminal antigen uptake in the mucosal surfaces of the intestinal and
respiratory tract
Soluble antigens such as food proteins and microbes might be transported directly across or
between enterocytes, or there might be M cells in the surface epithelium outside a specific
mucosal organ called Peyer's patches. Luminal antigens have several routes to get to the LP
where these antigens are engulfed and processed by DCs or macrophages.
A) Humoral antigens are transported by passive diffusion from the lumen to the lamina
propria.
B) M cells can internalize luminal samples and transport intact antigens to the DCs in the
LP. M cells are found in the small bowel epithelium, and in three different locations in
the respiratory tract namely the follicle-associated epithelium (FAE) of nasalassociated lymphoid tissue, the respiratory epithelium and the inducible bronchusassociated lymphoid tissue (iBALT) FAE overlying Peyer’s patches and LP lymphoid
follicles. Unlike neighboring epithelial cells with tall microvillus borders and primary
absorptive functions, M cells have shorter villi and engage in transport of intact
microbes or molecules across the mucosal barrier into the MALT, where they are
handed off to DCs. On its basal side, the M cell develops a pocket-like structure that
can hold immunocompetent cells. Because lysosome development in M cells is poor,
in most cases the incorporated antigens are just passed through the M cells unmodified
and then taken up by DCs. In addition to M cells, DCs that are located in the LP
directly take up luminal antigens by extending their dendrites.
C) Mucosal DC has access to luminal content and is able to sense and internalize bacteria
by several PRRs. Moreover, contact and uptake of bacteria may modify DC
differentiation, DC subset distribution, DC activation and pro-inflammatory cytokine
secretion. Mucosal DCs are able to directly sample antigens from the lumen by their
interepithelial lamellipodia (dendrits). These DC populations are efficient inducers of
local commensal-specific Th17 and Treg polarization.
D) Enterocytes can capture and internalize antigen-antibody complexes by means of the
FcRn on their surface and transport them across the epithelium by transcytosis. At the
basal face of the epithelium, LP dendritic cells expressing FcRn and other Fc receptors
pick up and internalize the complexes. FcRn expressed on epithelial cells bind to
immuncomplex and via transcytosis these complexes are transported to the basal
membrane of epithelia where APCs recognize these immuncomplexes.
E) Dying cells are also serve as a route for luminal antigen transfer. Captured antigens are
stored in apoptotic vesicles which are engulfed by subepithelial dendritic cells and
macrophages. After their activation they migrate to the local draining lymph node and
activate T-lymphocytes. An enterocyte infected with an intracellular pathogen
undergoes apoptosis and its remains are phagocytosed by the mononuclear
phagocytes.
4. The adaptive immune responses of the mucosal immunity are driven by the
special tissue microenvironment and professional antigen presenting cells
Commensal bacteria are recognized by the immune system but this is limited to the mucosa
and its draining lymphoid tissues, because they are presented to T cells by DCs that migrate
from the intestinal wall and migrate into the draining mesenteric lymph node. Mucosal DCs
regulate the induction of tolerance and immunity in the mucosa. Under normal conditions,
DCs acquire antigens derived from foods or commensal organisms and take these antigens to
the draining mesenteric lymph node, where they present them to naive CD4+ T cells. There is,
however, constitutive production by epithelial cells and mesenchymal cells of molecules such
as TGF-ß, thymic stromal lymphopoietin (TSLP), and prostaglandin E2 (PGE2), which
maintain the local DCs in a semi-mature state with low levels of co-stimulatory molecules, so
that when they present antigen to naive CD4+ T cells, both anti-inflammatory and regulatory
T cells are generated. These polarized T-cells recirculate back to the original mucosal tissue
and maintain tolerance to the harmless antigens. Treg cells accumulate in the mucosa,
producing IL-10 and TGF-ß, which help to prevent commensal-specific Th1 and Th17 cells
from causing overt inflammation. These effector cells also contribute to maintain the local
symbiotic relationship between the host and microbiota. For example, the Th17-derived IL-17
stimulates the production of IL-22 and antimicrobial peptides, which helps to restrict
epithelial penetration of local bacteria.
The gut-derived dendritic cells are specialized to support the differentiation of naïve B cells to
immunoglobulin (Ig) A secreting plasma cells or memory B cells in both direct (production of
NO, IL-10, ATRA) and indirect manner (priming of helper T lymphocytes). The commensal
bacteria covered by IgA antibodies are less effective to penetrate on the surface of mucosa
and cannot induce a longlasting inflammation.
The IgA class switching of mucosal B-cells can be induced by both T-dependent and Tindependent mechanisms. In T-dependent IgA class switching, DCs in the subepithelial dome
of Peyer's patches capture bacterial antigens delivered by M cells and migrate to the
interfollicular zone, where they present antigen to naive CD4+ T cells. Meanwhile the
activated T cells differentiate into polarized helper T cells, the naïve B-cells specific for the
same antigen are also become activated. The polarized T-cell performs immunological
synapses with the activated B-cell which presents antigens via MHCII to the T-cell. The
helper T-cell further stimulates the B-cell via CD40-CD40L interaction in the presence of
TGF-ß and this process leads to the class switch from IgM to IgA. The differentiation of Bcells with T-cell help leads to memory B cell and secretory IgA (sIgA) producing plasma cells
in the LP. The IgA class switching may be enhanced by NO derived from DCs, which
upregulates TGF-β receptor on B cells. This T cell–dependent B-cell differentiation yields
high-affinity IgA antibodies that preferentially target protein components of bacterial cell
wall, viruses and toxins.
The T-independent IgA class switching involves dendritic cell activation of IgM+IgD+ B cells,
including B-1 cells. TLR ligand–activated DCs secrete factors that induce IgA class switch,
including BAFF, APRIL, and TGF-β. This T cell–independent pathway yields relatively lowaffinity IgA antibodies to intestinal bacteria.
In the IgA plasma cells, membrane IgA (mIgA) and a J-chain are assembled to form sIgA just
before its externalization. The J-chain is required for the interaction between IgA and poly-Igreceptor (pIgR). The sIgA binds to poly-IgR expressed on the basal membrane of epithelial
cells. The complex is transported across the epithelial cell by transcytosis, and the bound IgA
is released into the lumen by proteolytic cleavage. The role of sIgA is pivotal for example in
the respiratory tract to neutralize viruses. There are at least three mechanisms of virus
neutralization mediated by sIgA in the respiratory tract: (1) sIgA recognizes the viral epitope
and inhibits attachment to the epithelial cells; (2) pIgA can sense and then eliminate viruses
that invade the lamina propria; or (3) Viruses that have invaded the cell can be recognized by
pIgA–pIgR complexes during their transcytosis.
Appendix (Non-obligatory)
The relationship between diet, microbiota and health: the hygiene hypothesis
Evidence now exists for bidirectional communication between the three key factors in the
gastrointestinal tract: diet, immune system, and commensal microflora. Diet can have a
profound influence on the immune system (eg. vitamin A, vitamin D), and the immune system
can also affect nutrient uptake. Diet also has dominant influence on the composition and
metabolic capacity of commensal bacteria, while this, in return, influences nutrient
absorption. The immune system is able to exert control over both commensal composition and
localization, whereas commensal signals are critical for development and function of the
immune system. In addition to combating infection, these regulatory interactions may have
had a wider influence on the evolution of the gut and the immune system, being one of the
factors underlying the hygiene hypothesis. According to this idea, the human immune system
has evolved in the face of continued exposure to ubiquitous pathogens and commensals,
whose immunomodulatory products have helped to condition the polarization of responses to
other foreign antigens. With the increasing cleanliness of the human environment, our
immune system is no longer exposed to this influence during the critical early period of life,
allowing hypersensitivity reactions of all kinds to develop unchecked against self antigens and
harmless environmental substances. As the main source of exposure to environmental
microbes, the intestine is heavily involved in these processes. In particular, there is clear
evidence that the increasing incidence of disorders such as type 1 diabetes, Crohn's disease,
and atopy correlates specifically with the eradication of immunomodulatory organisms such
as helminths and Helicobacter pylori from the Western world.