Download 12 inflammation

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.

The coagulation system: the tissue factor localized in subendothelial layer activates the
extrinsic pathway of blood coagulation, thus clots are formed around inflammation.

Activation of the kinin system results in bradykinin synthesis. Bradykinin increases
vascular permeability and it is important for the development of pain.

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

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.

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.

in the bone marrow facilitate the egress of neutrophils that are stored in the bone and
promote progenitor cells to produce further leukocytes.

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.