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Transcript
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.