Phagocytosis and Clearance of the Offending Agent Explain this in easy English and make notes like presentation style like u explain topic to ma'am

Phagocytosis and Clearance of the Offending Agent The two major phagocytes are neutrophils and macro- phages. Although these cell types share many functional properties, they also differ in significant ways (Table 3.4). Recognition of microbes or dead cells induces several responses in leukocytes that are collectively called leukocyte activation (Fig. 3.7). Activation results from signaling path- ways that are triggered in leukocytes, resulting in increases in cytosolic Ca2+ and activation of enzymes such as protein kinase C and phospholipase A2. The functional responses that are most important for destruction of microbes and other offenders are phagocytosis and intracellular killing. Several other responses aid in the defensive functions of inflam- mation and may contribute to its injurious consequences. Phagocytosis Phagocytosis involves sequential steps (Fig. 3.8): • Recognition and attachment of the particle to be ingested by the leukocyte; • Engulfment, with subsequent formation of a phagocytic vacuole; and • Killing of the microbe and degradation of the ingested material. Phagocytic Receptors. Mannose receptors, scavenger receptors, and receptors for various opsonins enable phago- cytes to bind and ingest microbes. The macrophage mannose receptor is a lectin that binds terminal mannose and fucose residues of glycoproteins and glycolipids. These sugars are typically part of molecules found on microbial cell walls, whereas mammalian glycoproteins and glycolipids contain terminal sialic acid or N-acetylgalactosamine. Therefore the mannose receptor recognizes microbes and not host cells. Scavenger receptors were originally defined as molecules that bind and mediate endocytosis of oxidized or acetylated low-density lipoprotein (LDL) particles that do not interact with the conventional LDL receptor. Macrophage scavenger receptors bind a variety of microbes in addition to modified LDL particles. Macrophage integrins, notably MAC-1 (CD11b/CD18), may also bind microbes for phagocytosis. The efficiency of phagocytosis is greatly enhanced when microbes are coated with opsonins for which the phagocytes express high-affinity receptors. The major opsonins are immunoglobulin G (IgG) antibodies, the C3b breakdown product of complement, and certain plasma lectins, notably mannose-binding lectin and collectins, all of which are recognized by specific receptors on leukocytes. Engulfment. After a particle is bound to phagocyte receptors, extensions of the cytoplasm flow around it, and the plasma membrane pinches off to form an intracellular vesicle (phagosome) that encloses the particle. The phagosome then fuses with a lysosomal granule, which discharges its contents into the phagolysosome (see Fig. 3.8). During this process the phagocyte may also release lysosome contents into the extracellular space. The process of phagocytosis is complex and involves the integration of many receptor-initiated signals that lead to mem- brane remodeling and cytoskeletal changes. Phagocytosis is dependent on polymerization of actin filaments; it is thereforenot surprising that the signals that trigger phagocytosis are many of the same that are involved in chemotaxis. Intracellular Destruction of Microbes and Debris Killing of microbes is accomplished by reactive oxygen species (ROS), also called reactive oxygen intermediates, and reactive nitrogen species, mainly derived from nitric oxide (NO), and these as well as lysosomal enzymes destroy phagocytosed materials (see Fig. 3.8). This is the final step in the elimination of infectious agents and necrotic cells. The killing and degradation of microbes and dead cell debris within neutrophils and macrophages occur most efficiently after activation of the phagocytes. All these killing mecha- nisms are normally sequestered in lysosomes, to which phagocytosed materials are brought. Thus, potentially harmful substances are segregated from the cell’s cytoplasm and nucleus to avoid damage to the phagocyte while it is performing its normal function. Reactive Oxygen Species. ROS are produced by the rapid assembly and activation of a multicomponent oxidase, NADPH oxidase (also called phagocyte oxidase), which oxidizes reduced nicotinamide-adenine dinucleotide phos- phate (NADPH) and, in the process, reduces oxygen to superoxide anion (O2 • ). In neutrophils, this oxidative reaction is triggered by activating signals accompanying phagocytosis and is called the respiratory burst. Phagocyte oxidase is anenzyme complex consisting of at least seven proteins. In resting neutrophils, different components of the enzyme are located in the plasma membrane and the cytoplasm. In response to activating stimuli, the cytosolic protein compo- nents translocate to the phagosomal membrane, where they assemble and form the functional enzyme complex. Thus, the ROS are produced within the phagolysosome, where they can act on ingested particles without damaging the host cell. O2 • is converted into hydrogen peroxide (H2O2), mostly by spontaneous dismutation. H2O2 is not able to efficiently kill microbes by itself. However, the azurophilic granules of neutrophils contain the enzyme myeloperoxidase (MPO), which, in the presence of a halide such as Cl− , converts H2O2 to hypochlorite (HOCl˙), the active ingredient in household bleach. The latter is a potent antimicrobial agent that destroys microbes by halogenation (in which the halide is bound covalently to cellular constituents) or by oxidation of proteins and lipids (lipid peroxidation). The H2O2-MPO- halide system is the most potent bactericidal system of neutrophils. Nevertheless, inherited deficiency of MPO by itself leads to minimal increase in susceptibility to infection, emphasizing the redundancy of microbicidal mechanisms in leukocytes. H2O2 is also converted to hydroxyl radical (˙OH), another powerful destructive agent. As discussed in Chapter 2, these oxygen-derived free radicals bind to and modify cellular lipids, proteins, and nucleic acids and thus destroy cells such as microbes. Oxygen-derived radicals may be released extracellularly from leukocytes after exposure to microbes, chemokines, and antigen-antibody complexes or following a phagocytic challenge. These ROS are implicated in tissue damage accompanying inflammation. Plasma, tissue fluids, and host cells possess antioxidant mechanisms that protect healthy cells from these potentially harmful oxygen-derived radicals. These antioxidants are discussed in Chapter 2 and include (1) the enzyme superoxide dismutase, which is found in, or can be activated in, a variety of cell types; (2) the enzyme catalase, which detoxifies H2O2; (3) glutathione peroxidase, another powerful H2O2 detoxifier; (4) the copper-containing plasma protein ceruloplasmin; and (5) the iron-free fraction of plasma transferrin. Inherited deficiencies of components of phagocyte oxidase cause an immunodeficiency disease called chronic granu- lomatous disease (CGD), which is discussed in Chapter 6. Nitric Oxide. NO, a soluble gas produced from arginine by the action of nitric oxide synthase (NOS), also participates in microbial killing. There are three different types of NOS: endothelial (eNOS), neuronal (nNOS), and inducible (iNOS). eNOS and nNOS are constitutively expressed at low levels, and the NO they generate functions to maintain vascular tone and as a neurotransmitter, respectively. iNOS, the type that is involved in microbial killing, is induced when macrophages (and, to a lesser extent, neutrophils) are activated by cytokines (e.g., interferon-γ [IFN-γ]) or microbial products. In macrophages, NO reacts with superoxide (O2 • ) to generate the highly reactive free radical peroxynitrite (ONOO− ). These nitrogen-derived free radicals, similar to ROS, attack and damage the lipids, proteins, and nucleic acids of microbes (Chapter 2). Reactive oxygen and nitrogen species have overlapping actions, as shown by the observa- tion that knockout mice lacking either phagocyte oxidase or iNOS are only mildly susceptible to infections, but mice lacking both succumb rapidly to disseminated infections by normally harmless commensal bacteria. In addition to its role as a microbicidal substance, NO relaxes vascular smooth muscle and promotes vasodilation. It is not clear if this action of NO plays an important role in the vascular reactions of acute inflammation. Lysosomal Enzymes and Other Lysosomal Proteins. Neu- trophils and macrophages contain lysosomal granules that contribute to microbial killing and, when released, may cause tissue damage. Neutrophils have two main types of granules. The smaller specific (or secondary) granules contain lysozyme, collagenase, gelatinase, lactoferrin, plas- minogen activator, histaminase, and alkaline phosphatase. The larger azurophil (or primary) granules contain MPO, bactericidal proteins (lysozyme, defensins), acid hydrolases, and a variety of neutral proteases (elastase, cathepsin G, nonspecific collagenases, proteinase 3). Both types of granules can fuse with phagocytic vacuoles containingengulfed material, or the granule contents can be released into the extracellular space during “frustrated phagocytosis” (discussed later). Different granule enzymes serve different functions. Acid proteases degrade bacteria and debris within the phagoly- sosomes, which are acidified by membrane-bound proton pumps. Neutral proteases are capable of degrading various extracellular components such as collagen, basement mem- brane, fibrin, elastin, and cartilage, resulting in the tissue destruction that accompanies inflammatory processes. Neutral proteases can also cleave C3 and C5 complement proteins and release a kinin-like peptide from kininogen. The released components of complement and kinins act as mediators of acute inflammation (discussed later). Neutrophil elastase has been shown to degrade virulence factors of bacteria and thus combat bacterial infections. Macrophages also contain acid hydrolases, collagenase, elastase, phos- pholipase, and plasminogen activator. Because of the destructive effects of lysosomal enzymes, the initial leukocytic infiltration, if unchecked, can potentiate further inflammation by damaging tissues. These harmful proteases, however, are normally controlled by a system of antiproteases in the serum and tissue fluids. Foremost among these is α1-antitrypsin, which is the major inhibitor of neutrophil elastase. A deficiency of these inhibitors may lead to sustained action of leukocyte proteases, as is the case in patients with α1-antitrypsin deficiency, who are at risk for emphysema due to destruction of elastic support fibers in the lung because of uncontrolled elastase activity (Chapter 15). α2-Macroglobulin is another antiprotease found in serum and various secretions. Other microbicidal granule contents include defensins, cationic arginine-rich granule peptides that are toxic to microbes; cathelicidins, antimicrobial proteins found in neutrophils and other cells; lysozyme, which hydrolyzes the muramic acid-N-acetylglucosamine bond found in the glycopeptide coat of all bacteria; lactoferrin, an iron-binding protein present in specific granules; and major basic protein, a cationic protein of eosinophils, which has limited bacte- ricidal activity but is cytotoxic to many helminthic parasites. Neutrophil Extracellular Traps Neutrophil extracellular traps (NETs) are extracellular fibrillar networks that concentrate antimicrobial substances at sites of infection and trap microbes, helping to prevent their spread. They are produced by neutrophils in response to infectious pathogens (mainly bacteria and fungi) and inflammatory mediators (e.g., chemokines, cytokines [mainly interferons], complement proteins, and ROS). The extracel- lular traps consist of a viscous meshwork of nuclear chromatin that binds and concentrates granule proteins such as antimicrobial peptides and enzymes (Fig. 3.9). NET forma- tion starts with ROS-dependent activation of an arginine deaminase that converts arginines to citrulline, leading to chromatin decondensation. Other enzymes that are produced in activated neutrophils, such as MPO and elastase, enter the nucleus and cause further chromatin decondensation, culminating in rupture of the nuclear envelope and release of chromatin. In this process, the nuclei of the neutrophils are lost, leading to death of the cells. NETs have also been detected in the blood during in the NETs, which includes histones and associated DNA, has been postulated to be a source of nuclear antigens in systemic autoimmune diseases, particularly lupus, in which individuals react against their own DNA and nucleoproteins (Chapter 6). Leukocyte-Mediated Tissue Injury Leukocytes are important causes of injury to normal cells and tissues under several circumstances. • As part of a normal defense reaction against infectious microbes, when adjacent tissues suffer collateral damage. In some infections that are difficult to eradicate, such as tuberculosis and certain viral diseases, the prolonged host response contributes more to the pathology than does the microbe itself. • When the inflammatory response is inappropriately directed against host tissues, as in certain autoimmune diseases. • When the host reacts excessively against usually harmless environmental substances, as in allergic diseases, including asthma. In all these situations, the mechanisms by which leukocytes damage normal tissues are the same as the mechanisms involved in antimicrobial defense because once the leukocytes are activated, their effector mechanisms do not distinguish between offender and host. During activation and phagocytosis, neutrophils and macrophages produce microbicidal substances (ROS, NO, and lysosomal enzymes) within the phagolysosome; under some circumstances, these substances are also released into the extracellular space. These sepsis. The nuclear chromatin in the NETs, which includes histones and associated DNA, has been postulated to be a source of nuclear antigens in systemic autoimmune diseases, particularly lupus, in which individuals react against their own DNA and nucleoproteins (Chapter 6). Leukocyte-Mediated Tissue Injury Leukocytes are important causes of injury to normal cells and tissues under several circumstances. • As part of a normal defense reaction against infectious microbes, when adjacent tissues suffer collateral damage. In some infections that are difficult to eradicate, such as tuberculosis and certain viral diseases, the prolonged host response contributes more to the pathology than does the microbe itself. • When the inflammatory response is inappropriately directed against host tissues, as in certain autoimmune diseases. • When the host reacts excessively against usually harmless environmental substances, as in allergic diseases, including asthma. In all these situations, the mechanisms by which leukocytes damage normal tissues are the same as the mechanisms involved in antimicrobial defense because once the leukocytes are activated, their effector mechanisms do not distinguish between offender and host. During activation and phagocytosis, neutrophils and macrophages produce microbicidal substances (ROS, NO, and lysosomal enzymes) within the phagolysosome; under some circumstances, these substances are also released into the extracellular space. Thesereleased substances are capable of damaging host cells such as vascular endothelium and may thus amplify the effects of the initial injurious agent. If unchecked or inappropriately directed against host tissues, the leukocyte infiltrate itself becomes the offender, and indeed leukocyte-dependent inflammation and tissue injury underlie many acute and chronic human diseases (see Table 3.1). This fact becomes evident in the discussion of specific disorders throughout this book. The contents of lysosomal granules are secreted by leukocytes into the extracellular milieu by several mecha- nisms. Controlled secretion of granule contents is a normal response of activated leukocytes. If phagocytes encounter materials that cannot be easily ingested, such as immune complexes deposited on large surfaces (e.g., glomerular basement membrane), the inability of the leukocytes to surround and ingest these substances (frustrated phagocy- tosis) triggers strong activation and the release of lysosomal enzymes into the extracellular environment. Some phago- cytosed substances, such as urate crystals, may damage the membrane of the phagolysosome, also leading to the release of lysosomal granule contents. Other Functional Responses of Activated Leukocytes In addition to eliminating microbes and dead cells, activated leukocytes play several other roles in host defense. Impor- tantly, these cells, especially macrophages, produce cytokines that can either amplify or limit inflammatory reactions, growth factors that stimulate the proliferation of endothelial cells and fibroblasts and the synthesis of collagen, and enzymes that remodel connective tissues. Because of theseactivities, macrophages are also critical cells of chronic inflammation and tissue repair after inflammation has subsided. These functions of macrophages are discussed later in the chapter. In this discussion of acute inflammation, we emphasize the importance of neutrophils and macrophages. However, it has recently become clear that some T lymphocytes, which are cells of adaptive immunity, also contribute to acute inflammation. The most important of these cells are those that produce the cytokine IL-17 (so-called Th17 cells), discussed in more detail in Chapter 6. IL-17 induces the secretion of chemokines that recruit other leukocytes. In the absence of effective Th17 responses, individuals are susceptible to fungal and bacterial infections and tend to develop “cold abscesses,” particularly in the skin, that lack the classic features of acute inflammation, such as warmth and redness.Termination of the Acute Inflammatory Response Such a powerful system of host defense, with its inherent capacity to cause tissue injury, needs tight controls to minimize damage. In part, inflammation declines after the offending agents are removed simply because the mediators of inflammation are produced for only as long as the stimulus persists, have short half-lives, and are degraded after their release. Neutrophils also have short half-lives in tissues and die by apoptosis within several hours after leaving the blood. In addition, as inflammation develops, the process itself triggers a variety of stop signals that actively terminate the reaction. These active termination mechanisms include a switch in the type of arachidonic acid metabolite produced, from proinflammatory leukot- rienes to antiinflammatory lipoxins (described later), and the liberation of antiinflammatory cytokines, including transforming growth factor-β (TGF-β) and IL-10, from macrophages and other cells. Other control mechanisms that have been demonstrated experimentally include neural impulses (cholinergic discharge) that inhibit the production of TNF in macrophages. Explain this in presentation style like u explain topic to ma'am ain that way cover imp point and explain in easy way with same topic name and same sequence as book