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![Recognition of Microbes and Dead
Tissues
Leukocyte – Receptors:
1. Toll-like receptors (TLRs)
2. G protein–coupled receptors
Found on neutrophils, macrophages
Recognize:
Bacterial peptides with N-formylmethionyl residues
Chemokines
Products of complement such as C5a
Lipid mediators [PAF, PGs, and LTs]
Ligand binding induces
Extravasation
Production of microbicidal substances (ROS).
v3-CSBRP-May-2012](https://image.slidesharecdn.com/inflammation-4-csbrp-120815183156-phpapp02/75/Inflammation-4-9-2048.jpg)
![Recognition of Microbes and
Dead Tissues
Leukocyte – Receptors:
1. Toll-like receptors (TLRs)
2. G protein–coupled receptors
3. Receptors for opsonins:
Leukocytes express receptors for proteins that coat
microbes
Opsonins include: Ig, C, and lectins
Phagocytes have:
• FcγRI (for Fc fragment)
• CR1 (for C3b)
• Receptor for plasma Lectins [mannan-binding lectin]
Receptors promotes phagocytosis
v3-CSBRP-May-2012](https://image.slidesharecdn.com/inflammation-4-csbrp-120815183156-phpapp02/75/Inflammation-4-10-2048.jpg)
Uploaded byPrasad CSBR
Inflammation 4
The document discusses leukocyte receptors that recognize microbes and dead tissues. It describes four main classes of leukocyte receptors: Toll-like receptors, G protein-coupled receptors, receptors for opsonins, and receptors for cytokines. Toll-like receptors bind to microbial products and mediate cellular responses. G protein-coupled receptors recognize bacterial peptides and chemokines. Receptors for opsonins promote phagocytosis by binding immunoglobulins, complement proteins, and lectins. Receptors for cytokines such as interferon-gamma activate leukocytes. The document then discusses the removal of microbes via recognition by receptors, leukocyte activation, phagocytosis, and intracellular and extracellular killing mechanisms. It also notes
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Inflammation 4
- 1. Inflammation and Repair -4 Dr.CSBR.Prasad, M.D. v3-CSBRP-May-2012
- 2. Recognition of Microbesand Dead Tissues 3Rs • Recruitment • Recognition • Removal v3-CSBRP-May-2012
- 3. Recognition of Microbesand Dead Tissues Leukocytes express several receptors that recognize external stimuli and deliver activating signal v3-CSBRP-May-2012
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- 7. Recognition of Microbesand Dead Tissues Leukocyte – Receptors: 1. Toll-like receptors (TLRs) 2. G protein – coupled receptors 3. Receptors for opsonins 4. Receptors for cytokines v3-CSBRP-May-2012
- 8. Recognition of Microbesand Dead Tissues Leukocyte – Receptors: 1. Toll-like receptors (TLRs) Bind microbial products 10 mammalian TLRs have been identified Mediate cellular responses to bacterial products LPS / Endotoxin Bacterial proteoglycans Lipids Unmethylated CpG nucleotides (abundant in bacteria / viruses) Function through receptor-associated kinases to stimulate the production of microbicidal substances and cytokines by the v3-CSBRP-May-2012 leukocytes
- 9. Recognition of Microbesand Dead Tissues Leukocyte – Receptors: 1. Toll-like receptors (TLRs) 2. G protein–coupled receptors Found on neutrophils, macrophages Recognize: Bacterial peptides with N-formylmethionyl residues Chemokines Products of complement such as C5a Lipid mediators [PAF, PGs, and LTs] Ligand binding induces Extravasation Production of microbicidal substances (ROS). v3-CSBRP-May-2012
- 10. Recognition of Microbesand Dead Tissues Leukocyte – Receptors: 1. Toll-like receptors (TLRs) 2. G protein–coupled receptors 3. Receptors for opsonins: Leukocytes express receptors for proteins that coat microbes Opsonins include: Ig, C, and lectins Phagocytes have: • FcγRI (for Fc fragment) • CR1 (for C3b) • Receptor for plasma Lectins [mannan-binding lectin] Receptors promotes phagocytosis v3-CSBRP-May-2012
- 11. Receptors for opsonins v3-CSBRP-May-2012
- 12. Recognition of Microbesand Dead Tissues Leukocyte – Receptors: 1. Toll-like receptors (TLRs) 2. G protein–coupled receptors 3. Receptors for opsonins 4. Receptors for cytokines: Leukocytes express receptors for cytokines Interferon-γ (IFN-γ) IFN-γ is the major macrophage-activating cytokine v3-CSBRP-May-2012
- 13.
- 14. Removal of theOffending Agents v3-CSBRP-May-2012
- 15. Removal of theOffending Agents 1. Recognition of microbes by the receptors 2. Leukocyte activation: o Increase in cytosolic Ca2+ & o Activation of enzymes: Protein kinase C and Phospholipase A2 1. Destruction of microbes o Phagocytosis and o Intracellular killing v3-CSBRP-May-2012
- 16. Killing & Degradation •Antibacterial substances kill the bacteria • Killed bacteria are degraded by the hydrolytic enzymes • These mechanisms may not degrade some eg: Myc.TB v3-CSBRP-May-2012
- 17. Killing & Degradation Followingmechanisms facilitate this process: A. INTRACELLULAR Mechanisms: 1. Oxidative – by free radicals of O2 i. MPO-dependednt ii. MPO-independent 2. Oxidative – by lysosomal granules 3. Non-oxidative mechanisms B. EXTRA CELLULAR Mechanisms v3-CSBRP-May-2012
- 18. Killing & Degradation Followingmechanisms facilitate this process: A. INTRACELLULAR Mechanisms: 1. Oxidative – by free radicals of O2 • This mechanism produces reactive O2 metabolites (O.2, H2O2, OH., HOCl, HOI, HOBr) • Respiratory burst by activated leucocytes requires presence of NADPH oxidase • Liberation of superoxide anion O.2 v3-CSBRP-May-2012
- 19.
- 20. Superoxide is subsequently convertedinto H2O2 which has bactericidal properties v3-CSBRP-May-2012
- 21. . Superoxide radicalsO 2 are utilized in MPO-dependent and MPO-independent killing v3-CSBRP-May-2012
- 22. MPO-dependent killing H2O2-MPO halidesystem v3-CSBRP-May-2012
- 23.
- 24. Killing & Degradation Followingmechanisms facilitate this process: A. INTRACELLULAR Mechanisms: 1. Oxidative – by free radicals of O2 i. MPO-dependednt ii. MPO-independent 2. Oxidative – by lysosomal granules 3. Non-oxidative mechanisms B. EXTRA CELLULAR Mechanisms v3-CSBRP-May-2012
- 25. Killing & Degradation Oxidative – by Lysosomal granules • The preformed lysosomal granules discharged into the phagosomes • They inlcude proteases, trypsinase, phospholipase and ALP • This induces proteolysis v3-CSBRP-May-2012
- 26. Killing & Degradation Followingmechanisms facilitate this process: A. INTRACELLULAR Mechanisms: 1. Oxidative – by free radicals of O2 i. MPO-dependednt ii. MPO-independent 2. Oxidative – by lysosomal granules 3. Non-oxidative mechanisms B. EXTRA CELLULAR Mechanisms v3-CSBRP-May-2012
- 27. Killing & Degradation Non-oxidativemechanisms (do not require oxygen for bactericidal activity) Include the following: 1. Granules: lysosomal hydrolases, cationic proteins, lipases, DNAses These enzymes cause lysis with in phagosome 1. Nitric oxide: Formed by nitric oxide synthase Similar to ROS in their action Potent microbial killers Produced by endothelial cells and by activated macrophages v3-CSBRP-May-2012
- 28. Killing & Degradation ONOO.damages the lipids, proteins, and nucleic acids v3-CSBRP-May-2012
- 29.
- 30. Killing & Degradation Followingmechanisms facilitate this process: A. INTRACELLULAR Mechanisms: 1. Oxidative – by free radicals of O2 i. MPO-dependednt ii. MPO-independent 2. Oxidative – by lysosomal granules 3. Non-oxidative mechanisms B. EXTRA CELLULAR Mechanisms v3-CSBRP-May-2012
- 31. Killing & Degradation EXTRACELLULAR Mechanisms: Immune mechanisms o Ab mediated lysis o Cell mediated cytotoxicity v3-CSBRP-May-2012
- 32. Is inflammation always protective? v3-CSBRP-May-2012
- 33. Release of LeukocyteProducts and Leukocyte-Mediated Tissue Injury v3-CSBRP-May-2012
- 34. Release of LeukocyteProducts and Leukocyte-Mediated Tissue Injury • Normal tissue is also damaged in some inflammatory processes • These mechanisms are similar to antimicrobial defense • Once the leukocytes are activated, their efector mechanisms do not distinguish between offender and host v3-CSBRP-May-2012
- 35. Release of LeukocyteProducts and Leukocyte-Mediated Tissue Injury • Collateral damage is more common in TB, Leprosy and viral infections • Inflammatory responses to self Ags – Autoimmunity • Excessive reaction to harmless environmental substances may result in Allergic diseases eg: asthma v3-CSBRP-May-2012
- 36. Clinical Examples of Leukocyte-Induced Injury Disorder Cells & molecules involved ACUTE ARDS Neutrophils Transplant Rejection Lymphocytes, Abs, C Asthma Eø Glomerulonephritis PMNs, Mø, C, Abs Septic shock Cytokines CHRONIC Arthritis Lymphocytes, macrophages; Abs Atherosclerosis Macrophages, Lymphocytes Pulmonary fibrosis Macrophages, Fibroblasts v3-CSBRP-May-2012
- 37. Mechanisms of entryof lysosomal contents into the extracellular milieu • Frustrated phagocytosis • Phagocytosis of membrane-damaging substances • Premature release of lysozymes before the formation of phagosome v3-CSBRP-May-2012
- 38. Mechanisms of entryof lysosomal contents into the extracellular milieu Premature release of lysozymes before the formation of phagosome v3-CSBRP-May-2012
- 39. Defects in LeukocyteFunction v3-CSBRP-May-2012
- 40. Defects in LeukocyteFunction • Inherited defects in leukocyte adhesion – LAD • Inherited defects in phagolysosome function – Chédiak-Higashi syndrome • Inherited defects in microbicidal activity – Chronic granulomatous disease • Acquired deficiencies – Cancer chemotherapy v3-CSBRP-May-2012
- 41. Disease Defect GENETIC LAD Defective adhesion molecules CGD Decreased oxidative burst MPO deficiency defective MPO—H2O2 system Chédiak-Higashi syndrome Lysosomal membrane ACQUIRED Bone marrow suppression: Production of leukocytes tumors, radiation, and chemotherapy Diabetes, malignancy, sepsis, Adhesion and chemotaxis chronic dialysis Leukemia, anemia, sepsis, Phagocytosis and microbicidal diabetes, malnutrition activity v3-CSBRP-May-2012
- 42. Chediak-Higashi Syndrome v3-CSBRP-May-2012
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- 44. Laboratory Findings in Inflammation v3-CSBRP-May-2012
- 45. Complete Blood Count (CBC) Total RBC Total WBC Hemoglobing(HB) Hematocrit (HCT) RBC Indices: MCV,MCH,MCHC WBC Differential v3-CSBRP-May-2012
- 46. Laboratory Findings in Inflammation Leukocytosis :15,000-20,000 cells/ul (4,000-10,000 cells/ul) Leukemoid reaction:40,000-100,000 cells/ul v3-CSBRP-May-2012
- 47. Laboratory Findings in Inflammation “Left Shift”: an increase in the number of immature neutrophils Immature neutrophils: Bands or stabs Meta or Juvenile Myleocyte v3-CSBRP-May-2012
- 48. “Left Shift” Normal 1 2 1 3 70 20 3 Baso Eos Meta Stabs Segs Lymph Mono 0 1 3 12 75 8 1 Left Shift v3-CSBRP-May-2012
- 49. Laboratory Findings in Inflammation Neutrophilia : bacterial Lymphocytosis : viral Leukopenia:many viruses Eosinophilia: parasites & allergies v3-CSBRP-May-2012
- 50. Laboratory Findings in Inflammation Erythrocyte Sedimentation Rate (ESR) will be increased v3-CSBRP-May-2012
- 51. Erythrocyte Sedimentation Rate (ESR) 0 0 10 The distance, in mm, 10 the RBC fall in 1 hr 20 20 is the Sed Rate 30 1hr 30 40 40 50 mm 50 mm 60 60 70 70 80 80 90 90 100 v3-CSBRP-May-2012 100
- 52. Acute Phase Proteins During an inflammatory response a number of interleukins(IL) are produced IL-6 stimulates the hepatic production of a number of proteins ,called acute phase proteins v3-CSBRP-May-2012
- 53. Acute Phase Proteins Fibrinogen C-Reactive Protein (CRP) C3 C4 Ceruloplasmin v3-CSBRP-May-2012
- 54. Acute Phase Proteins AcutePhase Proteins are normally found in the blood at low concentrations, but following hepatic stimulation by IL-6 their concentration increases Detection of elevated levels of acute phase proteins is an indication of an inflammatory response v3-CSBRP-May-2012
- 55.
- 56. Ligands • In biochemistry and pharmacology, a ligand (Latin ligare = to bind) is a substance that is able to bind to and form a complex with a biomolecule to serve a biological purpose. • In a narrower sense, it is a signal triggering molecule, binding to a site on a target protein. • The binding occurs by intermolecular forces, such as ionic bonds, hydrogen bonds and Van der Waals forces. The docking (association) is usually reversible (dissociation). Actual irreversible covalent binding between a ligand and its target molecule is rare in biological systems. In contrast to the meaning in metalorganic and inorganic chemistry, it is irrelevant whether the ligand actually binds at a metal site, as it is the case in hemoglobin. • Ligand binding to a receptor alters the chemical conformation, that is the three dimensional shape of the receptor protein. The conformational state of a receptor protein determines the functional state of a receptor. Ligands include substrates, inhibitors, activators, and neurotransmitters. The tendency or strength of binding is called affinity. • Radioligands are radioisotope labeled compounds and used in vivo as tracers in PET studies and for in vitro . v3-CSBRP-May-2012
- 57. The movement ofleucocytes from out of the blood vessels into the tissues spaces is known as DIAPEDESIS WOW! v3-CSBRP-May-2012
- 58. MPO-independent killing . O2 ++ Fe (Hydroxyl radical) v3-CSBRP-May-2012
Editor's Notes
- #3 Once leukocytes (neutrophils and monocytes) have been recruited to a site of infection or cell death, they must be activated to perform their functions. The responses of leukocytes consist of two sequential sets of events: (1) recognition of the offending agents, which deliver signals that (2) activate the leukocytes to ingest and destroy the offending agents and amplify the inflammatory reaction.
- #4 Leukocytes express several receptors that recognize external stimuli and deliver activating signal.
- #7 There are different receptors for different bacterial products.
- #8 Leukocytes express several receptors that recognize external stimuli and deliver activating signal.
- #9 Leukocytes express several receptors that recognize external stimuli and deliver activating signal: Receptors for microbial products: Toll-like receptors (TLRs) recognize components of different types of microbes. Thus far 10 mammalian TLRs have been identified, and each seems to be required for responses to different classes of infectious pathogens.[28] Different TLRs play essential roles in cellular responses to bacterial lipopolysaccharide (LPS, or endotoxin), other bacterial proteoglycans and lipids, and unmethylated CpG nucleotides, all of which are abundant in bacteria, as well as double-stranded RNA, which is produced by some viruses. TLRs are present on the cell surface and in the endosomal vesicles of leukocytes (and many other cell types), so they are able to sense products of extracellular and ingested microbes. These receptors function through receptor-associated kinases to stimulate the production of microbicidal substances and cytokines by the leukocytes. Various other cytoplasmic proteins in leukocytes recognize bacterial peptides and viral RNA.
- #10 Leukocytes express several receptors that recognize external stimuli and deliver activating signal: G protein–coupled receptors found on neutrophils, macrophages, and most other types of leukocytes recognize short bacterial peptides containing N -formylmethionyl residues. Because all bacterial proteins and few mammalian proteins (only those synthesized within mitochondria) are initiated by N -formylmethionine, this receptor enables neutrophils to detect and respond to bacterial proteins. Other G protein–coupled receptors recognize chemokines, breakdown products of complement such as C5a, and lipid mediators, including platelet activating factor, prostaglandins, and leukotrienes, all of which are produced in response to microbes and cell injury. Binding of ligands, such as microbial products and mediators, to the G protein–coupled receptors induces migration of the cells from the blood through the endothelium and production of microbicidal substances by activation of the respiratory burst.
- #11 Leukocytes express several receptors that recognize external stimuli and deliver activating signal: Receptors for opsonins : Leukocytes express receptors for proteins that coat microbes. The process of coating a particle, such as a microbe, to target it for ingestion (phagocytosis) is called opsonization , and substances that do this are opsonins . These substances include antibodies, complement proteins, and lectins. One of the most efficient ways of enhancing the phagocytosis of particles is coating the particles with IgG antibodies specific for the particles, which are then recognized by the high-affinity Fcγ receptor of phagocytes, called FcγRI ( Chapter 6 ). Components of the complement system, especially fragments of the complement protein C3, are also potent opsonins, because these fragments bind to microbes and phagocytes express a receptor, called the type 1 complement receptor (CR1), that recognizes breakdown products of C3 (discussed later). Plasma lectins, mainly mannan-binding lectin, also bind to bacteria and deliver them to leukocytes. The binding of opsonized particles to leukocyte Fc or C3 receptors promotes phagocytosis of the particles and activates the cells.
- #13 Leukocytes express several receptors that recognize external stimuli and deliver activating signal: Receptors for cytokines : Leukocytes express receptors for cytokines that are produced in response to microbes. One of the most important of these cytokines is interferon-γ (IFN-γ), which is secreted by natural killer cells reacting to microbes and by antigen-activated T lymphocytes during adaptive immune responses ( Chapter 6 ). IFN-γ is the major macrophage-activating cytokine.
- #14 FIGURE 2-8 Leukocyte receptors and responses. Different classes of cell surface receptors of leukocytes recognize different stimuli. The receptors initiate responses that mediate the functions of the leukocytes. Only some receptors are depicted (see text for details). IFN-γ, interferon-γ; LPS, lipopolysaccharide(s).
- #16 Recognition of microbes or dead cells by the receptors described above induces several responses in leukocytes that are referred to under the rubric of leukocyte activation (see Fig. 2-8 ). Activation results from signaling pathways 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 inflammation and may contribute to its injurious consequences.
- #17 Survival inside the phagocyte: Bacteria have developed ways to survive inside phagocytes, where they continue to evade the immune system. To get safely inside the phagocyte they express proteins called "invasins". When inside the cell they remain in the cytoplasm and avoid toxic chemicals contained in the phagolysosomes. Some bacteria prevent the fusion of a phagosome and lysosome, to form the phagolysosome. Other pathogens, such as Leishmania, create a highly modified vacuole inside the phagocyte, which helps them persist and replicate. Legionella pneumophilaproduces secretions which cause the phagosome to fuse with vesicles other than the ones that contain toxic substances. Other bacteria are capable of living inside of the phagolysosome. Staphylococcus aureus , for example, produces the enzymes catalase and superoxide dismutase which break down chemicals—such as hydrogen peroxide—produced by phagocytes to kill bacteria. Bacteria may escape from the phagosome before the formation of the phagolysosome: Listeria monocytogenes can make a hole in the phagosome wall using enzymes called listeriolysin O and phospholipase C.
- #19 This mechanism produces reactive O2 metabolites (O’2, H2O2, OH’, HOCl, HOI, HOBr) Respiratory burst by activated leucocytes requires presence of NADPH oxidase
- #23 Here MPO acts on H 2 O 2 in the presence of halides to form respective hypochlorus acid (HOCl, HOI, HOBr). This is called H 2 O 2 -MPO halide system and is more portent antibacterial system in PMNs than H 2 O 2 alone.
- #24 Mature macrophages lack the enzyme MPO and they carry out bactericidal activity by producing OH - ions and superoxide singlet oxygen O . from H 2 O 2 in the presence of O . 2 or in the presence of Fe ++ . Reactive oxygen metabolites are particularly useful in eliminating microbial organisms that grow within phagocytes eg: My.TB, Histoplasma capsulatum.
- #26 In this mechanism, the preformed granules stored in of PMNs, Macrophages are discharged or secreted into the phagosomes and the extracellular environment. These products inlcude preoteases, trypsinase, phospholipase and ALP. This induces proteolysis.
- #28 Some agents released from the granules of phagocytic cells do not require oxygen for bactericidal activity. These include the following: 1-Granules: lysosomal hydrolases, cationic proteins, lipases, DNAses. These enzymes cause lysis with in phagosome. They are indipendent of oxidative damage. 2-Nitric oxide: formed by nitric oxide synthase. Nitric oxide free radicals are similar to oxygen free radicals and are potent microbial killers. Nitric oxide is produced by endothelial cells and by activated macrophages. ========================================================== Interferon-gamma—which was once called macrophage activating factor—stimulates macrophages to produce nitric oxide. The source of interferon-gamma can be CD4+ T cells, CD8+ T cells, natural killer cells, B cells, natural killer T cells, monocytes, macrophages, or dendritic cells. Nitric oxide is then released from the macrophage and, because of its toxicity, kills microbes near the macrophage. Activated macrophages produce and secrete tumor necrosis factor. This cytokine—a class of signaling molecule—kills cancer cells and cells infected by viruses, and helps to activate the other cells of the immune system. In some diseases, e.g., the rare chronic granulomatous disease, the efficiency of phagocytes is impaired, and recurrent bacterial infections are a problem. In this disease there is an abnormality affecting different elements of oxygen-dependent killing. Other rare congenital abnormalities, such as Chediak-Higashi syndrome, are also associated with defective killing of ingested microbes.
- #29 NO reacts with superoxide (O . 2 ) to generate the highly reactive free radical peroxynitrite (ONOO•). These oxygen- and nitrogen-derived free radicals attack and damage the lipids, proteins, and nucleic acids of microbes as they do with host macromolecules.
- #32 Bactericidal activity occurs at extracellular level. These include: 1-contents liberated to the extracellular environment by macrophages continue to act. 2-Immune mechanisms: immune mediated cytolysis of microbes takes place out side the cells by Antibody mediated lysis and by cell mediated cytotoxicity. ============== Extracellular: Interferon-gamma—which was once called macrophage activating factor—stimulates macrophages to produce nitric oxide. The source of interferon-gamma can be CD4+ T cells, CD8+ T cells, natural killer cells, B cells, natural killer T cells, monocytes, macrophages, or dendritic cells. Nitric oxide is then released from the macrophage and, because of its toxicity, kills microbes near the macrophage. Activated macrophages produce and secrete tumor necrosis factor. This cytokine—a class of signaling molecule—kills cancer cells and cells infected by viruses, and helps to activate the other cells of the immune system. In some diseases, e.g., the rare chronic granulomatous disease, the efficiency of phagocytes is impaired, and recurrent bacterial infections are a problem. In this disease there is an abnormality affecting different elements of oxygen-dependent killing. Other rare congenital abnormalities, such as Chediak-Higashi syndrome, are also associated with defective killing of ingested microbes.
- #35 Release of Leukocyte Products and 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 release microbicidal and other products not only within the phagolysosome but also into the extracellular space. The most important of these substances are lysosomal enzymes , present in the granules, and reactive oxygen and nitrogen species . These released substances are capable of damaging normal cells and vascular endothelium, and may thus amplify the effects of the initial injurious agent. In fact, if unchecked or inappropriately directed against host tissues, the leukocyte infiltrate itself becomes the offender,[39] and indeed leukocyte-dependent tissue injury underlies many acute and chronic human diseases ( Table 2-2 ). This fact becomes evident in the discussion of specific disorders throughout the book.
- #36 Release of Leukocyte Products and 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 release microbicidal and other products not only within the phagolysosome but also into the extracellular space. The most important of these substances are lysosomal enzymes , present in the granules, and reactive oxygen and nitrogen species . These released substances are capable of damaging normal cells and vascular endothelium, and may thus amplify the effects of the initial injurious agent. In fact, if unchecked or inappropriately directed against host tissues, the leukocyte infiltrate itself becomes the offender,[39] and indeed leukocyte-dependent tissue injury underlies many acute and chronic human diseases ( Table 2-2 ). This fact becomes evident in the discussion of specific disorders throughout the book.
- #38 The contents of lysosomal granules are secreted by leukocytes into the extracellular milieu by several mechanisms.[40] 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 immovable flat surfaces (e.g., glomerular basement membrane), the inability of the leukocytes to surround and ingest these substances (frustrated phagocytosis) triggers strong activation, and the release of large amounts of lysosomal enzymes into the extracellular environment. Phagocytosis of membrane-damaging substances, such as urate crystals, may injure the membrane of the phagolysosome and also lead to the release of lysosomal granule contents.
- #41 Defects in Leukocyte Function: Because leukocytes play a central role in host defense, defects in leukocyte function, both inherited and acquired, lead to increased vulnerability to infections ( Table 2-3 ). Impairments of virtually every phase of leukocyte function have been identified—from adherence to vascular endothelium to microbicidal activity. These include the following: • Inherited defects in leukocyte adhesion . We previously mentioned the genetic defects of integrins and selectin-ligands that cause leukocyte adhesion deficiencies types 1 and 2. The major clinical problem in both is recurrent bacterial infections. • Inherited defects in phagolysosome function . One such disorder is Chédiak-Higashi syndrome , an autosomal recessive condition characterized by defective fusion of phagosomes and lysosomes in phagocytes (causing susceptibility to infections), and abnormalities in melanocytes (leading to albinism), cells of the nervous system (associated with nerve defects), and platelets (causing bleeding disorders).[41] The main leukocyte abnormalities are neutropenia (decreased numbers of neutrophils), defective degranulation, and delayed microbial killing. Leukocytes contain giant granules , which can be readily seen in peripheral blood smears and are thought to result from aberrant phagolysosome fusion. The gene associated with this disorder encodes a large cytosolic protein called LYST, which is believed to regulate lysosomal trafficking. • Inherited defects in microbicidal activity . The importance of oxygen-dependent bactericidal mechanisms is shown by the existence of a group of congenital disorders called chronic granulomatous disease , which are characterized by defects in bacterial killing and render patients susceptible to recurrent bacterial infection. Chronic granulomatous disease results from inherited defects in the genes encoding components of phagocyte oxidase , which generates ROS. The most common variants are an X-linked defect in one of the membrane-bound components (gp91phox) and autosomal recessive defects in the genes encoding two of the cytoplasmic components (p47phox and p67phox).[42] The name of this disease comes from the macrophage-rich chronic inflammatory reaction that tries to control the infection when the initial neutrophil defense is inadequate. This often leads to collections of activated macrophages that wall off the microbes, forming aggregates called granulomas (described in more detail later in the chapter). • Acquired deficiencies . Clinically, the most frequent cause of leukocyte defects is bone marrow suppression , leading to decreased production of leukocytes. This is seen following therapies for cancer (radiation and chemotherapy) and when the marrow space is compromised by tumors, which may arise in the marrow (e.g., leukemias) or be metastatic from other sites.
- #56 Adhesion cascade in leukocyte adhesion deficiency (LAD) syndromes. < emedicine.medscape.com/article/886248-media >
- #57 In biochemistry and pharmacology , a ligand ( Latin ligare = to bind) is a substance that is able to bind to and form a complex with a biomolecule to serve a biological purpose. In a narrower sense, it is a signal triggering molecule, binding to a site on a target protein . The binding occurs by intermolecular forces , such as ionic bonds , hydrogen bonds and Van der Waals forces . The docking (association) is usually reversible (dissociation). Actual irreversible covalent binding between a ligand and its target molecule is rare in biological systems. In contrast to the meaning in metalorganic and inorganic chemistry , it is irrelevant whether the ligand actually binds at a metal site, as it is the case in hemoglobin. Ligand binding to a receptor alters the chemical conformation, that is the three dimensional shape of the receptor protein. The conformational state of a receptor protein determines the functional state of a receptor. Ligands include substrates, inhibitors, activators, and neurotransmitters. The tendency or strength of binding is called affinity. Radioligands are radioisotope labeled compounds and used in vivo as tracers in PET studies and for in vitro .