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The Complement System and Soluble Mediators in Immune Response

This chapter covers the Complement System's activation pathways, functions, alterations in protein levels, and their clinical significance. It also explores other soluble mediators like cytokines and interleukins, their properties, and immunoregulatory activities.

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The Complement System and Soluble Mediators in Immune Response

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  1. Chapter 5 Soluble Mediators of the Immune System

  2. Main Topics for today • Complement System • Cytokines, Chemokines, Growth Factors • Expanding on the Immune Response • Review innate and natural immune response • Antigen capture, presentation • Primary and Secondary immune response

  3. The Complement System Classic Pathway: immune complex triggered. Apoptotic cells Certain viruses and Gram-negative bacteria C-Reactive protein bound to ligand Alternate Pathway: Various bacteria, fungi, viruses, or tumor cells Mannose-Binding Lectin Pathway: bacteria containing terminal mannose groups

  4. Physiologic Activities of the Complement system • Host defense against infection • Interface between innate and adaptive immunity • Disposal of waste

  5. The Complement System Activation of Complement Normally, complement components are present in the circulation in an inactive form. Complement can become activated by antigen-antibody complexes in solution or circulation, bacteria, fungi, mannose containing bacterial components.

  6. Three Activation Pathways of Complement (Redrawn from Walport MJ: Complement, N Engl J Med 344[14]:1058, 2001.)

  7. Enzyme activation occurs after complement is initially activated; each enzyme precursor is activated by the previous complement component or complex in a cascade-like fashion The pathways leading to the cleavage of C3 are triggered enzyme cascades.

  8. Complement receptors • surface membrane glycoproteins • react with one or more of the fragments of C3 produced during complement activation and degradation • Effects of complement activation • Production of inflammatory mediators • Cell membrane lysis of antibody-coated targets

  9. Opsonization • Enhances phagocytosis • Neutrophils • Macrophages • Antibody Dependent Cellular Cytotoxicity • Natural killer cells

  10. Classic Pathway Recognition: C1 recognizes the antigen-antibody reaction Amplification of Proteolytic Complement Cascade Membrane Attack Complex

  11. Alternate Pathway • Non antibody initiated pathway • Can be activated by microbial and mammalian cell surfaces • Factor H is a major controlling factor: blocks C3bBb complex

  12. Mannose-Binding Lectin Pathway • Family of Calcium dependant lectins • Bacteria • Deficiency: mutation reduces level of lectin

  13. Biologic Functions of Complement Proteins Two categories: Cell lysis by the membrane attack complex (MAC) Biologic effects of proteolytic fragments of complement C3a and C5a: chemotaxins, anaphylatoxins C3b: opsonization

  14. Alterations in Complement Proteins Elevated Complement Levels Increased in many inflammatory conditions. Limited clinical significance because separate complement components are acute-phase proteins. C3, C4 levels

  15. Alterations in Complement Proteins • Decreased Complement Levels • Decreased because of excessive activation, currently being consumed, or a single complement component is absent because of a genetic defect. • C1, C2 and C4 deficiencies assoc. with Systemic Lupus Erythematosus • C1q associated with Hereditary Angioedema (HAE)

  16. Three types of complement deficiency can cause increased susceptibility to pyogenic infections: Deficiency of opsonic activities of complement. Any deficiency that compromises the lytic activity of complement. Deficient function of mannose-binding lectin pathway.

  17. C3 deficiencies • Homozygous C3 deficiency: lifelong life threatening infections. • Hereditary C3 deficiency: pneumococcal septicemia. • Encapsulated bacterial infections • C5 associated with bacterial infections • C6, C7 and C8 assoc. with infections caused by Neisseria spp.

  18. Assessment of Complement component levels: • Radial Immunodiffusion • Nephelometry

  19. Other Soluble Mediators of Immune Response Cytokines are made by leukocytes (T cells, B cells, Monocytes)and act on other leukocytes. Interleukins is alternate term for cytokines.

  20. Interleukins • IL-1 APC signal to T-helper cell • IL-2 T-cell growth factor • IL-3 Cell growth factor from thymic epithelial cells, helps T cell differentiation • IL-4 produced by T-helper2 cells involved in Ig class switching to IgE. Also downregulates T-helper1 cells

  21. Interleukins • IL-5 produced by T-helper2 cells involved in IgA production • IL-10 produced by T-helper2 cells, it downregulates the cell-mediated immune system • IL-12 associated with the development of cell-mediated immunity

  22. Common Properties of Cytokines Secreted in response to cell activation. Bind to specific membrane receptors on target cells. Regulate receptor expression in T and B cells. Act on different cell types Excite same functional effects with multiple cytokines. Act close to the site of synthesis. Influence synthesis and actions of other cytokines.

  23. Immunoregulatory Activity of Other Cytokines Interferons: group of cytokines discovered in virally infected cultured cells; name derived from interference with viral replication. Tumor necrosis factor (TNF): principal mediator of acute inflammatory response to gram-negative bacteria and other infectious microbes. Stimulates recruitment of neutrophils and monocytes to sites of infection. Activates neutrophils and monocytes to eradicate microbes.

  24. Hematopoietic Stimulators Stem cell factor (c-kit ligand) Colony-stimulating factors: GM-CSF, M-CSF, G-CSF Transforming growth factor beta (TGF-) Chemokines: Chemotactic Cytokines

  25. Assessment of Cytokines • Traditional: bioassays, enzyme-linked immunosorbent assay (ELISA), intracellular staining, ribonuclease protection assay, polymerase chain reaction (PCR) • Newer methods: multiplexed assay, flow cytometry, cord blood cell stimulation, real-time PCR, ELISPOT assays, enhanced immunoassays for cytokines, high-sensitivity ELISA

  26. Let’s go back to the Immune Response

  27. First Line of Defense • Intact skin, mucosal membranes • Tears • Saliva • Skin secretions • Mucosal secretions • Normal flora • G.I. tract • Urinary tract

  28. Body Defenses—Resistance to Microbial Disease Natural Immunity: Innate or inborn resistance to infection; nonspecific mechanism.

  29. Monocyte (blood)

  30. Monocytes and Macrophages (From Barrett JT: Textbook of immunology, ed 5, St Louis, 1988, Mosby.)

  31. Monocytes and Macrophages (Modified from Roitt IM: Essential immunology, ed 5, Oxford, 1984, Blackwell Scientific.)

  32. Monocytes and Macrophages Functions of Monocytes and Macrophages in Host Defense (Modified from Johnston RB: Monocytes and macrophages, N Engl J Med 318[12]:749, 1988.)

  33. Monocytes and Macrophages Antigen presentation: induction of the immune response Secretion of biologically active molecules:cytokines

  34. Acute Inflammation (From Delves PJ, Roitt, IM: The immune system. Part I, N Engl J Med 343[1]:37-49, 2000.)

  35. Sepsis: is a systemic inflammatory response syndrome (SIRS) Sepsis is an infection-induced syndrome defined as the presence of two or more of the following: Fever or hypothermia Leukocytosis or leukopenia Tachycardia: increased heart rate Increased respiratory rate

  36. Process of Phagocytosis Chemotaxis Adherence Engulfment Digestion Subsequent phagocytic activity

  37. Process of Phagocytosis (Redrawn from Turgeon ML: Clinical hematology: theory and procedures, ed 3, Philadelphia, 2000, Lippincott–Williams & Wilkins.)

  38. Monocytes and Macrophages (From Barrett JT: Textbook of immunology, ed 5, St Louis, 1988, Mosby.)

  39. Monocytes and Macrophages Antigen presentation: induction of the immune response Secretion of biologically active molecules:cytokines

  40. Acute-Phase Proteins Produced as an innate body defense or response to tissue injury. (inflammation, infection, etc.) Group of glycoproteins ESR, CRP used as indicators

  41. Synthesis and Catabolism of Acute-Phase Proteins Level increases 2 to 5 fold during inflammation C-Reactive Protein: is the first one to appear Significance of Other Acute-Phase Reactants: C3, C4, Haptoglobin, coagulation factors Acute-Phase Reactant Assessment Methods: ESR, a1-antitrypsin, ceruloplasmin

  42. Acute phase proteins increase or decrease at different rates. • Most last 2 to 4 days • CRP half life of 5 to 7 hrs. • They are inflammation indicators, no diagnostic capability, no specificity

  43. Adaptive Immunity- organized around the T and B lymphocytes

  44. Comparison of Innate and Adaptive Immunity Innate immune system is an ancient form of host defense that appeared before the adaptive immune system. It may not recognize every possible antigen; it focuses on a few large groups of microorganisms called pathogen-associated molecular patterns (PAMPs).

  45. Comparison of Innate and Adaptive Immunity • Receptors of innate immune system that recognize these PAMPs are called pattern-recognition receptors (e.g., toll-like receptors). • Mechanisms of innate immunity (e.g., phagocytes, complement pathways) are activated immediately after infection.

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