Complement System PDF

Effector Functions of Antibodies 3 Humoral Immunity  The main functions of antibodies are to neutralize and eliminate infectious microbes and microbial toxins  Antibodies are produced by plasma cells in peripheral (secondary) lymphoid organs, inflamed tissues, and bone ma...

Effector Functions of Antibodies 3 Humoral Immunity  The main functions of antibodies are to neutralize and eliminate infectious microbes and microbial toxins  Antibodies are produced by plasma cells in peripheral (secondary) lymphoid organs, inflamed tissues, and bone marrow, and antibodies perform their effector functions at sites distant from their production.  Many of the effector functions of antibodies are mediated by Fc regions of immunoglobulin (Ig) molecules, and different Ig heavy chain isotypes serve distinct effector functions.  The effector functions of antibodies that are mediated by the Fc regions are triggered by the binding of antigens to the variable regions. 4 Vaccine-Induced Humoral Immunity 5 Functions of Antibody Isotypes 6 Neutralization of microbes and toxins by antibodies 7 Subunit composition of Fcγ receptors 8 Antibody-mediated opsonization and phagocytosis of microbes 10 Antibody-dependent cell-mediated cytotoxicity 11 Summary  Humoral immunity is mediated by antibodies and is the effector arm of the adaptive immune system responsible for defense against extracellular microbes and microbial toxins.  The antibodies that provide protection against infection may be produced by long-lived antibody-secreting cells generated by the first exposure to microbial antigen or by reactivation of memory B cells by the antigen.  Antibodies block, or neutralize, the infectivity of microbes by binding to the microbes and sterically hindering interactions of the microbes with cellular receptors. Antibodies similarly block the pathologic actions of toxins by preventing binding of the toxins to host cells.  Antibody-coated (opsonized) particles are phagocytosed by binding of the Fc portions of the antibodies to phagocyte Fc receptors. There are several types of Fc receptors specific for different subclasses of IgG and for IgA and IgE antibodies, and different Fc receptors bind the antibodies with varying affinities. Attachment of antigen-complexed Ig to phagocyte Fc receptors also delivers signals that stimulate the microbicidal activities of phagocytes. 12 Complement Activation 13  2 The classical pathway of complement activation 14 The alternative pathway of complement activation. 15 The alternative pathway of complement activation. 16 Complement Activation Regulatory Mechanisms 17  Complement Activation Regulatory Mechanisms Complement activation needs to be regulated because:  Low-level complement activation goes on spontaneously, and if such activation is allowed to proceed, the result can be damage to normal cells and tissues.  Even when complement is activated where needed, such as on microbial cells or antigen-antibody complexes, it needs to be controlled because degradation products of complement proteins can diffuse to adjacent cells and injure them.  Different regulatory mechanisms include:  Inhibition of the formation of C3 convertases in the early steps of complement activation.  Break down and inactivate C3 and C5 convertases.  Inhibition of the formation of the MAC in the late steps of the complement pathway. 18 Molecules and Receptors That Inhibit Complement Activation 19 Functions of complement 20 Complement Deficiencies Paroxysmal nocturnal hemoglobulinuria (PNH) Individuals with PNH are missing both DAF and CD59 and have increased sensitivity to complement lysis. This results in intravascular red cell hemolysis and hematoglobinuria (loss of iron) that is characteristic of the disease. The absence of CD59 on platelets also contributes to recurrent thrombosis that is often fatal in individuals with PNH. PNH Treatment:  Transfusion of packed red blood cells can replace lost cells.  Androgens and recombinant erythropoietin are commonly used to accelerate erythropoiesis.  Thrombotic complications are reduced by standard therapy, including heparin and maintenance doses of common anticoagulants.  Iron loss is corrected by the administration of supplemental iron.  To reduce complement activation, eculizumab can be used to block the activation of C5 and the generation of the MAC. 21 Complement Deficiencies Hereditary angioneurotic edema (HANE) is caused Hereditary Angioedema by C1 INH deficiency. Inherited (normal levels of nonfunctional C1 INH) and acquired (low serum levels of C1 INH) forms of HANE exist. During a clinical episode, well-circumscribed edema is localized to the face, tongue, and larynx. HANE Treatment:  Oral androgens, anabolic steroids, and antifibrinolytic agents are commonly used to treat HANE.  In cases of acquired C1 INH deficiency, glucocorticosteroids are effective as an The clinical appearance of hereditary angioedema, showing emergency treatment and are usually tapered the local transient swelling that affects mucous membranes off when the patient begins taking androgens. Other Complement Deficiencies  A defect in C2 synthesis is the most commonly identified deficiency and increases the risk for neisserial infections.  Individuals with a C3 deficiency usually have recurrent infections of the respiratory tract, gut, and skin.  Life-threatening meningitis is associated with defects in properdin, factor H, factor I, and the complement MAC. meningococcal vaccination is indicated to create high levels of protective antibodies. 22 Summary  The complement system consists of serum and membrane proteins that interact in a highly regulated manner to produce biologically active products.  The three major pathways of complement activation. All pathways converge on a common pathway that involves the formation of a membrane pore after the proteolytic cleavage of C5.  the alternative pathway, which is activated on microbial surfaces in the absence of antibody; the classical pathway, which is activated by antigen-antibody complexes;  and the lectin pathway, which is initiated by circulating lectins binding to carbohydrates on pathogens.  The biologic functions of the complement system include:  opsonization of organisms and immune complexes by proteolytic fragments of C3, followed by binding to phagocyte receptors for complement fragments and phagocytic clearance,  Activation of inflammatory cells by proteolytic fragments of complement proteins called anaphylatoxins (C3a, C4a, C5a),  Cytolysis mediated by MAC formation on cell surfaces,  Solubilization and clearance of immune complexes, and enhancement of humoral immune responses.  Complement components play critical roles in the immobilization of microbes, opsonization, chemotaxis, and B cell activation. Complement activation is regulated by various plasma and cell membrane proteins that inhibit different steps in the cascades.  Hereditary angioneurotic edema is caused by failure to regulate complement activation.  Paroxysmal nocturnal hemoglobulinuria (PNH) is caused by lack of membrane-bound complement inhibitors.  Complement deficiencies in C2, alternative pathway components, or the membrane attack complex (MAC) increase the risk of life-threatening neisserial infections. 23 The Primary Immunodeficiency Disorders Shields AM, Patel SY. 2017 27