or, alternatively, decreased risk of developing age‐related macular degeneration; in this condition, abnormal growth of new blood vessels behind the retina results in vision loss. Variations in factor B, C3, and factor I have also been implicated in this condition, suggesting that the development of age‐related macular degeneration is associated with dysregulation of the alternative complement pathway.
SUMMARY
1 The complement system—comprising approximately 30 serum and membrane‐expressed proteins—plays a key effector role in both innate immunity and antibody‐mediated adaptive responses to microbial pathogens.
2 Complement activation is a cascade that sequentially generates biologically active molecules. The major biological activities generated by complement activation are opsonins (enhancing uptake of pathogens by phagocytic cells) and anaphylatoxins (inducing inflammatory responses). The biologically active complement components interact with specific receptors expressed on multiple cell types. Complement activation also results in the direct lysis of pathogens.
3 Complement can be initiated by three distinct pathways: (a) the classical pathway, predominantly by antigen–antibody complexes binding to complement component C1; (b) the lectin pathway, mainly by terminal mannose residues on the surface of bacteria interacting with mannose‐binding lectin, but also by N‐acetyl carbohydrates binding to ficolin; and (c) the alternative pathway, by the deposition of complement component C3b on the surface of the pathogen. The alternative pathway has an amplification loop that greatly enhances activation.
4 The three activation pathways converge with the cleavage of C3 to form C3b and C3a.
5 The final stages of all complement pathways are identical: the formation of a membrane attack complex, comprising components C5b through C9. Formation of the membrane attack complex leads to lysis of the cell.
6 The activity of complement and its components is tightly regulated by several proteins. These are found in the fluid phase (factors H and I, C1 inhibitor, C4b binding protein) and on the surface of many mammalian cells (DAF, MCP, and CR1). Complement regulator proteins are not expressed on the surface of microbial cells.
7 Complement has important functions in addition to the generation of opsonins and anaphylatoxins, and cell lysis. These include enhancing B‐lymphocyte responses to antigen, controlling the formation and clearance of immune complexes, removal of dead and dying cells, and interactions with viruses.
8 Deficiencies of complement components, regulators of complement pathways, or receptors for complement components may result in increased susceptibility to infection or the development of inflammatory conditions.
REFERENCES AND BIBLIOGRAPHY
1 Ambati J, Atkinson JP, Gelfand BD. (2013) Immunology of agerelated macular degeneration. Nat Rev Immunol 13: 438.
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3 Frank MM. (2006) Hereditary angioedema: the clinical syndrome and its management in the United States. Immunol Allergy Clin North Am 26: 653.
4 Lubbers R, van Essen MF, van Kooten C, Trouw LA. (2017) Production of complement components by cells of the immune system. Clin Exp Immunol 188: 183.
5 Matsushita M. (2013) Ficolins in complement activation. Mol Immunol 55: 22.
6 Pettigrew HD, Teuber SS, Gershwin ME. (2009) Clinical significance of complement deficiencies. Ann N Y Acad Sci 1173: 108.
7 Riedemann NC, Ward PA. (2003) Complement in ischemia reperfusion injury. Am J Pathol 162: 363.
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9 Rus H, Cudrici C, Niculescu F. (2005) The role of the complement system in innate immunity. Immunol Res 33: 103.
10 Takahashi K, Ip WE, Michelow IC, Ezekowitz RA. (2006) The mannose‐binding lectin: a prototypic pattern recognition molecule. Curr Opin Immunol 18: 16.
11 Wallis R. (2007) Interactions between mannose‐binding lectin and MASPs during complement activation by the lectin pathway. Immunobiology 212: 289.
REVIEW QUESTIONS
For each question, choose the ONE BEST answer or completion.
1 A patient is admitted with multiple bacterial infections and is found to have a complete absence of C3. Which complement‐mediated function would remain intact in such a patient?lysis of bacteriaopsonization of bacteriageneration of anaphylatoxinsgeneration of neutrophil chemotactic factorsnone of the above
2 Complement is required for:lysis of erythrocytes by the enzyme lecithinaseNK‐mediated lysis of tumor cellsphagocytosisantibody‐mediated lysis of bacteriaall of the above
3 Which of the following is associated with the development of SLE‐like symptoms?deficiencies in C1, C4, or C2deficiencies in C5, C6, or C7deficiencies in the late components of complementincreases in the serum C3 levelincreases in the levels of C1, C4, or C2
4 Activated fragments of C5 can lead to all of the following except:contraction of smooth musclevasodilationattraction of leukocytes to a site of infectionattachment of lymphocytes to macrophagesinitiation of formation of membrane attack complex
5 The alternative pathway of complement activation is characterized by all of the following except:activation of complement components beyond C3 in the cascadeparticipation of properdingeneration of anaphylatoxinsactivation of C4regulation by factor H
6 DAF regulates the complement system to prevent complement‐mediated lysis of cells. This involves:dissociation of the C3 convertase complexblocking the binding of the C3 convertase to the surface of bacterial cellsinhibiting the membrane attack complex from binding to bacterial membranesacting as a co‐factor for the cleavage of C3bcausing dissociation of C5 convertase
7 The following activate(s) the alternative pathway of complement:lipopolysaccharidessome viruses and virus‐infected cellsfungal and yeast cell wallsmany strains of Gram‐positive bacteriaall of the above
ANSWERS TO REVIEW QUESTIONS
1 E. All these functions are mediated by complement components that are generated later in the complement activation sequence than C3. Thus, all these functions are disrupted in the absence of C3.
2 D. Complement is required for lysis of bacteria by IgM or IgG (classical pathway). Complement is not required for lysis of erythrocytes by lecithinase or for phagocytosis. However, opsonins such as C3b that are generated during complement activation can enhance phagocytosis. Although some tumor cells can initiate the alternative pathway of complement activation, complement plays no role in NK‐mediated lysis of these cells.
3 A. Inherited homozygous deficiency of one of the early proteins of the classical complement pathway (C1, C4, or C2) is strongly associated with the development of SLE‐like symptoms. These deficiencies probably result in abnormal processing of immune complexes in the absence of a functional classical pathway of complement fixation. In these conditions, serum levels of C3 and C4 decrease due to the large number of immune complexes that bind
