Multiple pathways for regulating complement activation limit the potential damage caused by complement deposition on host cells or caused by the spontaneous activation of complement proteins in the plasma. Genetic deficiencies in these mechanisms often lead to chronic inflammatory diseases, but in some cases can paradoxically lead to increased susceptibility to bacterial infections. This latter outcome may occur because: Complement regulatory proteins have dual functions in inhibiting and promoting complement activation. Uncontrolled complement activation leads to the depletion of serum complement proteins. The inhibition of the membrane attack complex by complement regulatory proteins normally leads to enhanced activation of the early steps of the complement pathway. Complement regulatory proteins normally cause the rapid depletion of plasma complement factors. Uncontrolled complement activation recruits the majority of phagocytic cells, leaving few remaining to fight infections in the tissues.

Multiple pathways for regulating complement activation limit the potential damage caused by complement deposition on host cells or caused by the spontaneous activation of complement proteins in the plasma. Genetic deficiencies in these mechanisms often lead to chronic inflammatory diseases, but in some cases can paradoxically lead to increased susceptibility to bacterial infections. This latter outcome may occur because: Complement regulatory proteins have dual functions in inhibiting and promoting complement activation. Uncontrolled complement activation leads to the depletion of serum complement proteins. The inhibition of the membrane attack complex by complement regulatory proteins normally leads to enhanced activation of the early steps of the complement pathway. Complement regulatory proteins normally cause the rapid depletion of plasma complement factors. Uncontrolled complement activation recruits the majority of phagocytic cells, leaving few remaining to fight infections in the tissues.

Human Physiology: From Cells to Systems (MindTap Course List)

9th Edition

ISBN:9781285866932

Author:Lauralee Sherwood

Publisher:Lauralee Sherwood

Chapter12: Body Defenses

Section: Chapter Questions

Problem 14RE

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IgM antibodies are much more efficient than IgG at activating the complement cascade. However, under certain circumstances, IgG antibodies will activate the complement pathway. One example of a situation in which IgG binding to its antigen will not trigger the complement cascade is when the IgG antibodies are neutralizing a bacterial toxin protein by blocking the receptor-attachment site on the toxin. the IgG antibodies are binding self-antigens, such as chromatin released from dead cells. the IgG antibodies bind to a bacterial surface by recognizing a repetitive polysaccharide component of the bacterial capsule. the IgG antibodies bind to a viral capsid protein that is present in more than 100 copies on the viral particle surface.
Although the complement cascade can be initiated by antibodies bound to the surface of a pathogen, complement activation is generally considered to be an innate immune response. This is because: Two of the three pathways for complement activation are initiated by constitutively produced recognition molecules that directly interact with microbial surfaces. When the complement cascade leads to the formation of a membrane-attack complex, the pathogen is killed. Several of the soluble products generated by complement activation lead promote the inflammatory response. Complement proteins bound to the pathogen promote uptake and destruction by phagocytic cells. The C3 convertase is only produced when complement activation is initiated by antibody binding to a pathogen.
Neutralizing antibodies are effective at preventing infection or toxicity mediated by pathogens or their toxic products. In fact, nearly all vaccines currently in use function by eliciting neutralizing antibodies. One example is the tetanus vaccine, in which neutralizing antibodies are generated against an inactivated form of the tetanus toxin (the tetanus toxoid). The most important feature of a neutralizing antibody is having high affinity for the antigen. being efficient at activating the complement cascade. having a high degree of multivalency, such as being a pentamer or hexamer of immunoglobulin monomers. being present at a high concentration in the circulation. 0 0 0 0
The terminal complement proteins polymerize to form pores in membranes that can kill certain pathogens. The terminal components of the complement pathway assemble to form a membrane attack complex that can induce pathogen lysis and death. Yet, evidence indicates that this feature of complement is less important than the earlier steps that promote pathogen opsonization and induce inflammation. This conclusion is based on: In vitro experiments showing that very few species of bacteria are susceptible to lysis by the membrane attack complex Experiments indicating that only bacteria, but not viruses or fungi, are susceptible to lysis by the membrane attack complex The very low levels of terminal complement components in the serum The fact that other mammalian species lack the terminal components of the complement pathway needed to form the membrane attack complex The limited susceptibility to infections of patients with deficiencies in terminal complement components
Ingestion of complement-tagged pathogens by phagocytes is mediated by receptors for the bound complement proteins. Even when the complement cascade fails to proceed beyond generating the C3 convertase, complement activation is effective at inducing pathogen uptake and destruction. This process of immune protection is mediated by: Activation of complement inhibitory receptors on phagocytes that promote pathogen uptake Activation of soluble proteases in the serum that disrupt pathogen membranes Engagement of complement receptors on phagocytes by C3b and its cleavage products which promotes phagocytosis Engagement of complement receptors on B cells that promotes antibody production Stimulation of antimicrobial peptide secretion by phagocytes
Mannose binding lectins (MBL) and ficolins are the two classes of proteins that can initiate the lectin pathway of complement activation. These proteins are selective for activating complement on the surfaces of microbial pathogens rather than host cells because: Their higher-order oligomeric structure can be assembled only after the monomers first bind to pathogen membranes. They only recruit MASP (MBL-associated serine proteases) proteins when bound to pathogen surfaces and not when bound to host cells. They only undergo the conformational change needed to activate MASP proteins when bound to a pathogen and not when bound to a host cell. They only bind to carbohydrate side chains and oligosaccharide modifications found on pathogen surfaces but not on host cell membranes. The activated MASP proteins are rapidly inactivated by hydrolysis when present on the surface of a host cell.
The alternative pathway is an amplification loop for C3b formation that is accelerated by properdin in the presence of pathogens. The alternative pathway of complement activation has an important role in innate immunity, due to its ability to greatly amplify the amount of C3b deposited onto the pathogen surface. This amplification occurs because: The C3 convertase of the alternative pathway is much more active than those of the classical and lectin pathways. The C3 convertase of the alternative pathway works as a soluble enzyme in the plasma. The C3 convertase of the alternative pathway cannot be inactivated by complement regulatory factors in the host. The C3 convertase of the alternative pathway is more efficiently recruited to pathogen surfaces than the C3 convertases of the classical and lectin pathways. The C3 convertase of the alternative pathway contains C3b, and can generate more of itself.
Opsonization of pathogens by both antibodies and complement proteins (C3b) leads to uptake and destruction of the pathogen by phagocytic cells that express both Fc receptors and complement receptors. Which of the following in the figure below is the most efficient form of dual opsonization of the pathogen by antibody and C3b to maximize phagocytosis?
B cells express a complement receptor that binds to C3b cleavage products, such as iC3b and C3dg. When a B cell with an antigen receptor that specifically recognizes that pathogen also has its complement receptor stimulated because the pathogen is opsonized with these C3 fragments, B cell activation is greatly enhanced. Due to this mechanism, B cells can be activated by much lower concentrations of antigen (in this case, the pathogen) than if the antigen is devoid of complement components. This mechanism functions to: Ensure that pathogens are readily detected by the adaptive immune system before they replicate to high levels in the host Prevent B cells from being activated in response to antigens that are not pathogens Allow B cells to phagocytose the pathogen and help destroy it Induce increased rounds of B cell replication to make more pathogen-specific B cells Allow the B cell to block pathogen replication by interfering with multiple pathogen surface functions
Pathogens produce several types of proteins that can inhibit complement activation. The importance of complement activation as an innate immune defense against infections is illustrated by: The evolution of complement avoidance strategies by many pathogens The large number of proteins involved in the complement pathway The large number of complement regulatory pathways expressed by the host The existence of three different mechanisms for initiating complement activation The ability of the membrane attack complex to lyse some pathogens
The classical complement pathway is initiated by C1q binding to the surface of a pathogen. In some cases, C1q can directly bind the pathogen, for instance by recognizing proteins of bacterial cell walls, but in most cases C1q binds to IgM antibodies that are bound to the pathogen surface. How does this IgM-binding feature of C1q contribute to rapid, innate immune responses rather than to slow, adaptive responses? C1q induces B lymphocytes to begin secreting antibody within hours of pathogen exposure. Natural antibody that binds to many microbial pathogens is produced prior to pathogen exposure. C1q binds to C-reactive protein which then binds to IgM on the pathogen surface. C1q directly induces inflammation, recruiting phagocytes and antibodies from the blood into the infected tissue. C1q binds to dendritic cells in the infected tissue, inducing them to secrete inflammatory cytokines.
Complement receptors and Fc receptors both contribute to removal of immune complexes from the circulation. Surprisingly, individuals with defects in the early components of the classical complement cascade (i.e., C1, C2, or C4) suffer from an autoimmune type of kidney damage, rather than from an immunodeficiency leading to increased susceptibility to infections. Why do these complement defects lead to autoimmune kidney damage?