Strict Regulation and Inhibition of the Complement System
Any biological system that has even the slightest potential to damage the host must be strictly regulated. As seen with the alternative pathway, which initiates spontaneously, the complement system can undergo amplification via a strong positive feedback loop, indicating the necessity for careful control. Activation of the complement must be confined to the surfaces of pathogens and should only target pathogens or damaged host cells that need to be removed and cleaned from the system.
Furthermore, the complement system generates inflammatory anaphylatoxins during its activation process, which can lead to anaphylactic situations similar to allergic shock. Therefore, the activation of the complement must be meticulously controlled to prevent unintended damage to normal host tissues during immune responses.
Most complement components are inherently unstable with very short half-lives. For instance, the C3 convertase (C3bBb) of the alternative pathway has a half-life of less than five minutes without stabilization. The shorter these half-lives, the lower the potential for causing severe harm to the host. As expected, the human body possesses several mechanisms to inhibit excessive complement activation. Let’s first examine the inhibitory mechanisms related to C3 convertase generation.
Inhibition Mechanism of C3 Convertase Generation
The strength of overall complement activity is determined by the level of complement activation. The degree of complement activation is proportional to the activation of C3 convertase. A high abundance of C3b will lead to an increased generation of C5 convertase. Contrary to the stabilization of the inherently unstable C3 convertase known as C3bBb by the protein properdin, there are complement regulatory proteins that act on the C3b molecule to either prevent the formation of C3 convertase or promote its rapid breakdown.
For example, membrane-bound decay-accelerating factor (DAF, or CD55) and membrane cofactor of proteolysis (MCP, or CD46) compete with factor B to bind to the C3b fragments that are attached to the cell surface. By doing so, DAF or MCP interferes with factor B's ability to bind to the cell surface-associated C3b, thus preventing C2 from binding to C4b on the cell surface or factor B from connecting with C3b on the cell surface. This blockage ultimately inhibits the pathway for C3 convertase generation, naturally suppressing its production.
Complement regulatory proteins
Factor I is an important inhibitor since it has the ability to degrade already cleaved and activated C3b and C4b fragments in the presence of co-factors such as C4b-binding protein (C4BP), Factor H, complement receptor 1 (CR1, or C3b/C4b receptor, or CD35), and membrane cofactor of proteolysis (MCP, or CD46). It is crucial to note that Factor I operates only under conditions where it is bound to these co-factors. Factor I first cleaves C3b to form iC3b and, through subsequent processes, can permanently inactivate it, thus preventing the generation of C3 convertase.
The complement receptor type 1 (CR1 or CD35) on host cells operates similarly to DAF and MCP. However, microbial cell walls lack sufficient MCP and CR1, making the degradation of C3b less frequent. C4b-binding protein (C4BP) acts primarily as an inhibitor mainly in the classical pathway before the proteins bind to cell membranes. As its name suggests, C4BP binds to C4b to inhibit the generation of C3 convertase, but it also binds to C3b, although with much weaker intensity.
Importance of Complement Factor H in Host Defense
Complement factor H is crucial from the perspective of host defense. It competes with complement factor B in the alternative pathway, binding to C3b. Factor H has a high affinity for sialic acid residues, which are glycoproteins on the cell membranes of vertebrates, including humans, allowing it to bind effectively to C3b on host cells. Essentially, by preferentially binding to C3b on host cells, factor H inhibits factor B from binding to C3b, thereby blocking the activation of C3b within the host cells.
It's important to note that microorganisms lack sialic acid residues, which makes them preferred targets for factor B, leading to increased formation of C3 convertase. Additionally, DAF (decay-accelerating factor), MCP (membrane cofactor protein), and CR1 (complement receptor 1) all facilitate the separation of the already formed two forms of C3 convertase (C4b2a, C3bBb) back to their unbound states before they were combined, thereby protecting host cells from excessive activation (see diagram below).
Other inhibition mechanisms
C1 inhibitor
The activation of C1 in the classical pathway is regulated by C1 inhibitor (C1INH), which is a serine protease inhibitor (serpin). When C1q is activated, it separates C1r and C1s from the C1 complex, thereby inhibiting the activation of C1.
vitronectin, protectin(CD59)
The membrane attack complex (MAC), which is polymerized around the C5b fragment cut by the C5 convertase, can mistakenly insert itself into the surface of host cells adjacent to the pathogen’s surface where complement activation has occurred. Various plasma proteins, such as vitronectin (S-protein), bind to the C5b67, C5b678, and C5b6789 complexes, preventing their random insertion into the cell membrane. Additionally, there is a unique protein called protectin (CD59) on the host's cell membrane that prevents the final synthesis stage of C9 fragments from binding to the C5b678 complex.
Carboxypeptidase
Carboxypeptidases are a general type of enzyme that remove amino acids from the carboxyl terminal of proteins. Among these, specific enzymes that mediate the regulation of anaphylatoxin activity are carboxypeptidase N, B, and R. These enzymes rapidly inactivate anaphylatoxins C3a and C5a by removing the arginine (Arg) residues from their carboxyl terminals.
Table of Complement Components Associated with Complement Inhibition
The following table summarizes the elements of the complement system related to complement inhibition. I borrowed an Illustrated representations of major inhibitors from a textbook to help clarify these concepts visually, making it easier to understand.
Complement system and autoimmunity
The mechanisms that regulate complement activation at appropriate levels are crucial. Individuals who lack molecules that catalyze the deposition (opsonization) of C3 or C3b fragments become vulnerable to infections caused by a wide range of extracellular bacteria, including Streptococcus pneumoniae. Conversely, if these fragments are overly deposited or activated excessively, the inflammatory response can attack the host, highlighting the importance of maintaining a balanced complement system. Indeed, when complement fragments are present in excessively high concentrations, they can trigger autoimmune diseases. As a result, the complement system is considered a target for autoimmune therapies. [1]
Pathogens' strategies to Evade complement activation
Thanks to its ability to rapidly recognize and eliminate pathogens, the complement system is a highly efficient component of the immune system. However, pathogens have evolved various mechanisms to evade complement attacks and to protect themselves for survival. Specifically, all stages of complement activation, including the generation of C3 convertase and C5 convertase, can become targets for these pathogens. Let's examine some examples of the evasion strategies utilized by pathogens.
To disguise themselves as their hosts, pathogens pull regulatory proteins meant for host protection onto their surfaces. For instance, the Gram-negative bacterium Neisseria meningitidis expresses factor H binding protein (fHbp) and PorA membrane proteins that bind to C4BP. By gathering factor H and C4BP to its surface, the pathogen cleverly inactivates C3b fragments bound to its surface, thereby shielding itself from the formidable assault of the complement system.
In the case of Gram-positive Staphylococcus aureus, the Staphylococcal protein A (Spa) binds to antibodies at their Fc regions, directly preventing this region from binding to C1. Another protein, staphylokinase (SAK), cleaves antibodies bound to the pathogen cell membrane, further blocking complement activation.
[References]
[1] Kuby Immunology. 8th New York: Macmillan Learning, 2019. Text. MLA Style. Punt, Jenni, Stranford, Sharon A, Jones, Patricia P, Owen, Judith A[Basic Data]
Kuby Immunology. 8th New York: Macmillan Learning, 2019. Text. MLA Style. Punt, Jenni, Stranford, Sharon A, Jones, Patricia P, Owen, Judith A.
Janeway's immunobiology. Kenneth Murphy, Janeway Jr., Paul Travers, Walport Sir. 9th Edition, New York, Garland Science/Taylor & Francis Group, LLC, [2016]
Fundamental Immunology 5th edition (August 2003): William E. Paul (Editor). Philadelphia: Lippincott Williams & Wilkins, c2003.
Roitt's Essential Immunology, Thirteenth Edition. Peter J. Delves, Seamus J. Martin, Dennis R. Burton, and Ivan M. Roitt. Published 2017 by John Wiley & Sons, Ltd
