Introduction
The complement system is a critical component of the innate immune system, renowned for its role in the immediate defense against pathogens. This complex network, composed of over 50 circulating and membrane-bound proteins, orchestrates a multifaceted response against pathogenic microorganisms that penetrate the body's initial mechanical and
chemical defenses. Most complement proteins are synthesized in the liver, though local production by fibroblasts, T and B cells, adipocytes, and endothelial cells contributes significantly, particularly in immune-privileged sites like the brain and the eye. Discovered as the heat-sensitive fraction of plasma that complements antibody activity, this system is crucial not only in inflammation and microbial defense but also in homeostatic processes such as the removal of dying cells and regulation of humoral immunity.
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Complement Activation Pathways
Complement activation involves structural rearrangements, proteolytic cleavages, and complex assemblies, transitioning from inactive to active states. It operates through three primary pathways: classical (CP), lectin (LP), and alternative (AP).
The Classical Pathway
Initiated by the recognition of pathogen-associated molecular patterns (PAMPs) by soluble pattern recognition molecules (PRMs) such as C1q. In antibody-dependent CP activation, C1q binds to the Fc portions of multivalent IgG-antigen complexes or antigen-bound IgM. Other ligands, such as C-reactive protein (CRP), pentraxin-3 (PTX-3), serum amyloid P component, β-amyloid fibrils, and tissue damage elements, can also initiate CP. C1r and C1s serine proteases follow C1q-ligand binding, leading to the cleavage of C4 into C4a and C4b, and the formation of the C3 convertase C4b2a. This complex cleaves C3, generating the major opsonin C3b.
The Lectin Pathway
The LP is activated by carbohydrate recognition molecules like mannan-binding lectin (MBL), collectin-LK (CL-LK), and ficolins. These oligomeric PRMs bind to specific carbohydrate patterns on pathogens, facilitating the activation of MBL-associated serine proteases (MASPs), particularly MASP-2, which cleaves C4 and C2 to form the C3 convertase C4b2a, similar to the CP pathway.
The Alternative Pathway
AP can amplify signals from CP and LP by forming the C3bBb C3 convertase. Properdin (FP) stabilizes this convertase, while spontaneous generation of C3 (H2O) initiates the AP independently of direct recognition patterns. This feedback mechanism generates extensive C3b deposition, which is crucial for pathogen clearance.
Fig. 1 Molecular view of complement activation (Bajic G., et al. 2015).
Regulation of Complement Activation
Host cells are protected from complement-induced damage by a suite of soluble and membrane-bound regulators. Factor H (FH) is a critical regulator of the AP, possessing decay-accelerating activity and serving as a cofactor for factor I (FI), which cleaves C3b into inactive fragments.
C4-binding protein (C4BP) regulates the CP and LP similarly by accelerating the decay of C4b2a and facilitating FI-mediated cleavage of C4b. C1 inhibitor (C1-INH) irreversibly inhibits C1r, C1s, MASP-1, and MASP-2, preventing unwarranted complement activation.
Membrane-bound regulators include membrane cofactor protein (MCP/CD46), decay-accelerating factor (DAF/CD55), and CD59, which inhibit complement activation on host cells through various mechanisms.
Complement Receptors and Their Roles
Complement receptors are integral to the function of the complement system, mediating various immune responses by binding to complement components. The anaphylatoxins C3a and C5a, generated during complement activation, bind to specific receptors on host cells, triggering a range of inflammatory responses.
C3a receptor (C3aR) and C5a receptors (C5aR1 and C5aR2) are seven transmembrane domain (7TM) receptors that play significant roles in immune cell signaling. C5aR1, a G protein-coupled receptor (GPCR), is particularly important in mediating pro-inflammatory responses such as chemotaxis, oxidative burst, and cytokine production. C5aR2, initially thought to be a decoy receptor, is now recognized for its role in modulating immune responses, including those in adipocyte metabolism and immunity.
Signaling through C3aR and C5aR1 is implicated in various chronic inflammatory diseases, such as rheumatoid arthritis, inflammatory bowel disease, asthma, and allergy. Interestingly, C3a can also elicit anti-inflammatory responses depending on the cell type and the phase of inflammation. For example, C3a has been shown to promote tissue regeneration and development in the liver and eye, highlighting its diverse roles in the immune system.
In addition to anaphylatoxin receptors, there are several complement receptors that mediate the effects of C3b and its degradation products. Complement receptor 1 (CR1 or CD35) is a large CCP module-based glycoprotein expressed on various immune cells, including erythrocytes and phagocytes. CR1 binds to C3b and C4b with high affinity, playing a critical role in clearing immune complexes and promoting phagocytosis.
Complement receptor 2 (CR2 or CD21) is primarily found on B cells and follicular dendritic cells (FDCs). CR2 is involved in trapping C3-opsonized antigens and stimulating B cells for affinity maturation, isotype switching, and memory formation. The interaction between CR2 and its ligands (C3b, iC3b, and C3d) is crucial for the activation of B cells and the initiation of adaptive immune responses.
CR3 and CR4 are integrin-type receptors expressed on phagocytes, and they play essential roles in promoting phagocytosis of opsonized pathogens and immune complexes. CR3, also known as CD11b/CD18 or Mac-1, recognizes iC3b, while CR4 (CD11c/CD18) binds to C3b. These receptors are involved in the recruitment and activation of immune cells at sites of infection and inflammation.
Conclusion
The complement system is a complex and tightly regulated network of proteins that plays a critical role in host defense and immune homeostasis. The regulation of complement activation is essential for preventing damage to host tissues and ensuring that immune responses are directed appropriately toward pathogens and other threats. Complement factor H, CFHRs, C4BP, and membrane-bound regulators such as MCP, DAF, and CD59 are all vital components of this regulatory network.
The interplay between complement regulators and receptors is crucial for maintaining immune balance, and dysregulation of this system can lead to a wide range of diseases. As our understanding of complement regulation continues to evolve, it opens up new possibilities for therapeutic interventions aimed at modulating the complement system in various diseases, from autoimmune disorders to cancer. By targeting specific regulators and receptors, we can develop more precise and effective treatments, improving patient outcomes and advancing the field of immunotherapy.
References
- Bajic G., et al. Complement activation, regulation, and molecular basis for complement‐related diseases. The EMBO Journal. 2015, 34 (22): 2735-57.
- Nayak A., et al. Complement and non-complement activating functions of C1q: a prototypical innate immune molecule. Innate Immunity. 2012, 18 (2): 350-63.
- Degn S. E., Thiel S. Humoral pattern recognition and the complement system. Scandinavian Journal of Immunology. 2013, 78 (2): 181-93.
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