The complement system plays a major role in host protection against invasive pathogens, in maintenance of organism’s homeostasis, and in immune complex processing. Involved in more than 40 zymogens, receptors and regulators, the complex system can be activated via 3 separate activation pathways which appear at different times in evolution: the classical, alternative, and lectin pathways.
Every step of the enzymatic cascade is under strict regulation to avoid excessive or insufficient activation. In immune reactions, two activation pathways appear before the evolution of the adaptive immune system, because they do not require antibody for initiation. Three pathways come together to activate C3, the principle opsonic protein of the complement cascade, and all continue together to the generation of membrane attack complex (MAC) for lysis of apoptotic/necrotic cells and microbes.
Genetic Disease
The indispensable role of complement system in immune system reveals that any deficiency in complement proteins may cause increased susceptibility to a variety of diseases, such as genetic disease. Usually, the complement defects are rare due to the rigorously genetic control, while defects in the proteins in circulation and on cell membranes that downregulate complement to limit uncontrolled inflammation are more common. These deficiencies can be inherited or acquired.
The typical complement related genetic disorder is angioedema, which is characterized by nonpitting edema of the dermis and subcutaneous layers. The acute, recurring, and self-limiting edematous episodes can occur on face, extremities, trunk, upper airways, genitals or the gastrointestinal tract, in which airway swelling is life-threatening. Hereditary angioedema and acquired angioedema are the common branches and both are closely associated with complement components.
Complement Regulatory Proteins
The complement system is an essential component of the innate immune response, targeting pathogens, exacerbating inflammation, and mediating host defense through a series of protein hydrolysis activation steps. Although the complement system is powerful, its uncontrolled activation can lead to tissue damage and immune dysregulation. Complement regulatory proteins are essential regulators that fine-tune this cascade of responses, ensuring host protection without collateral damage.
Regulator Types | Complement Regulatory Proteins | Mechanism of Action |
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Circulating complement regulators | C1 Inhibitor (C1-INH) | Classical pathway regulation: C1-INH binds to activated C1r and C1s within the C1 complex (C1qC1r2C1s2), irreversibly inhibiting their activity and preventing the downstream cleavage of C4 and C2. |
Lectin pathway regulation: Similarly, C1-INH inhibits the mannose-binding lectin-associated serine proteases (MASPs), blocking their ability to activate C4 and C2. | ||
Factor H | Competition with Factor B: Factor H competes with Factor B for binding to C3b, effectively inhibiting the formation of the alternative pathway C3 convertase (C3bBb). | |
Cofactor activity: Factor H serves as a cofactor for Factor I, facilitating the proteolytic degradation of C3b to iC3b, an inactive fragment incapable of further propagation in the cascade. | ||
Surface selectivity: Factor H preferentially binds to host cell surfaces that express sialic acid and glycosaminoglycans, distinguishing host cells from pathogens and ensuring selective regulation. | ||
Membrane-bound complement regulators | Decay-accelerating factor (DAF) | Convertase dissociation: DAF accelerates the decay of C3 and C5 convertases (C3bBb and C4b2a, respectively) by displacing their enzymatic subunits (Bb or C2a). This disruption halts the cleavage of C3 and C5, thereby inhibiting the downstream cascade. |
Membrane cofactor protein (MCP, CD46) | Cofactor role: MCP binds C3b and C4b deposited on cell surfaces, enabling Factor I to cleave these components into inactive fragments (iC3b and C4d). | |
Protection of host cells: By facilitating the inactivation of C3b and C4b, MCP prevents further propagation of the cascade on host cells, shielding them from complement-mediated damage. | ||
CD59 (Protectin) | MAC inhibition: CD59 binds to C8 and C9 during MAC assembly, blocking the polymerization of C9 into the pore-forming structure. This action prevents the formation of a functional MAC, thereby protecting host cell membranes from lysis. |
Complement regulatory proteins play a critical role in maintaining immune homeostasis by preventing excessive or misdirected complement activation. Dysregulation of this finely balanced system usually stems from genetic mutations or the presence of autoantibodies and may have profound biological and pathological consequences.
C1-INH is a serine protease inhibitor that regulates the classical complement pathway by inhibiting the protein hydrolyzing activity of C1r and C1s. Its deficiency leads to hereditary angioedema (HAE). On the other hand, autoantibodies can neutralize C1-INH function and actually reproduce the defective state despite normal C1-INH gene expression. This is often observed in acquired angioedema (AAE).
HAE is a rare disorder, which belongs to the group of bradykinin-mediated angioedemas. HAE-induced edema can affect the face, the extremities, the trunk, and the genitals. In the gastrointestinal tract, angioedema may mimic an abdominal catastrophe, whereas in the upper airways, it may cause obstruction leading to suffocation. There are two main types of HAE.
C1-INH can inhibit activation of C1 to regulate the complement, coagulation, and fibrinolytic plasma enzyme cascades. The deficiency of C1-INH leads to the uncontrolled, spontaneous activation of C1, and to the consumption of C4 and C2. nC1-INH-HAE is often due to a mutation of the factor XII (F12) gene, which results in the increased functional (amidolytic) activity and can escape inhibition by the C1-inhibitor.
Similar to HAE, AAE can also cause serious and potentially fatal attacks of subcutaneous and submucosal edemas of upper airways, facial structures, abdomen, and extremities, due to inadequate control of BK generation. The main etiology is similarly due to C1-inhibitor deficiency (C1-INH-AAE).
As a key correlation factor in the pathomechanism of genetic disease (HAE and AAE), complement has been studied as an important diadynamic criteria, and is beneficial to predict the severity of diseases. Therefore, the complement components have become an attractive therapeutic target for genetic disease.
The current state of treatment for C1-INH-related genetic disorders is characterized by well-established alternative therapies that provide critical relief and some cutting-edge innovations that open new horizons. The integration of gene therapy, targeted small molecules and precision biologics promises to address the limitations of current approaches.
Therapies | Mechanism of Action | |
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Alternative Therapies | Plasma-derived and Recombinant C1-INH Therapies | Restoration of functional C1-INH suppresses protease activity, rebalancing the kallikrein-kinin system and the complement pathway. |
Kallikrein Inhibitors | Therapies targeting plasma kallikrein, a key mediator in bradykinin generation, have gained traction as indirect strategies to address C1-INH deficiency. These inhibitors offer a targeted approach with minimal complement interference. | |
Bradykinin Receptor Antagonists | Icatibant, a selective bradykinin B2 receptor antagonist, directly counteracts the hyperactivity of bradykinin signaling pathways in C1-INH-deficient conditions. | |
Cutting-edge Innovations | Gene Therapy | Recent advancements in gene-editing technologies, including CRISPR-Cas9, present opportunities for addressing genetic defects in SERPING1. |
Small Molecule Inhibitors | Small molecules targeting upstream complement proteins (e.g., C1q or MASP-2) could prevent excessive complement activation while sparing the broader immune response. | |
Bi-specific Antibodies and Fusion Proteins | Innovative biologics combining complement inhibition with anti-inflammatory properties are under exploration, including engineered constructs targeting multiple pathways implicated in C1-INH deficiencies. |
Creative Biolabs has extensive experience in complement testing, providing clients with a full range of testing services to help develop new complement-targeted therapies to inhibit or enhance complement function in a research setting, and to determine the efficacy and potency of complement-targeted drugs. We have a robust and standardized testing platform, scientists experienced in developing complement assays and expertise in a variety of different technologies and methods to provide fast, reliable, objective and easy-to-interpret results.
Our services include:
Our comprehensive complement platform offers a great number of complement-related products in a rapid and cost-effective manner. If you are interested, please feel free to contact us for more details.
Cat.No | Product Name | Purity | Applications |
---|---|---|---|
CTA-756 | Mouse Anti-Human Cl Inhibitor Mono- clonal Antibody | ≥95% | ELISA; WB; IP |
CTA-058 | Anti-Complement Factor H Monoclonal Antibody | ≥95% | WB; IP |
CTA-620 | Mouse Anti-Human Factor H Monoclonal Antibody [Biotin] | ≥95% | ELISA |
CTA-331 | Rabbit Anti-Human Complement Factor H Polyclonal Antibody | ≥95% | WB; IHC |
CTP-360 | Native Human C1 Inhibitor Protein | >95% by SDS-PAGE | ELISA, Functional Assays |
CTP-033 | Recombinant Human Complement 1 Inhibitor | ≥95% by SDS-PAGE | Activity Assays |
CTP-111 | Recombinant Human Complement Factor H Protein-6His tag | 95% by SDS-PAGE | Bioactivity Assays |
CTP-458 | Native Human Complement Factor H Protein | >95% by SDS-PAGE | ELISA, Functiona Assays |
CTA-001 | Guinea Pig Complement Serum | - | Hemolytic plaque assays; Complement fixation assays; lymphocytotoxicity and hemolytic procedures. |
CTS-003 | Rat Complement Serum | - | Hemolytic plaque assays; Complement fixation assays; lymphocytotoxicity and hemolytic procedures. |
CTS-005 | Human Complement Serum (Single Donor) | - | Hemolytic plaque assays; Complement fixation assays; lymphocytotoxicity and hemolytic procedures. |
CTS-011 | Mouse C57BL6 Complement Serum | - | Hemolytic plaque assays; Complement fixation assays; lymphocytotoxicity and hemolytic procedures. |
CTS-014 | Goat Complement Serum | - | Hemolytic plaque assays; Complement fixation assays; lymphocytotoxicity and hemolytic procedures. |
A: Yes, several promising research directions are being explored in complement therapeutics. Personalized medicine approaches, where treatments are tailored to an individual's specific genetic mutations, show great potential. Additionally, novel drug delivery systems and gene therapies are being investigated to address complement dysregulation at its root caused by repairing or replacing faulty genes.
A: Several approaches are being explored, including monoclonal antibodies that target specific complement components, small molecule inhibitors, gene therapy to correct genetic mutations, and strategies to enhance complement regulation.
A: Eculizumab (Soliris) is a monoclonal antibody that inhibits the complement C5. It is used to treat PNH, a genetic disease characterized by red blood cell destruction. Eculizumab prevents the uncontrolled activation of the complement system in PNH.