regulation of complement-dependent cytotoxicity

Definition

Target type: biologicalprocess

Any process that modulates the frequency, rate or extent of complement-dependent cytotoxicity. [GO_REF:0000058, GOC:TermGenie, PMID:24280217]

Complement-dependent cytotoxicity (CDC) is a crucial immune effector mechanism that eliminates target cells, primarily pathogens and aberrant host cells, through the activation of the complement system. This intricate process involves a cascade of proteins, culminating in the formation of the membrane attack complex (MAC), which disrupts the target cell membrane, leading to cell lysis and elimination.

The regulation of CDC is tightly controlled to ensure appropriate targeting and prevent collateral damage to healthy cells. Key regulatory mechanisms include:

1. **Complement Activation Initiation:** CDC is initiated by the binding of antibodies, known as complement-fixing antibodies, to target cell antigens. These antibodies activate the classical complement pathway, which serves as the primary trigger for CDC.

2. **Complement Convertase Formation:** The classical pathway involves the sequential activation of complement components C1, C4, and C2, leading to the formation of the C3 convertase, a crucial enzyme responsible for cleaving C3 into C3a and C3b. C3b is a key component for the assembly of the MAC.

3. **C3b Deposition and Opsonization:** C3b binds to the target cell surface, serving as an opsonin that enhances phagocytosis by macrophages and neutrophils. This process promotes the clearance of target cells and facilitates the immune response.

4. **MAC Formation:** The deposition of C3b triggers the formation of the C5 convertase, which cleaves C5 into C5a and C5b. C5b initiates the assembly of the MAC, a pore-forming complex composed of C5b, C6, C7, C8, and multiple C9 molecules.

5. **Membrane Disruption and Cell Lysis:** The MAC inserts into the target cell membrane, creating pores that disrupt the cell's integrity. This leads to an influx of water and ions, resulting in cell swelling and eventual lysis, effectively eliminating the target cell.

6. **Complement Regulatory Proteins:** To prevent uncontrolled complement activation and damage to healthy cells, several regulatory proteins control the complement system. These include:

* **C1 inhibitor (C1INH):** Inhibits the activity of the C1 complex, blocking the activation of the classical pathway.
* **Decay-accelerating factor (DAF):** Accelerates the dissociation of the C3 convertase, preventing the formation of the MAC.
* **Membrane cofactor protein (MCP):** Acts as a cofactor for the cleavage of C3b by factor I, preventing the formation of the C5 convertase.
* **Protectin (CD59):** Prevents the assembly of the MAC by blocking the binding of C9 to the C5b-8 complex.

7. **Alternative Complement Pathway:** While the classical pathway is primarily responsible for CDC, the alternative pathway also contributes to the process. The alternative pathway is activated by the direct binding of C3b to target cell surfaces, providing an amplification loop for complement activation.

8. **Immune Cell Activation:** Complement components, such as C3a and C5a, also act as potent anaphylatoxins, stimulating the release of inflammatory mediators and promoting the recruitment of immune cells to the site of infection or inflammation.

In conclusion, the regulation of CDC is a complex and tightly controlled process involving a cascade of proteins, regulatory mechanisms, and immune cell interactions. This sophisticated system ensures that target cells are effectively eliminated while preventing collateral damage to healthy cells, safeguarding the integrity of the host.
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