Complement System: Key Roles in Immunity and Disease

Understanding the complement system is essential for grasping how our immune system functions and responds to threats. This network of proteins plays a role in identifying and eliminating pathogens, thus maintaining the body’s defense mechanisms. Its significance extends beyond pathogen elimination; it also involves orchestrating inflammation and bridging innate and adaptive immunity.

Despite its beneficial roles, dysregulation of the complement system can lead to various diseases, highlighting its dual nature as both protector and potential adversary.

Complement System Components

The complement system consists of small proteins, primarily synthesized by the liver, that circulate in the blood in an inactive form. These proteins, designated by the letter ‘C’ followed by a number, such as C1, C2, and so forth, are sequentially activated in a cascade-like manner. This activation is typically triggered by the presence of pathogens or immune complexes, leading to a rapid and amplified response. The initial components, like C1, recognize foreign invaders, setting off a chain reaction involving other complement proteins.

As the cascade progresses, the proteins undergo cleavages, forming active fragments. These fragments, such as C3a and C5a, are known as anaphylatoxins and mediate inflammatory responses. They recruit immune cells to the site of infection and enhance vascular permeability, facilitating the movement of immune cells and molecules to the affected area. Meanwhile, other fragments, like C3b, act as opsonins, marking pathogens for destruction by phagocytes.

Activation Pathways

The complement system can be activated through three pathways: the classical, lectin, and alternative pathways. Each pathway is initiated by different triggers but converges on the activation of the central component, C3, leading to a common terminal pathway.

Classical Pathway

The classical pathway is initiated by the binding of the C1 complex to antibodies attached to antigens on the surface of pathogens. This interaction links the adaptive immune system, which produces antibodies, and the innate immune response. The C1 complex is composed of C1q, C1r, and C1s subcomponents. Upon binding to the antibody-antigen complex, C1q undergoes a conformational change that activates C1r and C1s. This activation leads to the cleavage of C4 and C2, forming the C4b2a complex, also known as the C3 convertase of the classical pathway. The C3 convertase then cleaves C3 into C3a and C3b, amplifying the response and facilitating the opsonization of pathogens, recruitment of inflammatory cells, and further progression of the complement cascade.

Lectin Pathway

The lectin pathway is activated by the binding of mannose-binding lectin (MBL) or ficolins to specific carbohydrate patterns on the surface of pathogens. This pathway is independent of antibodies, making it a part of the innate immune response. MBL and ficolins are pattern recognition molecules that, upon binding to their targets, associate with MBL-associated serine proteases (MASPs). The activation of MASPs leads to the cleavage of C4 and C2, similar to the classical pathway, resulting in the formation of the C4b2a complex. This complex acts as the C3 convertase, cleaving C3 into C3a and C3b. The lectin pathway provides a rapid response to pathogens, particularly those with repetitive carbohydrate structures, and plays a role in the early stages of infection before the adaptive immune system is fully activated.

Alternative Pathway

The alternative pathway is unique in that it can be spontaneously activated without the need for specific recognition molecules. This pathway is continuously active at a low level, providing constant surveillance against pathogens. The process begins with the hydrolysis of C3, forming C3(H2O), which can bind factor B. Factor D then cleaves factor B, resulting in the formation of the C3bBb complex, the C3 convertase of the alternative pathway. This convertase is stabilized by properdin, allowing it to cleave additional C3 molecules into C3a and C3b. The alternative pathway serves as an amplification loop for the other pathways and can rapidly escalate the complement response. It is particularly effective against pathogens that have evaded the initial recognition by the classical and lectin pathways, ensuring a robust immune defense.

Membrane Attack Complex

The culmination of the complement cascade is the formation of the Membrane Attack Complex (MAC), a multiprotein structure that plays a role in the immune system’s ability to eliminate threats. The MAC is formed when the terminal components of the complement system, specifically C5b, C6, C7, C8, and multiple C9 molecules, come together to create a pore in the membrane of the target cell. This pore disrupts the integrity of the cell membrane, leading to cell lysis and death. The formation of the MAC directly eliminates pathogens by compromising their cellular structures.

Beyond its role in pathogen destruction, the MAC has implications for how the immune system interacts with host cells. In some instances, the MAC can insert into host cell membranes, potentially leading to unintended damage. To prevent this, host cells possess regulatory proteins, such as CD59, which inhibit the assembly of the MAC on their surfaces. These regulatory mechanisms are crucial for protecting host tissues from complement-mediated damage and maintaining self-tolerance.

Role in Immune Defense

The complement system serves as a sentinel in the immune defense, bridging innate and adaptive immunity while orchestrating a multifaceted response to pathogens. It acts as an early detector, recognizing and responding to threats swiftly to prevent infections from gaining a foothold. By doing so, it forms the first line of defense, engaging pathogens before they can proliferate. This rapid response is particularly advantageous during the initial stages of infection, where speed is of the essence.

Upon activation, the complement system not only marks pathogens for destruction but also modulates the broader immune response. It plays a role in the clearance of immune complexes and apoptotic cells, preventing potential tissue damage and autoimmunity. Complement components have been implicated in shaping adaptive immunity by influencing B and T cell responses, enhancing the body’s ability to remember and respond more effectively to subsequent encounters with the same pathogen.