Lecture 04: Complement System Overview and Pathways [SEQ 2]

Complement proteins, particularly C3b, bind to microbial cell surfaces via their reactive thioester bonds, targeting these cells for destruction. However, host cells express regulatory proteins like CD59, which inhibit the formation of the membrane attack complex (MAC) by blocking the recruitment of C9. This prevents the formation of pores in the host cell membrane and protects them from complement-mediated lysis.

The complement system contributes to opsonization by attaching C3b and C4b to bacterial surfaces. These complement components act as ligands for complement receptors on phagocytes, enhancing the recognition and engulfment of the microbes. In addition, complement activation produces anaphylatoxins like C5a, which act as pro-inflammatory mediators. These mediators attract immune cells like leukocytes and neutrophils to the site of infection, amplifying the inflammatory response.

The MAC is assembled by the sequential recruitment of complement components C5b, C6, C7, C8, and multiple C9 molecules. C5b initiates the assembly, followed by C6 and C7 binding to the membrane. C8 inserts into the membrane, and finally, C9 molecules polymerize to form a transmembrane pore. This pore disrupts the bacterial membrane, allowing the entry of antimicrobial enzymes and leading to cytosol leakage, bacterial lysis, and cell wall instability.

<p>Terminal complement deficiency refers to the lack of functional C5, C6, C7, C8, or C9 proteins, which are essential for the formation of the MAC. This deficiency renders the immune system unable to effectively lyse bacteria and other pathogens. Without the MAC's pore-forming ability, these pathogens can evade immune defenses and proliferate, resulting in recurrent infections.</p> Signup and view all the answers

<p>Both C3a and C5a are anaphylatoxins, cleaved products of complement proteins that trigger inflammatory responses. C3a contributes to the attraction and activation of leukocytes, while C5a is even more potent in this role. C5a also directly activates mast cells, leading to the release of histamine and other inflammatory mediators, amplifying the inflammatory response.</p> Signup and view all the answers

<p>The classical pathway initiates with antibody binding to an antigen, triggering the activation of the C1 complex, which consists of C1q, C1r, and C1s. The lectin pathway, on the other hand, is initiated by the binding of mannose-binding lectin (MBL) to mannose residues on bacterial surfaces, activating MBL-associated serine proteases (MASPs), particularly MASP2.</p> Signup and view all the answers

<p>C3 convertase is a key enzyme in the complement system responsible for the activation of C3, a central component of the cascade. Two primary forms of C3 convertase exist: C4bC2a, formed in the classical and lectin pathways, and C3bBb, generated in the alternative pathway, each with specific assembly processes involving different complement components.</p> Signup and view all the answers

<p>The alternative pathway, unlike the classical and lectin pathways, does not require antibodies or specific microbial patterns for initiation. It begins with the spontaneous hydrolysis of C3 in the blood, generating C3(H2O). This molecule then binds to Factor B, forming a complex that is susceptible to cleavage by Factor D, resulting in the release of Bb and the formation of the initial C3 convertase, C3(H2O)Bb.</p> Signup and view all the answers

<p>Opsonization refers to the process of tagging foreign material with proteins to enhance its recognition and uptake by phagocytes. In the complement system, C3b is a crucial opsonin. Lysis, on the other hand, is the direct killing of foreign cells. The membrane attack complex (MAC), formed by the assembly of complement components C5b through C9, perforates cell membranes, leading to cell death.</p> Signup and view all the answers

<p>The C1 complex is a multi-molecular structure composed of C1q, C1r, and C1s. C1q, a large hexamer with six globular heads, binds to the Fc region of two adjacent antibodies, leading to conformational changes that activate C1r. C1r then proteolytically cleaves C1s, allowing C1s to cleave C4, initiating the downstream cascade.</p> Signup and view all the answers

<p>The MAC is a complex structure formed from components C5b through C9 and is responsible for cell lysis. C5b binds to C6 and C7, followed by the insertion of C8 into the cell membrane. This complex then recruits multiple C9 molecules forming a pore in the target cell's membrane, disrupting its integrity and leading to cell death.</p> Signup and view all the answers

<p>The alternative pathway acts as an amplification loop by generating more C3b, which further activates the pathway. The initial C3 convertase (C3bBb) binds an additional C3b molecule, forming C3bBbC3b, which is the C5 convertase. This enzyme then cleaves C5, initiating the formation of the MAC and subsequent cell lysis.</p> Signup and view all the answers

<p>The complement system is a crucial component of innate immunity, providing a rapid and non-specific defense against pathogens. Its main functions include killing foreign cells through lysis, tagging them for phagocytosis through opsonization, and triggering inflammation and chemoattraction, attracting immune cells to the site of infection. By activating these effector mechanisms, the complement system initiates a cascade of events that help control and resolve infection, complementing the adaptive immune response.</p> Signup and view all the answers

A complex (C4b2a) that cleaves C3 into C3a and C3b in the complement system.

A complex (C4b2aC3b) formed by adding C3b to C3 convertase, cleaves C5 into C5a and C5b.

A powerful anaphylatoxin that recruits and activates immune cells, enhancing the inflammatory response.

Membrane Attack Complex forms from C5b, C6, C7, C8, and C9, creating a pore to lyse bacteria.

Mechanisms, such as CD59, that prevent complement activation on host cells to avoid self-destruction.

A part of the innate immune system involved in blood plasma responses.

A complement activation pathway initiated by antibodies binding to their antigens.

A pathway activated by Mannose Binding Lectin (MBL) binding to carbohydrates on pathogens.

A complement activation pathway that does not require antibodies, starting with spontaneous hydrolysis of C3.

The process of tagging pathogens for destruction by immune cells.

A structure formed by complement proteins that punctures the membranes of pathogens, causing cell lysis.