Lecture 04: The Complement System Overview [SEQ 1]

The C5 convertase, formed by the addition of C3b to the C4b2a complex, cleaves C5 into two fragments: C5a and C5b. C5a acts as an anaphylatoxin, attracting and activating immune cells. C5b initiates the assembly of the Membrane Attack Complex (MAC). It recruits C6, C7, and C8 to the membrane, leading to the insertion of C8 and the polymerization of C9, forming a cylindrical pore in the bacterial membrane. This pore disrupts the bacterial cell's integrity, allowing the entry of antimicrobial enzymes and leading to cytosol leakage, bacterial lysis, and cell wall instability.

C3b, a highly reactive fragment of C3, binds covalently to microbial surfaces via exposed -OH or -NH2 groups. This tagging process is called opsonization. The bound C3b acts as an opsonin, serving as a ligand for complement receptors on phagocytic cells like macrophages and neutrophils. This recognition facilitates the engulfment and destruction of the tagged microbe by the immune system.

C5a, a potent anaphylatoxin, attracts and activates immune cells like neutrophils, enhancing the inflammatory response and recruitment of phagocytes to the site of infection. Conversely, C5b initiates the formation of the Membrane Attack Complex (MAC), which directly lyses bacteria by creating pores in their membranes, disrupting their integrity and leading to cell death. Both actions contribute to the effective elimination of bacterial invaders.

<p>Host cells express regulatory proteins that inhibit the complement cascade. For example, CD59 on mammalian cell membranes blocks the assembly of the C5b-C8 complex, preventing the recruitment of C9 and the formation of the Membrane Attack Complex (MAC). This mechanism safeguards host cells from the destructive effects of complement activation. Furthermore, complement regulatory proteins like Factor H bind to host cell surfaces and promote the inactivation of C3b, further limiting complement-mediated damage.</p> Signup and view all the answers

<p>A deficiency in the terminal complement pathway, which leads to the formation of the Membrane Attack Complex (MAC), renders individuals susceptible to infections, particularly with encapsulated bacteria like <em>Neisseria</em> species. The MAC is crucial for directly lysing these bacteria. Without this mechanism, the body relies heavily on other immune responses, such as opsonization and phagocytosis, which may not be sufficient to combat these pathogens effectively, leading to recurrent infections.</p> Signup and view all the answers

<p>C1s, a protease activated by the C1 complex, cleaves both C4 and C2. When C1s cleaves C4, it generates C4b, which attaches to the bacterial surface. Subsequently, C1s cleaves C2 into C2a and C2b, with C2a associating with C4b to form the classical C3 convertase (C4bC2a).</p> Signup and view all the answers

<p>The lectin pathway is initiated by the binding of mannose-binding lectin (MBL) to repeating mannose residues found on bacterial and yeast surfaces. Conversely, the classical pathway requires the presence of antibodies bound to the pathogen surface for activation, with C1q binding to the Fc region of these antibodies.</p> Signup and view all the answers

<p>The alternative pathway is unique in that it doesn't require antibodies or microbes for initiation. Instead, the activation begins with the spontaneous hydrolysis of C3 in the blood, forming C3(H2O). This molecule then binds to Factor B, which is cleaved by Factor D, resulting in the formation of the initial C3 convertase, C3(H2O)Bb. The alternative pathway also amplifies the complement response by generating a larger pool of C3b molecules on microbial surfaces, further enhancing the formation of C3 convertases.</p> Signup and view all the answers

<p>The alternative pathway's C3 convertase, C3bBb, can bind an additional C3b molecule, forming the C5 convertase, C3bBbC3b. This convertase plays a crucial role in the terminal pathway, by cleaving C5 into C5a and C5b, initiating the formation of the membrane attack complex (MAC).</p> Signup and view all the answers

<p>The complement system is part of the innate immune system because it's a pre-existing, non-specific defense mechanism that's always present and can be immediately activated by the presence of foreign substances like bacteria or viruses. Unlike the adaptive immune system, which requires prior exposure to a pathogen to generate a response, the complement system provides an immediate frontline defense against infection.</p> Signup and view all the answers

<p>The complement system primarily functions in: 1) <strong>Killing:</strong> The formation of the membrane attack complex (MAC) leads to the lysis of foreign cells, such as bacteria. 2) <strong>Tagging:</strong> Complement proteins like C3b can bind to pathogen surfaces, acting as opsonins, making them more easily recognized and engulfed by phagocytes. 3) <strong>Proinflammatory signaling:</strong> Complement components like C5a can attract inflammatory cells like neutrophils and macrophages to the site of infection, contributing to the overall immune response.</p> Signup and view all the answers

<p>Mannose-binding lectin (MBL), a lectin produced by the liver, binds to repeating mannose residues found on microbial surfaces, such as bacteria and yeast. It interacts with MBL-associated serine proteases (MASPs), particularly MASP2. Upon binding to a microbial surface, MBL activates MASP2, which then cleaves C4 and C2, initiating the formation of the C3 convertase in the lectin pathway.</p> Signup and view all the answers

<p>The alternative pathway can be activated by both microbial surfaces and the spontaneous hydrolysis of C3 in the blood. Microbial surfaces trigger the alternative pathway by directly binding C3b, providing a platform for the formation of the C3 convertase. The spontaneous hydrolysis of C3, generating C3(H2O), also triggers the pathway, leading to the formation of an initial C3 convertase, C3(H2O)Bb. This inherent ability to activate in both scenarios highlights the alternative pathways' versatility in the complement response.</p> Signup and view all the answers

Part of the innate immune system found in blood plasma, produced in liver.

An enzyme complex crucial for activating the complement system and opsonization.

Complement activation starting with antibody binding, involving C1 complex and forming C3 convertase.

Complement activation initiated by lectins binding to carbohydrates on microbial surfaces.

A complement activation pathway that does not require antibodies, starts with hydrolyzed C3.

Enzyme formed from C3 convertase that cleaves C5, crucial for forming the membrane attack complex (MAC).

Final formation of proteins that can perforate foreign cell membranes, leading to lysis.

The process of tagging foreign material for destruction by immune cells.

Anaphylatoxin generated from C5, it recruits and activates immune cells.

Membrane Attack Complex, formed by C5b along with C6, C7, C8, and C9, that creates pores in bacterial membranes.

Mechanisms by which the body prevents complement from attacking its own cells, such as through CD59.