The Complement System Flashcards
What are three key functions of the complement system?
- Opsonization: The complement system enhances phagocytosis of antigens by marking them for recognition and ingestion by phagocytes. This process is known as opsonization and is primarily mediated by the complement protein C3b.
- Promotion of inflammation: Complement proteins help in promoting inflammation, which serves to limit the spread of infection and attract additional immune cells to the site of infection or injury. Inflammatory responses are facilitated by anaphylatoxins such as C3a and C5a, which are produced during complement activation.
- Lysis of pathogens: The complement system can directly lead to the lysis of pathogens through the formation of the membrane attack complex (MAC). The MAC creates pores in the cell membranes of pathogens, causing water and ions to flow into the cells, leading to their destruction.
Click on Answer for some background notes on the Complement System.
✪ there are 9 main complement proteins
✪ named with a C followed by a number
✪ once cleaved, products are given an a or b
- the a fragment is the smaller anaphylatoxin
- the b fragment is the larger binding portion
✪ C2 is the exception to the above
✪ fragments complex together to form enzymes
- when naming a protein complex its fragments are listed in the order in which they bind e.g. C3 convertase = C4b2a = C4b + C2a. When C3b binds to this complex to form C5 convertase, the complex becomes C4b2a3b.
✪ The complement system can be activated through one of three distinct pathways, each of which converges at the step of C3 cleavage, which kicks off the most important effector functions of the complement system.
Discuss the classical pathway of the complement system.
The classical pathway begins with a protein complex called C1. C1 is made up of three distinct subunits: C1q, C1r and C1s. C1r and C1s are proteases i.e. enzymes that cleave proteins [Diagram 1] [Diagram 2]. They are inactive during normal conditions. During an infection however, circulating C1q can bind directly to some bacterial surfaces, antibodies bound to a pathogen [the antibodies involved are specifically IgG or IgM], or to an acute phase protein called C-reactive protein that also binds to bacterial surfaces [C1q has six globular heads that recognize and bind to the Fc region of the antibodies].
C1q binding causes a conformational change, resulting in autocatalytic activation of C1r. Activated C1r then cleaves and activates C1s.
Once C1 is activated, it cleaves circulating complement proteins C4 and C2. C4b covalently binds to the pathogen’s surface or to pathogen-bound antibodies and C2a binds to C4b, forming the C4b2a complex. This complex is known as the C3 convertase, and it cleaves circulating C3 into C3a and C3b.
[Diagram]
Further notes:
What is the Fc region of an antibody? The Fc region, or fragment crystallizable region, is the tail part of an antibody that interacts with cell surface receptors known as Fc receptors, as well as some proteins of the complement system. This region is crucial for the antibody’s ability to activate the immune system. For example, through binding of Fc receptors, it mediates different phyisological effects of antibodies, such as detection of opsonized particles, cell lysis, and degranulation of mast cells, basophils and eosinophils.
What is degranulation?
Degranulation refers to the process where cells, particularly those involved in the immune response, release the contents of their granules into the extracellular space. These granules contain a variety of substances, such as enzymes, antimicrobial peptides, and other cytotoxic molecules, which play a role in the body’s defense mechanisms. For example, mast cells, upon activation, undergo degranulation to release histamine and other mediators that contribute to inflammation and allergic responses. Similarly, eosinophils degranulate to release substances that combat parasitic infections. Neutrophils also degranulate to release antimicrobial substances that help in controlling infections.
Discuss the lectin pathway of the complement system.
Lectins are proteins that can recognize and bind to specific carbohydrate groups. Some lectins play homeostatic roles within the host, while others act as pattern recognition receptors (PRRs) for pathogen sugars, such as those found on bacterial cell walls or adorning yeast cell surface proteins. There are four lectins that activate the complement system: mannose-binding lectin (MBL), ficolin 1, ficolin 2 and ficolin 3.
MBL is made in the liver and circulates in the bloodstream. It is a multimeric protein with multiple binding sites. It recognizes fructose, mannose, and N-acetylglucosamine. These sugar groups are commonly exposed on microbial polysaccharides but not on host cells. The ficolins are structurally similar to mannose binding lectin except that they bind acetylated sugars instead of mannose groups.
The lectin pathway is triggered when MBP or one of the ficolins binds to its respective sugar on a pathogen. The lectin will then complex with the circulating proteins MASP-1 and MASP-2, which are protease zymogens [homologous to C1r and C1s in the classical pathway]. MASP-1 and MASP-2 become activated and they cleave C4 and C2. C4b and C2a combine to form the C4b2a complex, known as the C3 convertase.
Discuss the alternative pathway of the complement system.
✈ The alternative pathway is initiated spontaneously when C3b directly binds to a microbe or pathogen surface. [Unlike the classical or lectin pathways, it does not rely on antibodies or lectins for activation.]
✈ Circulating Factor B then binds to C3b, and this allows another plasma protein called Factor D to cleave Factor B, resulting in a complex known as C3bBb.
✈ This complex acts as the C3 convertase in the alternative pathway.
✈ [Diagram]
Discuss the common pathway of the complement system.
Various pathways lead to the formation of the complex C3 convertase, which leaves C3 into two parts: C3a and C3b. C3a is an anaphylatoxin that promotes inflammation [it recruits neutrophils and other phagocytes to the site of infection]. C3b can do one of two things:
(1) many molecules of C3b can bind to the surface of the pathogen, coating it in a process called opsonization. This marks the pathogen for destruction by phagocytes e.g. macrophages. Phagocytes have receptors that recognize C3b.
(2) C3b may also bind to existing C3 convertase, creating a C5 convertase. C5 convertase cleaves C5 into C5a and C5b. C5a is released into circulation to recruit phagocytes [anaphylatoxin], while C5b initiates the assembly of membrane attack complex (MAC), leading to pathogen lysis.
Discuss the cascade that leads to the formation of the membrane attack complex.
☯︎ The process begins when C5 convertase cleaves C5 into two fragments: C5a and C5b.
☯︎ C6 then binds to C5b, forming the C5b6 complex.
☯︎ C7 binds to the C5b6 complex. Binding causes a conformational change in C7, which exposes a hydrophobic site on C7, allowing it to insert into the pathogen’s phospholipid bilayer.
☯︎ C8 binds to the complex, and this induces a conformational change that allows C8 to insert into the pathogen’s plasma membrane.
☯︎ This causes 10 to 16 molecules of C9 polymerize within the cell membrane to form a pore that allows water and solutes to flow out of the cell, hence killing it.
[Diagram 1] [Diagram 2] [Diagram 3] [Diagram 4] [Diagram 5]
