Complement Flashcards
Complement is a biochemical _______.
pathway/cascade
Complement is a key part of the ______ immune system, but it also assists ______ immunity
Complement is a key part of the INNATE immune system, but it also assists ADAPTIVE immunity
Complement plays an important part in defense against ______
Pyogenic organisms (bacteria capable of causing local purulent inflammation or generalized infection (pyemia, sepsis). Esp. staphylococci and streptococci
Complement _____ the inflammatory response, _____ pathogens, and _____ the immune response
Complement PROMOTES the inflammatory response, ELIMINATES pathogens, and ENHANCES the immune response
Complement is a component in both the ______ and ____ of immune complex diseases, such as systemic lupus erythematosus.
Complement is a component in both the PREVENTION and PATHOGENESIS of immune complex diseases, such as systemic lupus erythematosus.
What does OIL stand for and why is it relevant to complement?
O: opsonization; I: Inflammation; L: Lysis.
These give the overall big picture function of complement.
Opsonization:
Complement activation acts like a glue to attach substances or antibodies to invading organisms to help phagocytosis by PMN’s/macrophages.
[coat organism with C3b to make it easier for organism to be destroyed]
Inflammation:
Complement activation induces acute inflammation to dilate blood vessels by activating mast cells/basophils and to recruit inflammatory phagocytic cells to eat the invading organism.
Lysis:
Complement activation generates a group of proteins able to penetrate the invading organism’s cell wall to induce lysis.
[poke holes in the membrane]
Complement is one of the earliest/latest responses in innate immunity
earliest - complement shows up in serum protein of edema, and activates the C3b protein.
What is the most important step of the complement pathway?
The cleavage of C3 into C3a and C3b, because this allows C3b to covalently bind to the pathogen surface
Alternative pathway
C3, which is always present in the bloodstream and produced in large amounts by the liver, is proteolyzed into C3b (and C3a). C3b migrates to site of infection in edema fluid, finds organism, and binds the pathogen. Once bound to the pathogen, C3b, in conjunction with fragments D, B, and Bb, forms C3b convertase. The C3 convertase is C3bBb. The convertase cleaves more C3 into C3b (positive feedback look, huge amplification). C3b is also used to form C5 convertase, which converts C5 to C5b (and C5a, a pro-inflammatory peptide). C5b joins C6-9 to form the membrane attack complex, which results in pathogen lysis.
C3b acts as an _____ to facilitate phagocytosis by neutrophils and macrophages or further steps results in the generation of the ____ convertase which leads to the late steps of complement activation
opsonin; C5
Lectin pathway
A normal serum protein called mannose binding protein (MBP) binds to bacterial surfaces (bacteria have mannose) and becomes activated, giving rise to an enzyme activity identical to activated C1qrs in the classical pathway, called a C1-like complex. This complex/protein, on the surface of a bacterial cell, cleaves C4 into C4a and C4b and cleaves C2 into C2a and C2b. The resulting complex (C4bC2b) is the C3 convertase that cleaves C3 and therefore is another mechanism to generate C3b and the subsequent C5 convertase (C4b2bC3b). This can then generate C5b, which will combine with C6-C9 to generate the MAC and cause lysis.
Classic Pathway:
Activation of the classical pathway is the third pathway for complement activation when the host is exposed to the microbe for the first time because antibodies secreted by plasma cells take a few days to develop. Once generated, they can recognize and bind to the bacteria. This bound antibody to the surface of the microbe is the platform for complement activation. C1 is present in the plasma in an inactive form. The classical pathway of complement is initiated by the binding of C1 to the Fc portion of antibody. IgM and IgG subclasses 1, 2, and 3 can efficiently activate complement. Binding of C1 to Ig presumably produces a conformational change in C1 leading to the activation of C1r and C1s. C1r cleaves and activates C1s, which cleaves the next two components, C2 and C4 to produce C3 convertase. Then proceeds the same as alternative/lectin.
Complement has __ starting points that merge into a common pathway (explain).
3 starting points:
- Classical pathway (C1qrs, C2, and C4).
- Alternative pathway (C3, factors B, D, and properdin).
- Lectin pathway (plasma derived mannose-binding lectin or MBL).
The classical pathway is triggered by interaction of the Fc portion of an antibody (___, ___, ___, ___) or C-reactive protein with ____.
The classical pathway is triggered by interaction of the Fc portion of an antibody (IgM, IgG1, IgG2, IgG3) or C-reactive protein with C1q.
Anaphylatoxins:
Source of vasoactive mediators that increase vascular permeability.
(C3a, C4a, C5a)
Chemoattractants:
Attract neutrophils and monocytes (C3a, C5a)
What is the final phase of complement?
The assembly of the membrane attack complex (MAC). Components C5b-9 form a polymeric complex. MAC exerts powerful killing activity by creating perforations in cellular membranes.
Microbes coated with C3b are phagocytosed by virtue of C3b being recognized by _______.
complement receptor type 1 (CR1)
C3a, C4a, and C5a are chemotactic for ______, stimulate the release of ________ from various leukocytes, and act on endothelial cells to enhance movement of _______ and _______ into tissues.
C3a, C4a, and C5a are chemotactic for NEUTROPHILS, stimulate the release of INFLAMMATORY MEDIATORS from various leukocytes, and act on endothelial cells to enhance movement of LEUKOCYTES and ENDOTHELIAL CELLS into tissues.
[basically are super important in notifying the neutrophils where the site of infection is and getting them there to help destroy bacteria]
MAC can induce ______ lysis of cells, including microbes. MAC-induced lysis is effective only against microbes that have _____ cell walls, such as the Neisseria species.
MAC can induce OSMOTIC lysis of cells, including microbes. MAC-induced lysis is effective only against microbes that have THIN cell walls, such as the Neisseria species.
Key timing differences in alternative, lectin, and classic pathways:
Always have C3 in blood to activate alternative pathway, and always produce lectin binding proteins. These act quickly when an invasion occurs. Classic pathway takes time because need an antibody to bind to surface proteins on the bacteria to activate it.
