What is complement for? What does complement do?
Nomenclature
Each of the components of the classical pathway of activation and the proteins of the Big Mac is denoted by the letter C followed by a number, that is C1-C9. The components of the alternative pathway of activation are called factors and a letter D, B or P denotes each. The lectin pathway is very similar to the classical pathway and differs only in the substances that cause activation.
The third component of complement, abbreviated as C3, is the major player – everything revolves around her. The other components are just the posse!
The end result of all three pathways is to PUNCH A HOLE in the cell, whether that cell is a bacteria or something else. This is done through the Membrane Attack Complex, known affectionately as the Big MAC.
The Membrane Attack Complex
There are two alternate theories about how complement punctures membranes. One is that the Big MAC forms a donut-like shape that acts like a pore. The other theory is that it constitutes what is called a leaky patch by the disruption of the phospholipid bilayer allowing leakage of electrolytes.
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The formation of a sufficient number of these large pores or patches causes an electrolyte imbalance in the target cell, a rapid loss of cell function ensues and cell lysis follows. |
But there are three different pathways to get to the Big MAC:
Please note, that there are lots of details below regarding Complement activation via the three different pathways. These details are for those who really want them, and the animations may be helpful for all. The essentials of the 3 pathways are in your notes, and you are only responsible for knowing the essentials.
Alternative Pathway Activation
The alternative pathway can be activated by bacterial surface structures (LPS, etc). This generates C3i, a molecule which has the ability to react with Factor B. The enzyme D then cleaves B to form an initial C3 convertase termed C3iBb and liberates a fragment Ba. The resulting convertase then splits multiple molecules of C3 into C3b and liberates C3a, an anaphylatoxin, Some of the C3b binds covalently to surfaces. This process happens continuously.
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The alternative pathway convertase is stabilized by the binding of properdin so that the C3 convertase has a much longer longer half life. |
Classical Pathway Activation
The classical pathway is initiated primarily by antigen-antibody complexes.
Immune complexes consisting of IgM or IgG are potent activators of the classical pathway of complement. This proceeds by activation of C1. C1 actually consists of three subunits - C1 q,r, and s. Binding to the immune complex occurs via C1q.
Lectin Pathway
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C1 can also be activated by carbohydrate molecules of infectious agents complexed with host proteins called collectins. Once the collectin complex activates C1, activation proceeds along the classical pathway. |
Following the activation of C1, conformational change is then believed to occur that allows C1r to then cleave C1s. C1s has two natural substrates in plasma these are C4 and C2. C1s causes the conversion of these two molecules into the complex C4b2a, a C3 converting enzyme.
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C4b is cleaved off and converts C3 into C3b and C3a. C3b can then participate in alternative pathway activation and amplification loop. |
Once C3b is generated by any of the pathways, all heck breaks loose. It acts eventually to split C5 into C5a (an anaphylatoxin) and C5b. The C5b binds rapidly to cell surfaces and the complement components of the terminal sequence (C6-9) react with C5b to form the Membrane Attack Complex or BIG MAC as some people call it.
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| C4b2a3b (classical) |
C3bBb3b (alternative) |
Other Functions of Complement: What else does it do?
A number of well-defined biological activities are generated during complement activation. These are vital to host defense and the inflammatory response.
The most important functions of complement are centered upon C3.
Products and Functions of C3 Convertase
When C3 is cleaved by C3 convertases two primary products are formed - C3a and C3b. C3a is an anaphylatoxin and has profound effects on vascular smooth muscle tone. C3a and to a lesser extent C5a cause increased vascular permeability and vasodilation by causing mast cells to release histamine.
C5a is a powerful chemotactic agent for neutrophils and to a lesser extent, macrophages, attracting them to sites of inflammation.
C3b is a powerful OPSONIN. Cells coated with C3b taste better to the phagocytic cells and get scarfed down readily.
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