Author: 神州
Reviewer: 一毫秒的永恒

  In “Immunity in Five Minutes: How Do Antibodies Adapt?”, we caught a glimpse of just a few among the immune system’s many mechanisms. Today, let us continue exploring that system.

  Last time, we gained a general sense of the importance of antibodies in immunity. Antibodies cannot always do everything, however. Their usual role is to bind to an antigen and change its structure, removing its original toxicity or preventing it from binding to a cell, or to cause agglutination so that phagocytes can engulf it. But when an antibody encounters an intact pathogen such as a bacterium, binding to antigens on the bacterial membrane cannot kill the whole bacterium directly. Another system is needed to help: the complement system, our subject today.

  Unlike an antibody, complement is not a single large protein molecule. It is an ordered system made up of a series of functional proteins that interact to perform effective immune functions. Under normal circumstances, activation of the complement system and the ensuing chain of reactions eventually produce what is known as a membrane attack complex (MAC). A MAC can lyse bacteria and other pathogens, thereby destroying them. How does the complement system work?

  In the classical pathway of complement activation, complement itself is not very effective at recognizing and binding pathogens, so antibodies normally mark the pathogens first. When an antibody binds to an antigen on the pathogen’s surface and forms an antigen–antibody complex, its structure changes and exposes special sites that complement can recognize and bind. This begins the activation of the complement system.

  The classical pathway can be divided roughly into three stages:

  1. Recognition
  2. Activation
  3. Membrane attack

1. Recognition

  At this stage, a multimolecular complex in the complement system—the C1 complex—recognizes and binds to special sites exposed on the antibody in the antigen–antibody complex. In the accompanying diagram, panels (a) and (b) show complement and bacteria, while panel © shows salts and fluid. Binding activates C1 esterase.

2. Activation

  Under the action of C1 esterase, two other complement components, C4 and C2, are cleaved to form C3 convertase. C3 convertase then cleaves C3, amplifying the complement response and helping to form C5 convertase.

3. Membrane Attack

  Under the action of C5 convertase, the remaining components of the complement system are activated in sequence, ultimately forming a MAC on the target cell’s membrane. Once formed, the MAC can damage and lyse the target cell.

Image from *General Biology*

  A MAC is a tubular macromolecular complex whose formation changes the permeability of the target cell membrane. Its effect resembles opening a hole in the cell: small molecules, ions, and water can pass through freely, while large proteins and similar substances cannot. Eventually, the membrane can no longer maintain the osmotic-pressure difference between its two sides, causing the cell to lyse. At the same time, large quantities of Ca2+ ions enter the cell and ultimately cause cell death.

  The overall process is roughly this: antibodies first mark the target pathogen, then complement carries out the task of destroying it. This bacteriolytic action is one of the body’s important defenses against invading pathogens. Sometimes, however, if the body produces antigen–antibody complexes against itself, complement can also damage the body’s own tissues and cells. Our bodies therefore contain many complement inhibitors that prevent excessive MAC formation or keep MACs from acting on our own cells.