The Complement System

The complement system is one of the major effector mechanisms of humoral immunity and is also an important effector mechanism of innate immunity. We briefly discussed the role of complement in innate immunity in Chapter 4. Here we describe the activation and regulation of complement in more detail.

The name "complement" is derived from experiments performed by Jules Bordet shortly after the discovery of antibodies. He demonstrated that if fresh serum containing an antibacterial antibody is added to the bacteria at physiologic temperature (37°C), the bacteria are lysed. If, however, the serum is heated to 56°C or more, it loses its lytic capacity. This loss of lytic capacity is not due to decay of antibody activity because antibodies are relatively heat stable, and even heated serum is capable of agglutinating the bacteria. Bordet concluded that the serum must contain another heat-labile component that assists, or complements, the lytic function of antibodies, and this component was later given the name complement.

The complement system consists of serum and cell surface proteins that interact with one another and with other molecules of the immune system in a highly regulated manner to generate products that function to eliminate microbes. Complement proteins are plasma proteins that are normally inactive; they are activated only under particular conditions to generate products that mediate various effector functions of complement. Several features of complement activation are essential for its normal function.

• The complement system is activated by microbes and by antibodies that are attached to microbes and other antigens. The mechanisms of initial activation are described later.

• Activation of complement involves the sequential proteolysis of proteins to generate enzyme complexes with proteolytic activity. Proteins that acquire proteolytic enzymatic activity by the action of other proteases are called zymogens. The process of sequential zymogen activation, a defining feature of a proteolytic enzyme cascade, is also characteristic of the coagulation and kinin systems. Proteolytic cascades allow tremendous amplification because each enzyme molecule activated at one step can generate multiple activated enzyme molecules at the next step.

• The products of complement activation become cova-lently attached to microbial cell surfaces or to antibodies bound to microbes and to other antigens. In the fluid phase, complement proteins are inactive or only transiently active (for seconds), and they become stably activated after they are attached to microbes or to antibodies. Many of the biologically active cleavage products of complement proteins also bind covalently to microbes, antibodies, and tissues in which the complement is activated. This characteristic ensures that the full activation and therefore the biologic functions of the complement system are limited to microbial cell surfaces or to sites of antibodies bound to antigens and do not occur in the blood.

• Complement activation is inhibited by regulatory proteins that are present on normal host cells and absent from microbes. The regulatory proteins are an adaptation of normal cells that minimize complement-mediated damage to host cells. Microbes lack these regulatory proteins, which allows complement activation to occur on microbial surfaces.

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