Overall Stages in the Complement Cascade

In general, the complement cascade goes through four stages: initiation, amplification and cascade, polymerization, and membrane attack. The starting reaction requires some type of initiator molecule such as antibodies, lectins, or microbial surface receptors (figure 1 a),depending on the pathway. The presence of this initiator on the pathogen’s membrane propels the chain of actions involving complement chemicals C1 through C4, with each step serving a dual purpose. We are omitting the fine details of the amplification part of the complement system, but the end result is a molecule, C3,that is a key factor in subsequent polymerization and membrane attack for all three pathways. C3 is acted on by a convertase enzyme that gives rise to C5b, which forms the recognition site and anchor for the final series of reactions (figure 1 b).These amplification reactions also release cleavage products that serve other immune functions, including viral neutralization, allergic reactions, and immune regulation.

The final events in the complement series involve polymerization of C5b, C6, C7, and C8 into a half circular formation within the membrane (figure 1 c).This is followed by the insertion of several C9 molecules that complete a full ring-shaped polymer termed the membrane attack complex or MAC (figure 1 d).The MAC is the primary destructive force of the complement system. It effectively perforates and lyses the membranes of gram-negative bacteria, fungi, parasitic protozoans, and enveloped viruses. Except for the classical pathway, these reactions are non-specific and can be active against a wide spectrum of microbes.

Figure 1. Overview of the complement pathways. (a)All three pathways have different triggers and starting points, but they all converge at the same place, C3 convertase. This enzyme begins the series of reactions (b, c, d)that give rise to the membrane attack complex characteristic of the complement “machinery.” The final result is the formation of tiny openings in the cell membrane and the destruction of the target pathogen.

3. Specific Immunity: The Adaptive Line of Defense

Normal humans have an extremely specific and powerful system for resisting infectious agents called adaptiveor acquired immunity, sometimes known as the third line of defense. It can be observed in the long-term protection provided by developing infections such as measles or mumps or being vaccinated for diphtheria.

The absolute need for adaptive immunity is impressively documented in children with genetic defects in this system or in AIDS patients who have lost it. Even with heroic measures to isolate the patient, combat infection, or restore lymphoid tissue, the victim can be constantly vulnerable to life-threatening infections.

Acquired adaptive immunity is the product of a dual system of specialized leukocytes – the B and T lymphocytes. During fetal development, these lymphocytes undergo a selective process that prepares them for reacting only to one specific antigen. During this time, immunocompetence,the ability of the body to react with a wide spectrum of foreign substances begins to develop. An infant is born with the theoretical potential to produce an immune response to millions of different foreign molecules or antigens. But the completion of this immunocompetence takes many years, extending into late puberty.

Antigensfigure very prominently in specific immunity. They are defined as any molecules that can stimulate a response by T and B cells. They consist of protein, polysaccharide, and other compounds from cells and viruses. Environmental chemicals can also be antigens. In fact, any exposed or released substance is potentially an antigen, even those from our own cells. For reasons we discuss later, our own antigens do not usually evoke a response from our own immune systems, but they may do so in other persons.

Pathogen-associated molecular patterns (PAMPs) are molecules shared by many types of microbes that stimulate a nonspecific response. In contrast, antigens are unique molecules that stimulate specific immune responses. The two molecules do share two characteristics: (1) they are “parts” of foreign cells (microbes), and (2) they provoke a reaction by the white blood cells of the host.

Two features that most characterize adaptive immunity are specificityand memory.Unlike mechanisms such as anatomical barriers or phagocytosis, acquired immunity is selective. For example, the antibodies produced during an infection against the chickenpox virus will protect against that virus but not against the measles virus. The property of memory pertains to the rapid mobilization of lymphocytes that have been programmed to “recall” their first engagement with an invader and respond rapidly to it during subsequent exposures. These topics will be covered in some depth in several sections in this chapter.