Adaptive Immunity, the Third Line of Defense, Exhibits Specificity
Adaptive immunity is the term reserved for the highly specific recognition of foreign substances by antigen-specific receptors, the full elaboration of which requires days or weeks after occurrence of the initial exposure. Lymphocytes bearing antigen-specific receptors are the key cells responsible for adaptive immunity. An early indication of the specific nature of adaptive immune responses came with the discovery of antibodies, the key effector molecules of adaptive immunity, by Emil von Behring and Shibasaburo Kitasato in 1905. They began by transferring serum (the straw-colored liquid that separates from cellular debris upon completion of the blood-clotting process) from guinea pigs exposed to a sublethal dose of the deadly diphtheria toxin to animals never before exposed to the bacterium that produces it. The recipient animals were thus protected against a lethal dose of the same bacterium (Figure 23-8, left). Transfer of serum from animals never exposed to diphtheria toxin failed to protect, and protection was limited to the microbe that produced the diphtheria toxin and did not extend to other toxins. This experiment demonstrates specificity—that is, the ability to distinguish between two related substances of the same class. Such specificity is a hallmark of the adaptive immune system. Even proteins that differ by a single amino acid may be distinguished by immunological means.
EXPERIMENTAL FIGURE 23-8 The existence of antibody in serum from infected animals was demonstrated by von Behring and Kitasato. Exposure of animals to a sublethal dose of diphtheria toxin (or the bacteria that produce it) elicits in their serum a substance that protects against a subsequent challenge with a lethal dose of the toxin (or the bacteria that produce it). The protective effect of this serum substance can be transferred from an animal that has been exposed to the pathogen to a naive (unexposed) animal. When the serum recipient is subsequently exposed to a lethal dose of the bacteria, the animal survives. This effect is specific for the pathogen used to elicit the response. Serum thus contains a transferable substance (antibody) that protects against the harmful effects of a virulent pathogen. Serum harvested from these animals, said to be immune, displays bactericidal activity in vitro. Heating of immune serum destroys its bactericidal activity. Addition of fresh unheated serum from a naive animal restores the bactericidal activity of heated immune serum. Serum thus contains another substance that complements the activity of antibodies.
From these experiments, von Behring inferred the existence of transferable factors responsible for protection, which he called “corpuscles” (Antikörper), or antibodies. The antibody-containing sera not only afforded protection in vivo, but also killed microbes in the test tube (Figure 23-8, right). Heating the antibody-containing sera to 56° C destroyed this killing activity, but it was restored by the addition of unheated fresh serum from naive animals (i.e., animals never exposed to the bacterium). This finding suggested that a second factor (which turned out to be complement) acts in synergy with antibodies to kill bacteria.
We now know that von Behring’s antibodies are serum proteins referred to as immunoglobulins and that complement is actually the series of proteases described above, which carry out the destruction of pathogens tagged by antibodies (see the classical pathway in Figure 23-5). Immunoglobulins can neutralize (render inactive) not only bacterial toxins but also harmful agents such as viruses by binding directly to them in a manner that prevents the virus from attaching itself to host cells. Generation of neutralizing antibodies is the rationale underlying virtually all vaccination strategies. Vaccination is a form of active immunization that consists of deliberately exposing an individual to a foreign antigen to elicit protective immunity by generating an adaptive immune response (described below) and antibodies. In the same vein, antibodies raised against snake venoms can be administered to the victims of snake bites to protect them from intoxication, provided the administration occurs relatively soon after the bite: the antibodies bind to the toxic proteins in the venom, keeping them from binding to their targets in the host, and in so doing neutralize them. This procedure, called passive immunization, can save lives by instant neutralization of a noxious substance such as a toxin. Passive immunization is also used prophylactically to protect those who travel to areas where a disease such as viral hepatitis is endemic: administration of serum from immune individuals provides temporary protection against infection. Antibodies can thus have immediate protective effects. Given that today’s medical advances allow the survival of individuals whose immune systems are severely compromised (cancer patients receiving chemotherapy or radiation, transplant patients with a pharmacologically suppressed immune system, patients who suffer from AIDS, individuals with inborn deficiencies of the immune system), passive immunization can be of immediate practical importance. The deliberate exposure of an animal such as a mouse or rabbit to a foreign substance (immunization) allows the production of antisera that specifically recognize that substance (the antigen). These antisera have become standard components of the cell biologist’s toolbox.