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Adaptive Immune Response

  • The Adaptive Immune Response refers to the aspects of the host immune response which depend on the generation of proteins which are highly specific to particular microbial antigenic moieties. Evolutionarily, Adaptive Immunity is a relatively new part of the immune system and appears first in jawed fish. The adaptive immune response allows for the generation of proteins which can bind with extremely high specificity and affinity to nuanced microbial antigenic structures. These proteins can thus specifically identify a microbe or a microbe-infected cell and then signal other immune cells to kill the microbe or the infected cell. Importantly, antigen-specific proteins can be maintained in the body for years and thus can immediately recognize and destroy invading microbes before a serious infection can develop. Clearly, this represents a major advance over the Innate Immune Response which can only recognize the presence of generic microbial molecules in the environment and respond only with phagocytosis of the offending material once infection has developed.
Basic Architecture
  • Overview
    • One of the major mysteries of immunology for over a century has been the mechanism by which antigen-specific proteins are generated. It is now clear that the basic architecture of this mechanism occurs in several steps: Random Generation, Selection, Proliferation, and Memory. In general, development of a successful adaptive immune response to a previously un-encountered microbe requires roughly 7-10 days. Thus, the Innate Immune Response must control the infection as much as possible before adaptive immunological reinforcements are mature.
  • Random Generation
    • Antigen-specific proteins are generated through nearly random mutation of particular structural pockets within these protein known as their antigen-binding pockets. Through this process, enormously diverse "libraries" of antigen-specific proteins are generated without any purposeful bias. Consequently, antigen-specific proteins are generated which might bind self-proteins as well as microbial structures. This library is so large that inevitably several antigen-specific proteins will be able to bind virtually any microbial protein.
  • Selection
    • Once the diverse "library" of antigen-specific proteins is generated it undergoes extremely rigorous selection based on several criteria. However, the major criteria on which antigen-specific proteins are selected is by their inability to bind self-proteins. Therefore, the "library" is selected in such a way that no antigen-specific proteins survive selection which could potentially bind proteins generated by the host itself. This approach has several advantages: 1) When an infection does occur the immune system does not need to take the time to actually develop antigen-specific proteins since they are pre-made, 2) Destruction of self-binding proteins avoids the possibility that the destructive actions of the immune system will be directed against host tissues.
  • Proliferation
    • Once an infection does occur, the major challenge of the immune system is to induce proliferation of those antigen-specific proteins which actually do bind to the invading microbe. This aspect of adaptive immunity occurs in concert with the Innate Immune Response which helps initiate and coordinate this proliferation. It is thought that innate immune cells first phagocytose microbes and through their "Pattern Recognition Receptors" recognize that some type of microbial infection is occurring (See: Innate Immune Response). These innate cells then interact with cells of adaptive immunity and present microbial antigens to the adaptive cells while providing additional signals that give some context regarding the type of microbial infection (i.e. bacterial, viral, fungal, etc). When a antigen-specific protein is found that specifically binds to microbial antigens presented by innate immune cells, that antigen-specific protein is highly proliferated and modified to effectively engage microbes.
  • Memory
    • One of the key aspects of adaptive immunity is its capacity to "remember" which antigen-specific proteins were previously used to effectively combat infection. These previously-utilized antigen-specific proteins are maintained at high circulating levels in the body or in such a way that re-infection allows their much more rapid and robust re-proliferation if the microbe is encountered a second time. Consequently, adaptive immunity can largely eliminate re-infections of the same organism before any clinical consequences arise. Although currently least understood, immunological memory was perhaps the first function of the immune system historically recognized, as it provided "Immunity" to those who had previously been infected by plague.
Molecular Basis
  • Now we turn to the molecular basis of the antigen-specific proteins which form the foundation of the adaptive immune response. There are two basic classes of antigen-specific molecules which detect antigens in different contexts.
  • Antibody: Antibodies can detect freely floating antigens
  • T-cell Receptor: T-cell Receptors can detect small fragments of microbial proteins presented on host cell membranes by MHC proteins.
Cellular Basis
  • The cells which direct the generation, selection, and synthesis of antigen-specific proteins are B-cells and T-cells. B-cells coordinate development of Antibody while T-cells coordinate development of T-cell Receptor. One of the major conceptual breakthroughs of immunology was the appreciation that each B-cell or T-cell can synthesize only a single type of antigen-specific protein. In other words, all of the antigen-specific proteins synthesized by a single B-cell or T-cell will have the same sequence and thus identical antigen-specificity. Because of this "Clonal" nature of antigen-specific-protein-producing cells, all of the processes of random generation, selection, proliferation, and memory discussed earlier occur at the level of individual cells. This means that each cell randomly generates a single type of antigen-specific protein, selection occurs by the destruction of cells which produce self-binding proteins, proliferation is coordinated by inducing replication of single cells which produce microbe-specific proteins, and memory is established by maintaining cells which have previously undergone proliferation.
Member Components
  • Immunologists have conceptually separated the adaptive immune response into two arms which separately highlight the development of antigen-specific B-cells and antigen specific T-cells.
  • Humoral Immunity: Refers to the processes involved in the generation, selection, proliferation, and memory establishment of Antibody-producing B-cells.
  • Cell-mediated Immunity: Refers to the processes involved in the generation, selection, proliferation, and memory-establishment of TCR-producing T-cells.