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The Human Adaptive Immune System

By: , Posted on: April 13, 2016

Pathobiology of Human Disease

The following excerpt is taken from the chapter The Adaptive Immune System by V.K. Vanguri that is included in both Pathobiology of Human Disease and the Reference Module in Biomedical Sciences.

Pathobiology of Human Disease provides the definitive knowledge on morphologic, experimental, and molecular pathology. View the table of contents here.

The Reference Module in Biomedical Sciences combines thousands of related reference work articles into one authoritative resource on ScienceDirect that is continuously updated by experts. Check it out on ScienceDirect.

The human adaptive immune system is a marvel of nature – a complex and dynamic web of cells, tissues, and molecules that serves as a very capable system of defense throughout life. In contrast to the innate immune system that is similar in other animals, the highly regulated mammalian adaptive immune system appears designed to efficiently cope with constantly evolving microbial antigens with relative minimization of collateral damage to the host.

Pillars of Adaptive Immunity

While the innate immune system is able to recognize conserved motifs on pathogens, microbes can mutate some of their antigens for immune evasion. The adaptive immune system is capable of responding to the diversity of constantly evolving pathogens throughout life with highly specialized, yet specific, host defenses. There are several characteristics of the adaptive immune system that help define its capabilities and strengths: specificity, diversity, specialization, tolerance, regulation, and memory.

Specificity

Although innate immune cells make use of evolutionarily conserved motifs on pathogens to facilitate clearance, cells of the adaptive immune system known as B and T lymphocytes have the ability to identify pathogenic epitopes that may evolve or mutate over time to evade innate defenses. Specificity is driven by high-affinity lymphocyte antigen recognition receptors – the B-cell receptor (BCR) and the T-cell receptor (TCR) – created by and expressed on the surface of B or T cells. Mature B cells or plasma cells can also secrete a high-affinity form of their receptor known as an immunoglobulin (Ig), or antibody, which binds its specific antigen for microbe neutralization or clearance. Unlike the TCR, which can only recognize small peptides derived from antigens, antibodies can recognize epitopes on proteins, sugars, lipids, or nucleic acids. Antibodies can even be produced and purified in laboratory settings, leading to their use in scientific applications for labeling target molecules or in clinical applications as pharmaceutical agents to specifically block pathways that mediate disease.

Diversity

While an individual B or T cell has a narrow specificity defined by the BCR or TCR it expresses, the vast lymphocyte repertoire is extremely diverse, covering an enormous range of specificities for any potential pathogen encountered throughout life. When antigen is encountered, the relevant lymphocyte is activated, and it proliferates to comprise a larger population of lymphocytes within the repertoire, at least transiently until the antigen is cleared from the body. In addition to activation and proliferation of antigen-specific T cells during an adaptive immunity response, activated B cells undergo a process of maturation in germinal centers of secondary lymphoid tissue, whereby the Igs produced are tested for selectivity for the antigenic epitopes, in order to produce antigen-specific B-cell clones producing antibodies with high affinity for antigen. This process of cultivation of relevant lymphocytes when needed is known as clonal selection.

In order to produce specific responses to an essentially infinite number of evolving pathogenic epitopes, the immune system has developed ingenious methods to produce an essentially infinite number of antigen recognition molecules from a finite amount of genetic material. Diversity is generated at several points beyond the germline in individual lymphocytes during B- and T-cell development, through recombination of gene segments in individual lymphocytes and through hypermutation of highly variable portions of the genes encoding the recognition molecules.

Specialization

Specialization refers to the refinement of the immune response to the type, nature, or site of the antigen. In order to combat the innumerable pathogenic species of bacteria, fungi, parasites, and viridae, the human adaptive immune system has several layers of defense mechanisms that are tailored to the properties of the infection. Intracellular pathogens, extracellular pathogens, and larger parasites resistant to phagocyte engulfment each elicit distinct effector responses to best attain clearance or containment.

Major histocompatibility complex (MHC) molecules are important determinants of specialized responses. Nearly every nucleated cell in the body can express MHC class I molecules, which, in association with an antigenic peptide, can bind to antigen-specific TCRs bearing the CD8 coreceptor, located on CD8 + cytotoxic T lymphocytes (CTLs). The wide cellular distribution of MHC class I and the ability to trigger a CTL response make this pathway important for killing cells infected with an intracellular pathogen, such as a virus, that would otherwise escape detection by circulating antibodies. MHC class II molecules, on the other hand, are located on specialized antigen-presenting cells (APCs) and can present processed peptides to T cells bearing the cognate TCR and the CD4 coreceptor. These CD4 + helper T (Th) cells orchestrate distinct immune response patterns based on the type, nature, and route of the antigen through the use of surface-bound costimulatory molecules and secreted cytokines, which provide signals to cells and tissues to assist in host defense. The signaling pattern generated by these molecules helps to dictate the intensity and pattern of the resulting host immune response.

Tolerance

With an efficient, powerful, and broad immune repertoire comes the need to accurately discriminate self from nonself so as to appropriately mount immunity upon encounter of a foreign antigen and to appropriately suppress immunity to maintain tolerance to self-antigens. Tolerance is accomplished in part during lymphocyte development, in which clones of lymphocytes with randomly generated antigen receptors that have reactivity to self molecules are eliminated in a process called negative selection.

Costimulatory molecules also play roles in tolerance induction peripherally. When an APC interacts with its cognate T cell through MHC–TCR interactions, the nature of the processed antigen is incompletely described. That is, whether the peptide was derived from pathogenic microbes or from inconsequential particles in the tissue is unable to be communicated through the MHC–TCR interaction alone. There is an additional requirement for a second signal between the APC and T cell, which is performed through cell surface costimulatory molecules and which can control the T-cell response by activating it to induce immunity or by inhibiting it to effect tolerance. Importantly, autoimmune diseases can occur if there is failure of immunologic tolerance during lymphocyte development or later with inappropriate cellular or molecular signals.

Regulation

The ability to mount highly efficient and powerful immune responses in the presence of foreign antigen can be dangerous to host tissues if effector responses are left unchecked. Regulatory mechanisms of the adaptive immune system serve to prevent unwanted immune responses under conditions requiring tolerance, to cease immune responses after clearance or containment of pathogen, and to maintain immune responses when necessary. Subsets of lymphocytes known as regulatory cells, suppressive cytokines, and inhibitory actions of costimulatory molecules all help to provide cessation of immunity and a homeostatic return to tolerance to minimize collateral damage to the host. While a lack of responsiveness of immune mechanisms can be seen in inherited or acquired immunodeficiency, failure of these regulatory mechanisms can lead to hypersensitivity reactions and autoimmunity.

Memory

Memory is a uniquely adaptive mechanism that generates an improved, more efficient response upon a second exposure to pathogen than the initial response. A naive immune system is thus sensitized after the initial exposure to antigen and mounts a more rapid and stronger response when rechallenged with the same antigen. After an initial pathogen infection, the body retains a small but significant number of long-lived B cells that produce antibodies specific for that pathogen and long-lived T cells with the precise TCR specificity. Upon re-encountering the pathogen, clearance can be accomplished more rapidly than at initial infection, due to preformed circulating antibodies that neutralize the pathogen or mark it for complement-mediated killing, via rapid reactivation of antigen-specific memory B and plasma cells and by reactivation of specific memory T cells that carry out specialized responses tailored to the pathogen. This facet of the adaptive immune system can be exploited to produce protective immunity in people through purposeful and controlled inoculation of antigen in vaccine design.

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This excerpt is taken from the chapter The Adaptive Immune System by V.K. Vanguri that is included in both Pathobiology of Human Disease and the Reference Module in Biomedical Sciences.

Pathobiology of Human Disease provides the definitive knowledge on morphologic, experimental, and molecular pathology. View the table of contents here.

The Reference Module in Biomedical Sciences combines thousands of related reference work articles into one authoritative resource on ScienceDirect that is continuously updated by experts. Check it out on ScienceDirect.

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