11.1 BIOLOGY OF THE IMMUNE RESPONSE

The immune system has evolved primarily to defend the body against the invasion of microorganisms, although normal immune function is important in regulating and sustaining the internal environment as well, such as recognition and removal of malignant cells. There are two types of immunity: natural immunity (also termed innate immunity) and acquired immunity (also termed specific immunity).

Innate immunity encompasses a wide variety of protective mechanisms, including physical (e.g., barrier activity of skin), chemical (e.g., acidic environment in the stomach), and mechanical (e.g., coordinated movement of cilia in the respiratory tract removing particulate matter). It is also mediated by a number of agents, both secreted (e.g., complement, defensins, type I interferons) and cellular (e.g., neutrophils, macrophages, and natural killer (NK) cells). While originally thought that cells of the innate immune system were activated with little specificity, recent research has identified a number of pattern recognition receptors for ligands that represent potentially dangerous events. These include the recognition of common motifs from exogenous threats, collectively called PAMPs (pathogen-associated molecular patterns) and endogenous triggers, known as DAMPs (damage-associated molecular patterns). A family of 11 TLR (“toll-like” receptors), for example, recognizes specific motifs either not usually seen in mammalian cells or found in unexpected places. These motifs include bacterial lipoproteins, single-stranded and double-stranded RNA, flagellin, and bacterial DNA. Natural immunity differs from adaptive immunity in that the receptors are DNA-encoded at the germ line and is rarely enhanced by prior exposure to these substances.

Acquired immunity, in contrast, increases in magnitude and specificity with successive exposure to foreign substances. Substances that trigger these specific immune responses are termed immunogens, and may be either foreign or endogenous. In many cases, immunogens are proteins or contain a protein as part of the complex. There are two major types of acquired immune responses: humoral immunity and cell-mediated immunity. Humoral immunity involves the production of proteins capable of binding to foreign substances. These belong to a special class of proteins called immunoglobulins (Igs), and the secreted proteins themselves are called antibodies. The substances to which the antibodies bind are called antigens. Antibody binding can neutralize toxins, cause agglutination of bacteria and other microorganisms, and lead to precipitation of soluble foreign proteins. By coating the pathogen with antibody that can activate complement, it can also direct cells of the innate immune system to eliminate the pathogen through enhanced phagocytosis—a process known as opsonization. Each of these is important in defense of the host. In cell-mediated immunity, specialized cells rather than antibodies are responsible for the destruction of foreign cells.

A critical function of the immune system is to effectively distinguish between macromolecules that belong, or do not belong, in the body. The specific immune response is believed to be highly individualistic, a process which defines “self” while also defending the organism against “nonself.” This is evident by the response to certain environmental toxicants, to allergens or antigens, and the specific rejection of allografts. Recognition of “self” is known to be guided, in part, by genetic variations in proteins of the class I and II major histocompatibility complex (MHC). Initially, the ability of the immune system to differentiate “self” from “nonself” is the result of a rigorous selection process. During maturation, the system must ignore an infinite variety of self-molecules and yet be primed and ready to respond to an array of exogenous antigens. Immunomodulatory control mechanisms lead to immune tolerance of self and carefully orchestrate the immune response to targets and removal of foreign macromolecules and cells. These control mechanisms arise from interactions among the several different cell types with roles in proper immune function.

Lymphocytes are considered to be the major cells involved in a specific immune response in humans. They are derived from pluripotent stem cells and undergo an orderly differentiation and maturation process to become T cells or B cells, with critical functional roles in the host defense. T-cell development occurs primarily in the thymus, where certain cell surface protein markers are acquired during the selection and differentiation process. Collectively, protein markers expressed on cells of the immune system are called CD antigens (for cluster of differentiation), and well over 300 different CD antigens have been identified in humans. The presence of combinations of CD antigens, detectable by immunofluorescence, has been used to positively identify immunocytes. In general, mature T cells exiting the thymus and present in the circulation and secondary lymphoid tissue (lymph nodes and spleen) are characterized by the presence of CD3⁺ and either CD4⁺ or CD8⁺ surface markers and are devoid of surface or cytoplasmic Ig. CD3 is a complex that associates with a T cell receptor (TCR), and it is the TCR that has been the target of the selection process, mainly to avoid those receptors that either cannot bind to self MHC (and are therefore useless) or bind too avidly to self MHC (and are therefore likely self-reactive). There are various subtypes of T cells, such as T-helper (T_H) cells, regulatory T (T_reg) cells, and cytotoxic T cells (T_C). T_H and most T_reg lymphocytes carry the CD4⁺ marker, while T_C lymphocytes have the CD8⁺ marker. Together, these T-lymphocyte populations play a vital role in initiating and regulating the immune response.

Human B cells develop from stem cells in the fetal liver and, after birth, B-cell development occurs principally in the bone marrow. B-cell development and maturation are characterized by class-specific Ig expression on the cell surface. B cells also undergo a selection process to avoid self-reactivity, although it is not as rigorous as for T cells. Monoclonal reagents can identify the Ig expressed on the surface of B cells. Immunophenotypic characterization of cells via these and other CD markers has proved to be invaluable in certain clinical situations (such as identifying the type of lymphoma) and a useful research tool. B cells play an important role in recognition of antigens and are responsible for antibody production.

Another important cell in the specific immune response is the “professional” antigen presenting cell (APC). These cells make first contact with the antigen and may also process the antigen; that is, modify it in such a way as to enable its recognition by T cells. This category of cells is defined more by function than cell type. There are three types of professional APCs: peripheral blood monocytes (which can differentiate into tissue macrophages), B cells, and dendritic cells. Professional APCs are distinguished by their ability to express both MHC class I and II; virtually all other nucleated cells express only class I. Peptides processed and bound to class II are generally of extracellular origin, while peptides bound to class I are derived from the cytoplasm of that cell, providing a pathway for internal surveillance against important pathogens, such as viruses. Dendritic cells are responsible for initiating most primary (naïve) T cell responses, and are unique in their ability to process exogenous antigen by both the class I and II pathways (cross-presentation).

In order for the APC to present the antigen to T cells, the antigen must have a polypeptide component to it which is processed, or partially digested by the APC, and sequences from that peptide are “presented” on its cell surface bound to an MHC class I or class II molecule. Presentation of antigen to B cells does not require this processing, and in fact B cells are capable of recognizing antigens directly. These antigens interact with Igs serving as receptors on the cell surface of B-cell clones. Every Ig molecule expressed by an individual B cell has identical specificity, and these Igs can be quite specific in terms of the antigens with which they will interact. Thus, a particular antigen may interact with only one or a few B cell clones, a critical aspect in creating a specific immune response. When the antigen binds to an Ig receptor on the B cell surface, the antigen–receptor complex migrates to one pole of the cell and is internalized within the cell. While the Ig receptor can bind to virtually any structure, for the B cell to become activated and productively engage specific T cells, the antigenic complex must also have a polypeptide component that can be processed and antigenic peptides displayed via the MHC class II pathway.

Naïve T-cell activation requires at least two signals. The first signal results from an interaction between the T-cell receptor and the MHC/peptide complex and provides the specificity. The second signal is the product of interactions between co-stimulatory receptors constitutively expressed by T cells and their ligands, usually inducibly expressed by the APCs. Expression of the co-stimulatory ligands is induced by the danger signals of the innate immune system. To facilitate the interactions between the rare T cell specific for a peptide derived from the pathogen and the APC presenting those peptides, dendritic cells activated by danger signals at the site of contact take up antigen and migrate (along with free antigen) via the lymphatic system to the nearest draining lymph node. There, they encounter naïve T cells that are programmed to continuously circulate through lymph nodes. The architecture of the lymph node promotes efficient cell-to-cell contact and intercellular signaling.