Chapter 1: Basic Concepts in Immunology

antigen-presenting cells

(APC's) Highly specialized cells that can process antigens and display their peptide fragments on the cell surface together with other, co-stimulatory, proteins required for activating naive T cells. The main antigen-presenting cells for naive T cells are dendritic cells, macrophages, and B cells.

bronchus-associated lymphoid tissues

(BALT) Organized lymphoid tissue found in the bronchi in some animals. Adult humans do not normally have such organized lymphoid tissue in the respiratory tract, but it may be present in some infants and children.

constant region

(C region) That part of an immunoglobulin or a T-cell receptor that is relatively constant in amino acid sequence between different molecules. Also known as the Fc region in antibodies. The constant region of an antibody determines its particular effector function.

complement receptors

(CR's) Cell-surface proteins of various types that recognize and bind complement proteins that have become bound to an antigen such as a pathogen. Complement receptors on phagocytes enable them to identify and bind pathogens coated with complement proteins, and to ingest and destroy them.

heavy chain

(H chain) One of the two types of protein chain in an immunoglobulin molecule, the other being called the light chain. There are several different classes, or isotypes, of heavy chain (α, δ, ε, γ, and μ), each of which confers a distinctive functional activity on the antibody molecule. Each immunoglobulin molecule contains two identical heavy chains.

follicular helper T cell

(TFH cell) Type of effector CD4 T cell that resides in lymphoid follicles and provides help to B cells for antibody production.

natural killer cell

- (NK cell) Large granular, non-T, non-B lymphocyte, which kills virus-infected cells and some tumor cells. NK cells bear a wide variety of invariant activating and inhibitory receptors, but do not rearrange immunoglobulin or T-cell receptor genes. NK cells are important in innate immunity to viruses and other intracellular pathogens, and in antibody-dependent cell-mediated cytotoxicity (ADCC). - These cells can recognize and kill some abnormal cells, for example some tumor cells and cells infected with herpes viruses, and are thought to be important in holding viral infections in check before the adaptive immune response kicks in.

T cells orchestrate cell-mediated immunity and regulate B-cell responses to most antigens.

- Antibodies are accessible to pathogens only in the blood and the extracellular spaces. However, some bacteria and parasites, and all viruses, replicate inside cells, where they cannot be detected by antibodies. The destruction of intra cellular invaders is the function of the T lymphocytes, which are responsible for the cell-mediated immune responses of adaptive immunity. ButT lym phocytes participate in responses to a wide variety of pathogens, including extracellular organisms, and so must exert a wide variety of effector activities. - The most direct action ofT cells is cytotoxicity. Cytotoxic T cells are effector T cells that act against cells infected with viruses. Antigens derived from the virus multiplying inside the infected cell are displayed on the cell's surface, where they are recognized by the antigen receptors of cytotoxic T cells. These T cells can then control the infection by directly killing the infected cell before viral replication is complete and new viruses are released. - From the end of their development in the thymus, T lymphocytes are composed of two main classes, one of which carries the cell-surface protein called CDS on its surface and the other bears a protein called CD4. These are not just random markers, but are important for a T cell's function, because they help to determine the interactions between the T cell and other cells. Cytotoxic T cells carry CDS, while the helper T cells involved in activating, rather than killing, the cells that they recognize carry CD4. - CDS T cells are destined to become cytotoxic T cells by the time they leave the thymus as naive lymphocytes. Naive CD4 T cells, in contrast, can differentiate into several types of effector T cells after their initial activation by antigen. At least four main types of CD4 effector T cells are distinguished, called TH

Antibodies protect against extracellular pathogens and their toxic products.

- Antibodies are found in the fluid component of blood, or plasma, and in extracellular fluids. Because body fluids were once known as humors, immunity mediated by antibodies is known as humoral immunity. - antibodies are Y-shaped molecules whose arms form two identical antigen-binding sites. These are highly variable from one molecule to another, providing the diversity required for specific antigen recognition. The stem of the Y is far less variable. There are only five major forms of this constant region of an antibody, and these are known as the antibody classes or isotopes. The constant region determines an antibody's functional properties-how it will engage with the effector mechanisms that dispose of antigen once it is recognized-and each class carries out its particular function by engaging a distinct set of effector mechanisms. - The first and most direct way in which antibodies can protect against patho gens or their products is by binding to them and thereby blocking their access to cells that they might infect or destroy (Fig. 1.25, left panels). This is known as neutralization and is important for protection against viruses, which are prevented from entering cells and replicating, and against bacterial toxins. - For bacteria, however, binding by antibodies is not sufficient to stop their replication. In this case, the function of the antibody is to enable a phagocytic cell such as a macrophage or a neutrophil to ingest and destroy the bacterium. Many bacteria evade the innate immune system because they have an outer coat that is not recognized by the pattern recognition receptors of phago cytes. However, antigens in the coat can be recognized by antibodies, and phagocytes have receptors that bind the stems of the antibodies coating the bacterium, leading to phagocytosis (see Fig. 1.25, center panel

Lymphocytes encounter and respond to antigen in the peripheral lymphoid organs. (Page 39).

- Antigen and lymphocytes eventually encounter each other in the peripheral lymphoid organs-the lymph nodes, spleen, and the mucosal lymphoid tis sues. Mature naive lymphocytes are continually recirculating through these tissues, to which pathogen antigens are carried from sites - of infection, primarily by dendritic cells. The peripheral lymphoid organs are specialized to trap antigen-bearing dendritic cells and to facilitate the initiation of adaptive immune responses. Peripheral lymphoid tissues are composed of aggregations of lymphocytes in a framework of nonleukocyte stromal cells, which provide the basic structural organization of the tissue and provide survival signals to help sustain the life of the lymphocytes. Besides lymphocytes, peripheral lymphoid organs also contain resident macro phages and dendritic cells. - When an infection occurs in a tissue such as the skin, free antigen and antigen-bearing dendritic cells travel from the site of infection through the afferent lymphatic vessels into the draining lymph nodes peripheral lymphoid tissues where they activate antigen-specific lymphocytes. The activated lymphocytes then undergo a period of proliferation and differentiation, after which most leave the lymph nodes as effector cells via the efferent lym phatic vessel.This eventually returns them to the bloodstream (see Fig. 1.8), which then carries them to the tissues where they will act. This whole process takes about 4-6 days from the time that the antigen is recognized, which means that an adaptive immune response to an antigen that has not been encountered before does not become effective until about a week after infection (see Fig. 1.34). Naive lymphocytes that do not recognize their antigen also leave through the efferent lymphatic vessel and are returned to the blood, from which they continue t

adjuvant

- Any substance that enhances the immune response to an antigen with which it is mixed. - We know now that adjuvants are needed, at least in part, to activate dendritic cells to full antigen-presenting status in the absence of an infection. Finding suitable adjuvants is still an important part of vaccine preparation.

Lymphocytes activated by antigen give rise to clones of antigenspecific effector cells that mediate adaptive immunity.

- Cells of the innate immune system express many different pattern recognition receptors, each recognizing a different feature shared by many pathogens. - In contrast, lymphocyte antigen receptor expression is 'clonal'-in other words, each mature lymphocyte emerging from the central lymphoid organs differs from the others in the specificity of its antigen receptor. When that lymphocyte proliferates it forms a clone of identical cells bearing identical antigen receptors. The diversity in antigen receptors is generated by a unique genetic mechanism that operates during lymphocyte development in the bone marrow and the thymus to generate millions of different variants of the genes encoding the receptor molecules. This ensures that the lymphocytes in the body collectively carry millions of different antigen receptor specifici ties-the lymphocyte receptor repertoire of the individual.

Vaccination

- Immunology is a relatively new science. Its origin is usually attributed to Edward Jenner (Fig.l.1), who observed in the late 18th century that the relatively mild disease of cowpox, or vaccinia, seemed to confer protection against the often fatal disease of smallpox. In 1796, Jenner demonstrated that inoculation with cowpox could protect against smallpox. He called the procedure vaccination, and this term is still used to describe the inoculation of healthy individuals with weakened or attenuated strains of disease-causing agents to provide protection from disease. - The discoveries of Koch and other great 19th-century microbiologists extended Jenner's strategy of vaccination to other diseases. In the 1880s, Louis Pasteur devised a vaccine against cholera in chickens, and developed a rabies vaccine that proved a spectacular success upon its first trial in a boy bitten by a rabid dog.

Immunoglobulins bind a wide variety of chemical structures, whereas the T-cell receptor is specialized to recognize foreign antigens as peptide fragments bound to proteins of the major histocompatibility complex.

- In principle, almost any chemical structure can be recognized by the adaptive immune system as an antigen, but the usual antigens encountered in an infection are the proteins, glycoproteins, and polysaccharides of patho gens. An individual antigen receptor or antibody recognizes a small part of the molecular structure of an antigenic molecule, which is known as an antigenic determinant or epitope. - The antigen receptors of B cells and T cells recognize antigen in fundamentally different ways. B cells directly recognize the native antigen that either has been secreted by a pathogen or is expressed on its surface. B cells eventually differentiate into effector plasma cells that secrete antibod ies that will bind to and neutralize these antigens and pathogens. - In contrast, T-cell receptors do not directly recognize native antigens. Rather, they recognize antigens that have been processed, partly degraded, and displayed as peptides bound to proteins on the surface of antigen-presenting cells. - A main source of the antigens recognized byT cells is cells infected with a pathogen, commonly a virus. In this case, the antigen that is recognized by the effector T cells is derived from within the infected cell. Importantly, T-cell receptors will only recognize antigen -derived pep tides when these are bound to particular cell-surface glycoproteins called MHC molecules, which are encoded in a cluster of genes called the major histocompatibility complex (MHC). The antigen recognized by T-cell receptors is thus a complex of a for eign peptide antigen and an MHC molecule

Inherited and acquired defects in the immune system result in increased susceptibility to infection.

- In the most severe of these immunodeficiency diseases, adaptive immunity is completely absent, and death occurs in infancy from overwhelming infection unless heroic measures are taken. - a devastating form of immunodeficiency appeared, the acquired immune deficiency syndrome, or AIDS, which is caused by an infectious agent, the human immunodeficiency viruses HIV-1 and HIV-2. This disease destroys T cells, dendritic cells, and macrophages bearing CD4, leading to infections caused by intracellular bacteria and other pathogens normally controlled by such cells.

Lymphocytes mature in the bone marrow or the thymus and then congregate in lymphoid tissues throughout the body.

- Lymphocytes circulate in the blood and the lymph and are also found in large numbers in lymphoid tissues or lymphoid organs, which are organized aggregates of lymphocytes in a framework of nonlymphoid cells. - Lymphoid organs can be divided broadly into the central or primary lymphoid organs, where lymphocytes are generated, and the peripheral or secondary lymphoid organs, where mature naive lymphocytes are maintained and adaptive immune responses are initiated. The central lymphoid organs are the bone marrow and the thymus, an organ in the upper chest. The peripheral lymphoid organs comprise the lymph nodes, the spleen, and the mucosal lymphoid tissues of the gut, the nasal and respiratory tract, the urogenital tract, and other mucosa. - Both B and T lymphocytes originate in the bone marrow, but only the B lymphocytes mature there. The precursor T lymphocytes migrate to the thymus, from which they get their name, and mature there. Once they have completed maturation, both types of lymphocytes enter the bloodstream as mature naive lymphocytes. They circulate through the peripheral lymphoid tissues, in which an adaptive immune response is initiated if a lymphocyte meets its corresponding antigen. Before this, however, an innate immune response to the infection has usually occurred, and we now look at how this alerts the rest of the immune system to the presence of a pathogen.

Lymphocyte activation requires additional signals beyond those relayed from the antigen receptor when antigen binds.

- Peripheral lymphoid tissues promote the interaction between antigen-bearing APCs and lymphocytes, but antigen alone is not sufficient to initiate an adaptive immune response. Lymphocytes require other signals to become activated and to acquire effector functions. These signals are delivered to lymphocytes by another cell through cell-surface molecules known generally as co-stimulatory molecules (see Section 1-8). For naive T cells, an activated dendritic cell usually delivers these signals, but for naive B cells, the second signal is delivered by an activated helper T cell. The induction of co-stimulatory molecules is important in initiating an adaptive immune response because contact with antigen without accompanying co-stimulatory molecules inactivates naive lymphocytes rather than activating them, leading either to clonal deletion or an inactive state known as anergy. - Macro phages and B cells can also present foreign antigens on their surface and can be induced to express co-stimulatory molecules and thus can activate T cells. These three specialized antigen-presenting cells of the immune system are illustrated in Fig. 1.22. Dendritic cells are the most important of the three in initiating the adaptive immune response, whereas the others function as antigen-presenting cells at later stages, when T cells have acquired particular effector activities.

The development and survival of lymphocytes is determined by signals received through their antigen receptors.

- The continuous generation of lymphocytes throughout life creates a prob lem of keeping total numbers of peripheral lymphocytes relatively constant. In addition, with so many different antigen receptors being generated during lymphocyte development, it is inevitable that potentially dangerous receptors that can react against an individual's own self antigens will be produced. Both these problems seem to be solved by making the survival of a lymphocyte dependent on signals received through its antigen receptor. - Lymphocytes that react strongly to self antigens during development are removed by clonal deletion, as predicted by Burnet's clonal selection theory, before they mature to a stage at which they could do damage. The complete absence of signals from the antigen receptor during development can also lead to cell death. Lymphocytes that receive either too much or too little signal during develop ment are eliminated by a form of cell suicide called apoptosis or programmed cell death. - L astly, if a lymphocyte's receptor is not used within a relatively short time of its entering the repertoire in the periphery, the cell bearing it dies, making way for new lymphocytes with different receptors. In this way, self-reactive receptors are eliminated, and receptors are tested to ensure that they are potentially functional. The mechanisms that shape and maintain the lymphocyte receptor repertoire

Pattern recognition receptors of the innate immune system provide an initial discrimination between self and nonself.

- The defense systems of innate immunity are effective in combating many pathogens, but rely on a limited number of invariant receptors that recognize microorganisms. The pathogen-recognition receptors ofmacrophages, neutrophils, and dendritic cells recognize simple molecules and regular patterns of molecular structure known as pathogen-associated molecular patterns (PAMPs) that are present on many microorganisms but not on the body's own cells. The receptors that recognize PAMPs are known generally as pattern recognition receptors (PRRs), and they recognize structures such as mannose-rich oligosaccharides, peptidoglycans, and lipopolysaccharides in the bacterial cell wall, and unmethylated CpG DNA, which are common to many pathogens and have been conserved during evolution, making them excellent targets for recognition because they do not change -(PAMPs) Molecules specifically associated with groups of pathogens that are recognized by cells of the innate immune system. - The pattern recognition receptors allow the innate immune system to distin guish self (the body) from nonself (pathogen). Detection of nonself activates innate cells and initiates adaptive immunity: macrophages are triggered to engulf microbes; immature dendritic cells are triggered to activate naive T lymphocytes. The molecules recognized by pattern recognition receptors are quite distinct from the individual pathogen-specific antigens recognized by lymphocytes. The fact that microbial constituents were needed to stimulate immune responses against purified proteins highlights the requirement that an innate response must precede the initiation of an adaptive response.

COST cells recognize peptides bound to two different classes of MHC molecules.

- The different types of effector T cells must be directed to act against the appropriate target cells. Antigen recognition is obviously crucial, but correct target recognition is also ensured by additional interactions between the CD8 and CD4 molecules on the T cells and the MHC molecules on the target cell. - T cells detect peptides derived from foreign anti gens after antigens are degraded within cells, their peptide fragments are cap tured by MHC molecules, and this complex is displayed at the cell surface. There are two main types of MHC molecules, called MHC class I and MHC class II. They have slightly different structures but both have an elongated cleft in the extracellular surface of the molecule, in which a single peptide is trapped during the synthesis and assembly of the MHC molecule inside the cell. The MHC molecule bearing its cargo of peptide is transported to the cell surface, where it displays the peptide to T cells - There are some important functional differences between the two classes of MHC molecules. 1. First, as noted earlier, the CD8 and CD4 molecules that dis tinguish different T-cell subsets are not just random markers. These two proteins have the ability to recognize parts of the MHC class I and MHC class II molecules, respectively. CD8 T cells therefore selectively recognize peptides that are bound to MHC class I molecules, and CD4 T cells recognize peptides presented by MHC class II. CD4 and CD8 are known as co-receptors, because they are inextricably involved in signaling to the T cell that the receptor has bound the correct antigen. 2. There are also differences in the source of pep tides that are processed and eventually bound to the two types ofMHC proteins. In most cells, MHC class I molecules collect pep tides derived from proteins syn thesized in the cytosol and are thus able t

Lymphocytes activated by antigen proliferate in the peripheral lymphoid organs, generating effector cells and immunological memory.

- The great diversity of lymphocyte receptors means that there will usually be at least a few that can bind to a given foreign antigen. However, this number will be very small, certainly not enough to mount a response against a pathogen. To generate sufficient antigen-specific effector lymphocytes to fight an infection, a lymphocyte with an appropriate receptor specificity is activated first to proliferate. Only when a large clone of identical cells has been produced do these finally differentiate into effector cells. On recognizing its specific antigen on an activated antigen-presenting cell, a naive lymphocyte stops migrat ing, the volume of the nucleus and cytoplasm increases, and new mRNAs and new proteins are synthesized. Within a few hours, the cell looks completely different and is known as a lymphoblast. - Dividing lymphoblasts are able to duplicate themselves two to four times every 24 hours for 3-5 days, so that a single naive lymphocyte can produce a clone of around 1000 daughter cells of identical specificity. These then dif ferentiate into effector cells. In the case of B cells, the differentiated effector cells are the plasma cells, which secrete antibody; in the case ofT cells, the effector cells are cytotoxic T cells able to destroy infected cells, or helper T cells that activate other cells of the immune system. Effector lymphocytes do not recirculate like naive lymphocytes. Some effector T cells detect sites of infection and migrate into them from the blood; others stay in the lymphoid tissues to activate B cells. Some antibody-secreting plasma cells remain in the peripheral lymphoid organs, but most plasma cells generated in the lymph nodes and spleen migrate to the bone marrow and take up residence there, pouring out antibodies into the blood system. Effector cells generated in the mucosal imm

Understanding adaptive immune responses is important for the control of allergies, autoimmune disease, and the rejection of transplanted organs.

- The main function of our immune system is to protect the human host from infectious agents. However, many medically important diseases are associated with a normal immune response directed against an inappropriate antigen, often in the absence of infectious disease. - disease. Immune responses directed at noninfectious antigens occur in allergy, in which the antigen is an innocu ous foreign substance; in autoimmune disease, in which the response is to a self antigen; and in graft rejection, in which the antigen is borne by a transplanted foreign cell (both discussed in Chapter 15). The major antigens provoking graft rejection are, in fact, the MHC molecules, as each of these is present in many different versions in the human population-that is, they are highly polymorphic-and most unrelated people differ in the set of MH C molecules they express, a property commonly known as their 'tissue type.'

Most infectious agents activate the innate immune system and induce an inflammatory response.

- The skin and the mucosal epithelia lining the airways and gut are the first defense against invading pathogens, forming a physical and chemical barrier against infection. Microorganisms that breach these defenses are met by cells and molecules that mount an immediate innate immune response. - Macrophages resident in the tissues, for example, can recognize bacteria by means of receptors that bind common constituents of many bacterial surfaces. Engagement of these receptors triggers the macrophage both to engulf the bacterium and degrade it internally, and to secrete proteins called cytokines and chemokines that convey important signals to other immune cells. Similar responses occur to viruses, fungi, and parasites. Cytokine is a general name for any protein that is secreted by cells and affects the behavior of nearby cells bearing appropriate receptors. Chemokines are secreted proteins that act as chemoattractants (hence the name 'chemokine'), attracting cells bearing chemokine receptors, such as neutrophils and monocytes, out of the bloodstream and into infected tissue. - The cytokines and chemokines released by activated macrophages initiate the process known as inflammation. Inflammation is beneficial to combating infection by recruiting proteins and cells from the blood into infected tissues that help to directly destroy the pathogen. In addition, inflammation increases the flow of lymph carrying microbes and antigen-presenting cells from the infected tissue to nearby lymphoid tissues, where they activate lymphocytes and initiate the adaptive immune response. Once adaptive immunity has been triggered, inflammation also recruits the effector components of the adaptive immune system-antibody molecules and effector T cells-to the site of infection.

Pathogens

- When Jenner introduced vaccination he knew nothing of the infectious agents that cause disease: it was not until late in the 19th century that Robert Koch proved that infectious diseases are caused by microorganisms, each one responsible for a particular disease (pathogens - Viruses, bacteria, fungi and unicellular and multicellular eukaryotic organisms collectively termed parasites. - bacteria don't grow in the blood for two reasons 1. blood have immune cells that kill bacteria, 2. all organisms require iron to survive and blood it is safely sequestered in hemoglobin.

The structure of the antibody molecule illustrates the central puzzle of adaptive immunity.

- antibodies are the secreted form of the B cell's antigen receptor. - The startling feature that emerged from the biochemical studies was that antibody molecules are composed of two distinct regions. One is a constant region that takes one of only four or five biochemically distinguishable forms; the other is a variable region that can be composed of a seemingly infinite variety of different amino acid sequences, forming subtly different structures that allow antibodies to bind specifically to an equally vast variety of antigens. Antibody is depicted as a Y-shaped molecule. The variable region determines the antigen binding specificity of the antibody. There are two identical variable regions in an antibody molecule, and it thus has two identical antigen-binding sites. The constant region determines the effector function of the antibody: that is, how the antibody will interact with various immune cells to dispose of antigen once it is bound. - Each antibody molecule has a two -fold axis of symmetry and is composed of two identical heavy chains and two identical light chains. - Heavy and light chains each have variable and constant regions; the variable regions of a heavy chain and a light chain combine to form an antigen-bind ing site, so that both chains contribute to the antigen-binding specificity of the antibody molecule. - The T-cell receptor for antigen shows many similarities to the B -cell antigen receptor, and the two molecules are clearly related to each other evolutionarily. There are, however, important differences between the two that, as we shall see, relate to their different roles within the immune system.The T-cell receptor, is composed of two chains of roughly equal size, called the T-cell receptor a and beta chains, each of which spans the T-cell membrane. Each chain has a variable region a

Each developing lymphocyte generates a unique antigen receptor by rearranging its receptor gene segments.

- discovered that the genes for immunoglobulin vari able regions are inherited as sets of gene segments, each encoding a part of the variable region of one of the immunoglobulin polypeptide chains. During B-cell development in the bone marrow, these gene segments are irreversibly joined by DNA recombination to form a stretch of DNA encoding a complete variable region. 1. First, it is the combinatorial assembly of a large number of different gene segments that makes possible the enormous size of the antigen receptor repertoire. This means that a finite number of gene segments can generate a vast number of different proteins. 2. Second, the assembly process is regulated in a manner that ensures that each lymphocyte expresses only one receptor specificity. 3. Third, because gene segment rearrangement involves an irreversible change in a cell's DNA, all the progeny of that cell will inherit genes encoding the same receptor specificity. This general scheme was later also confirmed for the genes encoding the antigen receptor on T cells.

Adaptive immune responses are initiated by antigen and antigen presenting cells in secondary lymphoid tissues.

- presenting cells, particularly dendritic cells bearing antigens picked up at sites of infection, reach the secondary lymphoid organs. Like the neutrophils and macrophages described earlier, dendritic cells have pattern recognition receptors that recognize molecular patterns common to microorganisms, such as bacterial lipopolysaccharide. Microbial components binding to these receptors stimulate the immature dendritic cell to engulf the pathogen and degrade it intracellularly. Immature dendritic cells also take up extracellular material, including virus particles and bacteria, by receptor-independent macropinocytosis, and thus internalize and degrade pathogens that their cell-surface receptors do not detect. In addition to the display of antigens that activates the antigen-receptors of lymphocytes, mature dendritic cells also express cell-surface proteins called costimulatory molecules, which provide signals that act together with antigen to stimulate the T lymphocyte to proliferate and differentiate into its final fully functional form (Fig. 1.11). Free antigens can also stimulate the antigen receptors of B cells, but most B cells require 'help' from activated helper T cells for optimal antibody responses. The activation of naive T lymphocytes is therefore an essential first stage in virtually all adaptive immune responses.

lymphocytes

A class of white blood cells that bear variable cell-surface receptors for antigen and are responsible for adaptive immune responses. There are two main types— B lymphocytes (B cells) and T lymphocytes (T cells)— which mediate humoral and cell-mediated immunity, respectively. On antigen recognition, a lymphocyte enlarges to form a lymphoblast and then proliferates and differentiates into an antigen-specific effector cell. - white blood cells known as lymphocytes possess the most powerful ability to recognize and target pathogenic microorganisms, they need the participation of the innate immune system to initiate and to mount their offensive. Indeed, the adaptive immune response and innate immunity use many of the same destructive mechanisms to finally destroy invading microorganisms. - There are two types of lymphocytes-B lymphocytes (B cells) and T lymphocytes (T cells)-each with quite different roles in the immune system and distinct types of antigen receptors. After antigen binds to a B-cell antigen receptor, orB-cell receptor (BCR), on the B-cell surface, the lymphocyte will proliferate and differentiate into plasma cells. These are the effector form of B lymphocytes and they produce antibodies, which are a secreted form of the B-cell receptor and have an identical antigen specificity. Thus the antigen that activates a given B cell becomes the target of the antibodies produced by that cell's progeny. Antibody molecules as a class are known as immunoglobulins (lg), and so the antigen receptor of B lymphocytes is also known as membrane immunoglobulin (mig) or surface immunoglobulin (sag). - The T-cell antigen receptor, or T-cell receptor (TCR), is related to immunoglobulin but is quite distinct in its structure and recognition properties. After aT cell has been activated by its first encounter with antigen

apoptosis

A form of cell death common in the immune system, in which the cell activates an internal death program. It is characterized by nuclear DNA degradation, nuclear degeneration and condensation, and the rapid phagocytosis of cell remains. Proliferating lymphocytes experience high rates of apoptosis during their development and during immune responses.

autograft

A graft of tissue from one site to another on the same individual.

appendix

A gut-associated lymphoid tissue located at the beginning of the colon.

fungi

A kingdom of single-celled and multicellular eukaryotic organisms, including the yeasts and molds, that can cause a variety of diseases. Immunity to fungi is complex and involves both humoral and cell-mediated responses.

mast cell

A large granule-rich cell found in connective tissues throughout the body, most abundantly in the submucosal tissues and the dermis. The granules store bioactive molecules including the vasoactive amine histamine, which are released on mast-cell activation. Mast cells are thought to be involved in defenses against parasites and they have a crucial role in allergic reactions. - Mast cells, whose blood-borne precursors are not well defined, differentiate in the tissues. Although best known for their role in orchestrating allergic responses, they are believed to play a part in protecting the internal surfaces of the body against pathogens, and are involved in the response to parasitic worms. They have large granules in their cytoplasm that are released when the mast cell is activated; these help induce inflammation.

macrophage

A large mononuclear phagocytic cell type important as scavenger cells, as pathogen-recognition cells, as a source of pro-inflammatory cytokines in innate immunity, as antigen-presenting cells, and as effector phagocytic cells in humoral and cell-mediated immunity. Macrophages derive from bone marrow precursors and are found in most tissues of the body. - Macrophages are resident in almost all tissues and are the mature form of monocytes, which circulate in the blood and continually migrate into tissues, where they differentiate. Together, monocytes and macrophages make up one of the three types of phagocytes in the immune system: the others are the granulocytes (the collective term for the white blood cells called neutrophils, eosinophils, and basophils) and the dendritic cells. Macrophages are relatively long-lived cells and perform several different functions throughout. - the innate immune response and the subsequent adaptive immune response. One is to engulf and kill invading microorganisms. In this phagocytic role they are an important first defense in innate immunity and also dispose of pathogens and infected cells targeted by an adaptive immune response. Both monocytes and macro phages are phagocytic, but most infections occur in the tissues, and so it is primarily macrophages that perform this important protective function. An additional and crucial role of macro phages is to orchestrate immune responses: they help induce inflammation, which, as we shall see, is a prerequisite to a successful immune response, and they secrete signaling proteins that activate other immune-system cells and recruit them into an immune response.

draining lymph node

A lymph node downstream of a site of infection that receives antigens and microbes from the site via the lymphatic system. Draining lymph nodes often enlarge enormously during an immune response and can be palpated; they were originally called swollen glands.

clone

A population of cells all derived from the same progenitor cell.

complement system

A set of plasma proteins that act together as a defense against pathogens in extracellular spaces. The pathogen becomes coated with complement proteins that facilitate its removal by phagocytes and that can also kill certain pathogens directly. Activation of the complement system can be initiated in several different ways.

epitope

A site on an antigen recognized by an antibody or an antigen receptor. A T-cell epitope is a short peptide derived from a protein antigen. It binds to an MHC molecule and is recognized by a particular T cell. B-cell epitopes are antigenic determinants recognized by B cells and are typically structural motifs on the surface of the antigen. Also called an antigenic determinant.

eosinophil and Basophil

A type of white blood cell containing granules that stain with eosin. It is thought to be important chiefly in defense against parasitic infections, but is also medically important as an effector cell in allergic reactions. - Eosinophils and basophils are less abundant than neutrophils, but like neut rophils they have granules containing a variety of enzymes and toxic proteins, which are released when the cells are activated. - activated. Eosinophils and basophils are thought to be important chiefly in defense against parasites, which are too large to be ingested by macrophages or neutrophils. They can also contribute to allergic inflammatory reactions, in which their effects are damaging rather than protective.

bacteria

A vast kingdom of unicellular prokaryotic microorganisms.

cell-mediated immune response

An adaptive immune response in which antigen-specific effector T cells have the main role. The immunity to infection conferred by such a response is called cell-mediated immunity. A primary cell-mediated immune response is the T-cell response that occurs the first time a particular antigen is encountered.

booster immunization

An additional immunization commonly given after a primary immunization, to increase the amount, or titer, of antibodies.

follicle

An area of predominantly B cells in a peripheral lymphoid organ, such as a lymph node, which also contains follicular dendritic cells.

B lymphocyte

Antigen-specific lymphocyte.The function of B cells is to produce antibodies. Two classes: Conventional B cells have highly diverse antigen receptors and are generated in the bone marrow throughout life, emerging to populate the blood and lymphoid tissues. B-1 cells have much less diverse antigen receptors and form a population of self-renewing B cells in the peritoneal and pleural cavities.

antigen

Any molecule that can bind specifically to an antibody or generate peptide fragments that are recognized by a T-cell receptor. - they could stimulate antibody generation. - it was discovered that antibody production is not the only function of adaptive immune responses, and the term antigen is now used to describe any substance that can be recognized and responded to by the adaptive immune system. - The proteins, glycoproteins, and polysaccharides of pathogens are the antigens normally responded to by the immune system, but it can recognize and make a response to a much wider range of chemical structures-hence its ability to produce allergic immune responses to metals such as nickel, drugs such as penicillin, and organic chemicals in the leaves of poison ivy.

dendritic cells

Bone marrow derived cells found in most tissues, including lymphoid tissues. There are two main functional subsets. Conventional dendritic cells take up antigen in peripheral tissues, are activated by contact with pathogens, and travel to the peripheral lymphoid organs, where they are the most potent stimulators of T-cell responses. Plasmacytoid dendritic cells can also take up and present antigen, but their main function in an infection is to produce large amounts of the antiviral interferons as a result of pathogen recognition through receptors such as TLRs. Both these types of dendritic cells are distinct from the follicular dendritic cell that presents antigen to B cells in lymphoid follicles. - There are several kinds of dendritic cells, which form the third class of phagocytic cell of the immune system. Most dendritic cells have long fingerlike processes, like the dendrites of nerve cells, which give them their name. Immature dendritic cells migrate through the bloodstream from the bone marrow to enter tissues. - They take up particulate matter by phagocytosis and also continually ingest large amounts of the extracellular fluid and its contents by a process known as macropinocytosis. - Like macro phages and neutrophils, they degrade the pathogens they take up, but their main role in the immune system is not the clearance of microorganisms. Instead, the encounter with a pathogen stimulates dendritic cells to mature into cells that can activate a particular class of lymphocytes-the T lymphocytes.

Leukocytes

Both innate and adaptive immune responses depend upon the activities of white blood cells or leukocytes. These cells all originate in the bone marrow, and many of them also develop and mature there. Once mature, they migrate to guard the peripheral tissues: some of them reside within tissues, while others circulate in the bloodstream and in a specialized system of vessels called the lymphatic system, which drains extracellular fluid and free cells from tissues, transports them through the body as lymph, and eventually empties back into the blood system. - All the cellular elements of blood, including the red blood cells that transport oxygen, the platelets that trigger blood clotting in damaged tissues, and the white blood cells of the immune system, derive from the hematopoietic stem cells of the bone marrow. Because these stem cells can give rise to all the different types of blood cells, they are often known as pluripotent hematopoietic stem cells. They give rise to cells of more limited developmental potential, which are the immediate progenitors of red blood cells, platelets, and the two main categories of white blood cells, the lymphoid and myeloid lineages.

endothelial cell

Cell type that forms the endothelium, the epithelium of a blood vessel wall.

co-receptor

Cell-surface protein that increases the sensitivity of a receptor to its ligand by binding to associated ligands and participating in signaling. The antigen receptors on T cells and B cells act in conjunction with co-receptors, which are either CD4 or CD8 on T cells, and a co-receptor complex of three proteins, one of which is the complement receptor CR2, on B cells.

co-stimulatory molecules

Cell-surface proteins on antigen-presenting cells that deliver co-stimulatory signals to naive T cells. Examples are the B7 molecules on dendritic cells, which are ligands for CD28 on naive T cells.

inflammatory cells

Cells such as macrophages, neutrophils and effector TH1 lymphocytes that invade inflamed tissues and contribute to the inflammation. - Local inflammation and the phagocytosis of invading bacteria can also be triggered as a result of the activation of a group of plasma proteins known collectively as complement. Activation of the complement system by bacterial surfaces leads to a cascade of proteolytic reactions that coats microbes, but not the body's own cells, with complement fragments. Complement-coated microbes are recognized and bound by specific complement receptors on macrophages, taken up by phagocytosis, and destroyed. - Heat, redness, and swelling result from the dilation and increased permeability of blood vessels during inflammation, leading to increased local blood flow and leakage of fluid and blood proteins into the tissues. Cytokines and complement fragments have important effects on the endothelium that lines blood vessels; the endothelial cells themselves also produce cytokines in response to infection. The pro-inflammatory cytokines produce changes in the adhesive properties of the endothelial cells, in turn causing circulating leukocytes to stick to the endothelial cells and migrate between them into the site of infection, to which they are attracted by chemokines. The migration of cells into the tissue and their local actions account for the pain. - The main cell types seen in the initial phase of an inflammatory response are macrophages and neutrophils, the latter being recruited into the inflamed, infected tissue in large numbers. Macrophages and neutrophils are thus also known as inflammatory cells. - Like macrophages, neutrophils have surface receptors for common bacterial constituents and for complement, and they are the principal cells that engulf and destroy the invading microorgan

clonotypic

Describes a feature unique to members of a clone. For example, the distribution of antigen receptors in the lymphocyte population is said to be clonotypic, as the cells of a given clone all have identical antigen receptors.

autoimmune disease

Disease in which the pathology is caused by adaptive immune responses to self antigens.

antibody

Each antibody molecule has a unique structure that enables it to bind specifically to its corresponding antigen, but all antibodies have the same overall structure and are known collectively as immunoglobulins. Antibodies are produced by differentiated B cells (plasma cells) in response to infection or immunization, and bind to and neutralize pathogens or prepare them for uptake and destruction by phagocytes. Are a protein. - could confer short-lived protection against the effects of diphtheria or tetanus toxins in people. This activity was due to the proteins we now call antibodies, which bound specifically to the toxins and neutralized their activity.

helper CD4 T cells

Effector CD4 T cells that stimulate or 'help' B cells to make antibody in response to antigenic challenge. TH2, TH1, and the TFH subsets of effector CD4 T cells can perform this function.

adaptive immunity

Immunity to infection conferred by an adaptive immune response. - The responses we make against infection by potential pathogens are known as immune responses. A specific immune response, such as the production of antibodies against a particular pathogen or its products, is known as an adaptive immune response because it is developed during the lifetime of an individual as an adaptation to infection with that pathogen. - The innate and adaptive immune responses together provide a remarkably effective defense system. - The immune system must be able to mount an immune response against any of the wide variety of different pathogens a person is likely to encounter during their lifetime. Lymphocytes (specifically antigen-specific lymphocytes) collectively make this possible through the highly variable antigen receptors on their surface, by which they recognize and bind antigens. Each lymphocyte matures bearing a unique variant of a prototype antigen receptor, so that the population of lymphocytes expresses a huge repertoire of receptors that are highly diverse in their antigen-binding sites. Among the billion or so lymphocytes circulating in the body at any one time there will always be some that can recognize a given foreign antigen. - In the absence of an infection, most lymphocytes circulating in the body are small, featureless cells with few cytoplasmic organelles and much of the nuclear chromatin inactive, as shown by its condensed state. - these small lymphocytes have no functional activity until they encounter their specific antigen. Lymphocytes that have not yet been activated by antigen are known as naive lymphocytes; those that have met their antigen, become activated, and have differentiated further into fully functional lymphocytes are known as effector lymphocytes.

cytokine

In the most general sense, any small protein made by a cell that affects the behavior of other cells. Cytokines made by lymphocytes are often called interleukins (abbreviated IL). Cytokines act via specific cytokine receptors on the cells that they affect.

bursa of Fabricius

Lymphoid organ associated with the gut that is the site of B-cell development in chickens.

antigen:antibody complexes

Noncovalently associated groups of antibody molecules bound to their specific antigen.

gut-associated lymphoid tissues

Organized lymphoid tissues closely associated with the gastrointestinal tract, comprising Peyer's patches, the appendix, and isolated lymphoid follicles found in the intestinal wall. They have an anatomically compartmentalized structure typical of peripheral lymphoid organs and are sites at which adaptive immune responses are initiated. The tissues are connected to the mesenteric lymph nodes by lymphatic vessels.

adenoids

Paired mucosal-associated lymphoid tissues located in the nasal cavity.

complement regulatory proteins

Proteins that control complement activity and prevent complement from being activated on the surfaces of host cells.

gene segments

Sets of short DNA sequences at the immunoglobulin and T-cell receptor loci that encode different regions of the variable domains of antigen receptors. Gene segments of each type are joined together by somatic recombination to form a complete variable-domain exon. There are three types of gene segments: V gene segments encode the first 95 amino acids, D gene segments (in heavy-chain and TCRα chain loci only) encode about 5 amino acids, and J gene segments encode the last 10-15 amino acids of the variable domain. There are multiple copies of each type of gene segment in the germline DNA, but only one of each type is joined together to form the variable domain.

chemokines

Small chemoattractant protein that stimulates the migration and activation of cells, especially phagocytic cells and lymphocytes. Chemokines have a central role in inflammatory responses. Individual chemokines and their receptors are listed in 17V.

high endothelial cells

Specialized small venous blood vessels in lymphoid tissues. Lymphocytes migrate from the blood into lymphoid tissues by attaching to the high endothelial cells in the walls of the venules and squeezing between them.

common lymphoid progenitor

Stem cell that can give rise to all the types of lymphocytes of the adaptive immune system and also to a type of lymphocyte that responds to the presence of infection but is not specific for antigen, and is thus considered to be part of the innate immune system.

common myeloid progenitor

Stem cells that can give rise to the myeloid cells of the immune system— macrophages, granulocytes, mast cells, and dendritic cells of the innate immune system. This stem cell also gives rise to megakaryocytes and red blood cells.

innate immune response

That part of a response to an infection that is due to the presence of, and immediate activation of, the body's innate and relatively nonspecific defense mechanisms, in contrast to an adaptive immune response that develops later and involves antigen-specific lymphocytes. - diphtheria, innate immunity was known chiefly through the work of the great Russian immunologist Elie Metchnikoff, who discovered that many microorganisms could be engulfed and digested by phagocytic cells, which he called 'macrophages.' These cells are always present and ready to act, and are a front-line component of innate immune responses. In contrast, an adaptive immune response takes time to develop and is highly specific; antibodies against the influenza virus, for example, will not protect against poliovirus. - Innate immune responses occur rapidly on exposure to an infectious organ ism. In contrast, responses by the adaptive immune system take days rather than hours to develop. However, the adaptive immune system is capable of eliminating infections more efficiently because of the exquisitely specific recognition functions of lymphocytes. These cells can recognize and respond to individual antigens by means of highly specialized antigen receptors on the lymphocyte surface. The billions of lymphocytes present in the body collectively possess a vast repertoire of antigen receptors, which enables the immune system to recognize and respond to virtually any antigen a person is likely to be exposed to. In this way, adaptive immunity can more effectively focus its resources to overcome pathogens that have evaded or overwhelmed innate immunity. Antibodies and activated lymphocytes produced by an adaptive immune response can also persist after the original infection has been eliminated. They help to prevent immediate reinfection and also provid

antigenetic determinant

That portion of an antigenic molecule that is bound by the antigen-binding site of a given antibody or antigen receptor; it is also known as an epitope.

complement activation

The activation of the normally inactive proteins of the complement system that occurs on infection.

antigen receptor

The cell-surface receptor by which lymphocytes recognize antigen. Each individual lymphocyte bears receptors of a single antigen specificity.

effector lymphocytes

The cells that differentiate from naive lymphocytes after initial activation by antigen and can then mediate the removal of pathogens from the body without further differentiation. They are distinct from memory lymphocytes, which must undergo further differentiation to become effector lymphocytes.

clonal selection theory

The central paradigm of adaptive immunity. It states that adaptive immune responses derive from individual antigen-specific lymphocytes that are self-tolerant. These specific lymphocytes proliferate in response to antigen and differentiate into antigen-specific effector cells that eliminate the eliciting pathogen, and into memory cells to sustain immunity.

antibody class

The class of an antibody is defined by the type of heavy chain it contains. There are five main antibody classes: IgA, IgD, IgM, IgG, and IgE, containing heavy chains α, δ, μ, γ, and ε, respectively. The IgG class has several subclasses.

CD8

The co-receptor for T-cell receptors that recognize peptide antigens bound to MHC class I molecules. It binds to the lateral face of the MHC molecule.

CD4

The co-receptor for T-cell receptors that recognize peptide antigens bound to MHC class II molecules. It binds to the lateral face of the MHC molecule.

clonal deletion

The elimination of immature lymphocytes when they bind to self antigens, which produces tolerance to self as required by the clonal selection theory of adaptive immunity. Clonal deletion is the main mechanism of central tolerance and can also occur in peripheral tolerance.

endothelium

The epithelium that forms the walls of blood capillaries and the lining of larger blood vessels.

hematopoiesis

The generation of blood cells, which in humans occurs in the bone marrow.

affinity maturation

The increase in affinity for their specific antigen of the antibodies produced as an adaptive immune response progresses. This phenomenon is particularly prominent in secondary and subsequent immunizations.

H-2

The major histocompatibility complex of the mouse. Haplotypes are designated by a lower-case superscript, as in H-2b.

neutrophil (one of the 3 types of granulocytes)

The most numerous type of white blood cell in human peripheral blood. Neutrophils are phagocytic cells with a multilobed nucleus and granules that stain with neutral stains. They enter infected tissues and engulf and kill extracellular pathogens. - The phagocytic neutrophils are the most numerous and most important cells in innate immune responses: they take up a variety of microorganisms by phagocytosis and efficiently destroy them in intracellular vesicles using degradative enzymes and other antimicrobial substances stored in their cytoplasmic granules.

cortex

The outer part of a tissue or organ; in lymph nodes it refers to the follicles, which are mainly populated by B cells.

clonal expansion

The proliferation of antigen-specific lymphocytes in response to antigenic stimulation that precedes their differentiation into effector cells. It is an essential step in adaptive immunity, allowing rare antigen-specific cells to increase in number so that they can effectively combat the pathogen that elicited the response.

acquired immune response

The response of antigen-specific lymphocytes to antigen, including the development of immunological memory. Adaptive immune responses are distinct from the innate and nonadaptive phases of immunity, which are not mediated by clonal selection of antigen-specific lymphocytes.

efferent lymphatic vessel

The route by which circulating lymphocytes leave a lymph node and some other types of peripheral lymphoid organs.

antigen-binding site

The site at the tip of each arm of an antibody that makes physical contact with the antigen and binds it noncovalently. The antigen specificity of the site is determined by its shape and the amino acids present.

central lymphoid organs

The sites of lymphocyte development; in humans, these are the bone marrow and thymus. B lymphocytes develop in bone marrow, whereas T lymphocytes develop within the thymus from bone marrow derived progenitors. Also called the primary lymphoid organs.

Ig

The standard abbreviation for immunoglobulin.

allergy

The state in which a symptomatic immune reaction is made to a normally innocuous environmental antigen. It involves the interaction between the antigen and antibody or primed T cells produced by earlier exposure to the same antigen.

cellular immunology

The study of the cellular basis of immunity.

bone marrow

The tissue where all the cellular elements of the blood— red blood cells, white blood cells, and platelets— are initially generated from hematopoietic stem cells. The bone marrow is also the site of further B-cell development in mammals and the source of stem cells that give rise to T cells on migration to the thymus. Thus, bone marrow transplantation can restore all the cellular elements of the blood, including the cells required for adaptive immune responses.

B-cell corona

The zone of the white pulp in the spleen that is primarily made up of B cells.

effector mechanisms

Those processes by which pathogens are destroyed and cleared from the body. Innate and adaptive immune responses use most of the same effector mechanisms to eliminate pathogens.

The immune system recognizes infection and induces protective responses

To protect the individual effectively against disease, the immune system must fulfill four main tasks: 1. is immunological recognition: the presence of an infection must be detected. This task is carried out both by the white blood cells of the innate immune system, which provide an immediate response, and by the lymphocytes of the adaptive immune system. - When an individual first encounters an infectious agent, the initial defenses against infection are physical and chemical barriers, such as antimicrobial proteins secreted at mucosal surfaces, that prevent microbes from entering the body. If these barriers are overcome or evaded, other components of the immune system come into play. The complement system can immediately recognize and destroy foreign organisms, and phagocytic white blood cells, such as macrophages and neutrophils of the innate immune system, can ingest and kill microbes by producing toxic chemicals and powerful degradative enzymes. 2. The second task is to contain the infection and if possible eliminate it completely, which brings into play immune effector functions such as the complement system of blood proteins, the antibodies produced by some lymphocytes, and the destructive capacities of lymphocytes and the other white blood cells. At the same time the immune response must be kept under control so that it does not itself do damage to the body. 3. Immune regulation, or the ability of the immune system to self-regulate, is thus an important feature of immune responses, and failure of such regulation contributes to conditions such as allergy and autoimmune disease. 4. The fourth task is to protect the individual against recurring disease due to the same pathogen. A unique feature of the adaptive immune system is that it is capable of generating immunological memory, so that having b

cytotoxic T cell

Type of T cell that can kill other cells. Most cytotoxic T cells are MHC class I-restricted CD8 T cells, but CD4 T cells can also kill in some cases. Cytotoxic T cells are important in host defense against intracellular pathogens that live or reproduce in the cell's cytosol.

hematopoietic stem cell

Type of pluripotent cell in the bone marrow that can give rise to all the different blood cell types.

afferent lymphatic vessels

Vessels of the lymphatic system that drain extracellular fluid from the tissues and carry antigen, macrophages, and dendritic cells from sites of infection to lymph nodes or other peripheral lymphoid organs.

granulocytes

White blood cells with multilobed nuclei and cytoplasmic granules. They comprise the neutrophils, eosinophils, and basophils. Also known as polymorphonuclear leukocytes. - The granulocytes are so called because they have densely staining granules in their cytoplasm; they are also called polymorphonuclear leukocytes because of their oddly shaped nuclei. There are three types of granulocytes-neutrophils, eosinophils, and basophils-which are distinguished by the different staining properties of the granules. In comparison with macro phages they are all relatively short -lived, surviving for only a few days, and are produced in increased numbers during immune responses, when they leave the blood to migrate to sites of infection or inflammation.