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Lymphoid (Immune) System


The lymphoid system is responsible for the immunological defense of the body. Some of its component organs— bone marrow , lymph nodes , thymus , and spleen —are surrounded by connective tissue capsules, whereas its other components, members of the diffuse lymphoid system , are not encapsulated. The cells of the lymphoid system protect the body against foreign macromolecules, viruses, bacteria, and other invasive microorganisms, and they kill cells of the self that were virally transformed.

There are two categories of lymphoid organs: primary and secondary. Primary lymphoid organs (bone marrow and thymus) participate in the development of immunocompetent lymphocytes. Secondary lymphoid organs (lymph nodes, spleen, tonsils, and diffuse lymphoid tissue) function in trapping antigens and providing sites for the interactions of antigen-presenting cells (APCs) with immunocompetent lymphocytes, where they can mount an immune response and thereby remove the antigenic assault.

Overview of the Immune System

The immune system has two components: the innate immune system and the adaptive immune system.

The first line of defense against invading pathogens is a physical barrier—the skin and the mucosa—structures that completely cover and line the external and internal surfaces of the body. Breaching of the skin and mucosa, permitting foreign substances to attempt penetration or actually penetrate the intact barrier, activates the innate and the adaptive immune systems—the second and third lines of defense, respectively.

The complexity of the immune system prevents a complete treatment of the topic here. To make the reading of this material easier for the student, certain information is repeated in various sections of the presentation to avoid the need for cross-referencing.

The innate immune system (natural immune system) is nonspecific and is composed of (1) a system of blood-borne macromolecules (C1 to C9) known as complement ; (2) natural (polyreactive) antibodies present in the bloodstream; (3) Toll-like receptors (TLRs) , a family of integral proteins localized on either the plasmalemma or endosomal (and RER) membranes of cells; (4) groups of cells known as macrophages and neutrophils , which phagocytose invaders; and (5) another group of cells, natural killer (NK) cells , which kill tumor cells, virally infected cells, bacteria, and parasites.

The adaptive immune system ( acquired immune system ) is responsible for eliminating threats from specific invaders. Whereas a macrophage can phagocytose most bacteria, the adaptive immune system not only reacts against one specific antigenic component of a pathogen but also its ability to react against that particular component improves with subsequent confrontations with it.

Although the two systems differ in their mode of responses, they are intimately related to one another, and each affects the other’s activities.

The Innate Immune System

The innate immune system responds rapidly, has no immunological memory, and depends on complement and TLRs for initiating inflammatory and/or immune responses.

Although the innate immune system is much older than the adaptive immune system, it responds rapidly, usually within a few hours, to an antigenic invasion; it responds in a nonspecific manner; and it has no immunological memory. The critical components of the innate immune system are complement, antimicrobial peptides, cytokines, macrophages, neutrophils, NK cells, and TLRs. ( Table 12.1 presents acronyms and abbreviations used in this chapter.)

TABLE 12.1
Acronyms and Abbreviations
Acronym/Abbreviation Meaning of Acronym/Abbreviation
ADDC Antibody-dependent cellular cytotoxicity
AIDS Acquired immunodeficiency syndrome
APC Antigen-presenting cell
BALT Bronchus-associated lymphoid tissue
B lymphocyte Bursa-derived lymphocyte (bone marrow-derived lymphocyte)
C3b Complement 3b
CD Cluster of differentiation molecule (followed by an Arabic numeral)
CLIP Class II-associated invariant protein
CSF Colony-stimulating factor
CTL Cytotoxic T lymphocyte (T killer cell)
Fab Antigen binding fragment of an antibody
Fas protein CD95 (induces apoptosis)
Fc Crystallized fragment (constant fragment of an antibody
GALT Gut-associated lymphoid tissue
G-CSF Granulocyte–colony-stimulating factor
GM-CSF Granulocyte-macrophage–colony-stimulating factor
HEV High endothelial venules
HIV Human immunodeficiency virus
IFN- γ Interferon-gamma
Ig Immunoglobulin (followed by a capital letter: A, D, E, G, or M)
IL Interleukin (followed by an Arabic numeral)
M cell Microfold cell
MAC Membrane attack complex
MALT Mucosa-associated lymphoid tissue
MHC I and MHC II Major histocompatibility class I molecules and class II molecules
MIIC vesicle MHC class II–enriched compartment
NK cell Natural killer cells
PALS Periarterial lymphatic sheath
sIgs Surface immunoglobulins
TAP Transporter protein (1 and 2)
TCM Central memory T cell
TCR T-cell receptor
TEM Effector T memory cell
T h cell T helper cell (followed by an Arabic numeral)
TLRs Toll-like receptors
T lymphocyte Thymus-derived lymphocyte
TNF- α Tumor necrosis factor-alpha
T reg cell Regulatory T cell

Complement is a series of blood-borne proteins that attack microbes that found their way into the bloodstream. As complement proteins precipitate on the surface of these invading pathogens, they form a membrane attack complex ( MAC ) that damages the microbe’s cell membrane. Phagocytic cells, such as neutrophils and macrophages, of the host have receptors for a specific moiety of complement ( C3b ) and the presence of C3b on the microbial surface facilitates phagocytosis of microbes by these host defense cells.

Natural ( polyreactive ) antibodies are formed prior to birth, even in germ-free mice by innate B cells that have not as yet been exposed to antigens and are able to bind to many different antigens. These antibodies are able to recognize and react against oxidized lipids on cells that have entered apoptosis, as well as membrane lipids present in invading microorganisms. Unlike antibodies of the adaptive immune systems, polyreactive antibodies bind with a low binding affinity.

Antimicrobial peptides , such as defensins , are synthesized and released by epithelial cells. They not only defend the body against Gram-negative bacteria but also are chemoattractants for immature dendritic cells and T lymphocytes.

Cytokines are signaling molecules that are released by various cells of the innate and adaptive immune systems to effect responses from their target cells. Cytokines that are released by lymphocytes are known as lymphokines , usually named interleukins , whereas cytokines that possess chemoattractant capabilities are usually referred to as chemokines . Those cytokines that stimulate differentiation and mitotic activity of hemopoietic cells are known as colony-stimulating factors ( CSFs ), whereas cytokines displaying antiviral properties are referred to as interferons .

Macrophages possess (1) receptors for the constant portions of antibodies (Fc receptors), (2) complement receptors, and (3) receptors that recognize carbohydrates that are not usually present on the surface of vertebrate cells. Macrophages are also antigen-presenting cells (APCs) because they are able to present antigens to both T and B lymphocytes. They also release CSFs and other signaling molecules that induce the formation of neutrophils and their release into the circulating blood.

Neutrophils leave the vascular system in the region of inflammation and enter the bacteria-laden connective tissue compartment, where they phagocytose and destroy bacteria. Bacterial killing is effected either in an oxygen-dependent manner, by the formation of hydrogen peroxide, hydroxyl radicals, and singlet oxygen within the phagolysosomes/endosomes, or via enzymatic digestion, using cationic proteins as well as myeloperoxidase and lysozymes.

NK cells are similar to cytotoxic T cells of the adaptive immune system. However, unlike T cells, they do not have to enter the thymus to become mature killer cells. NK cells use nonspecific markers to recognize their target cells via two different methods.

  • 1.

    NK cells possess Fc receptors, recognizing the constant portion of the immunoglobulin G (IgG) antibody that acts as a signal to kill the target cell. This is known as antibody-dependent cellular cytotoxicity ( ADDC ).

  • 2.

    The NK cell surface also displays transmembrane proteins known as killer activating receptors that bind to certain markers on the surface of nucleated cells. In order to control this killing process, NK cells also possess killer inhibitory receptors ( KIPs ) that recognize major histocompatibility (MHC) type I molecules located on the plasma membranes of all cells. The presence of MHC I molecule activates the KIPs, which prevent NK cells from killing healthy cells. The absence of MHC I molecules from the cell membrane or the presence of defective or altered MHC I molecules on the cell membrane indicates to NK cells that these are either foreign cells or virally altered self cells (target cells) that have to be destroyed.

The presence of various cytokines—such as interleukins 12, 15, and 18 (IL-12, IL-15, and IL-18) and type I interferons—enhance the cytotoxic activities of NK cells by causing them to become effector NK cells . IL-12 and IL-15 also induce NK cells to enter the cell cycle, thus increasing the number of effector NK cells.

Effector NK cells release perforin molecules that attach to the plasmalemmae of target cells, where they assemble to form pores. They also release granzymes that pass through these pores to enter the target cell cytoplasm, forcing them into apoptosis. Effector NK cells also release interferon gamma (IFN-γ), which recruits and activates macrophages to the area of the response. The activated macrophages destroy invading microorganisms and provide time for the adaptive immune system to control the infection.

Clinical Correlations

Major histocompatibility (MHC) I molecules, discussed later, are required to be present on cell membranes of almost every nucleated cell for cytotoxic T lymphocytes (CTLs) to recognize them as targets for destruction. However, tumor cells and cells that are infected by viruses suppress the production of MHC I molecules in order to prevent their recognition as targets for CTLs. This evasive maneuver permits them to become targets of NK cells because their killer inhibitory receptors do not become activated. In addition to MHC I molecules, MHC II molecules are located on the surface of APCs.

TLRs are highly conserved integral proteins present in the plasma and endosomal membranes of macrophages and dendritic cells of the innate immune system. Humans have been shown to possess at least 10 different TLRs ( Table 12.2 ), each with different roles. TLRs function in pairs so that two TLR partners form a single active receptor. These may be the same TLRs (e.g., TLR4-TLR4; homodimers) or different TLRs (TLR1-TLR2; heterodimers). Some of the TLRs are present on cell membranes so that they have both intracellular and extracellular moieties , whereas other TLRs are located only intracellularly on the membranes of endosomes and rough endoplasmic reticulum (RER) and possess no extracellular moieties.

TABLE 12.2
Toll-Like Receptors, Their Locations, and Their Putative Functions
Domains Toll-Like Receptor Pair Located on/in Cell Functions
Intracellular and extracellular (on cell membrane) TLR1–TLR2 Monocytes, macrophages, dendritic cells, B cells, mast cells Binds to bacterial lipoprotein; also binds to certain proteins of parasites
TLR2–TLR2 Monocytes, macrophages, dendritic cells, B cells, mast cells Binds to peptidoglycan of bacteria
TLR2–TLR6 Monocytes, macrophages, dendritic cells, B cells, mast cells Binds to lipoteichoic acid of gram-positive bacterial wall; also binds to zymosan, a fungally derived polysaccharide
TLR4–TLR4 Monocytes, macrophages, mast cells, lining cells of the digestive system Binds to LPS (lipoprotein saccharide) of Gram-negative bacteria
TLR5–?? a Monocytes, macrophages, dendritic cells, mast cells, lining cells of the digestive system Binds to flagellin of bacterial flagella
Intracellular only TLR3–?? a Dendritic cells and B cells Binds to double-stranded viral RNA (dsRNA)
TLR7–?? a Monocytes, macrophages, dendritic cells, B cells Binds to single-stranded viral RNA (ssRNA)
TLR8–?? a Monocytes, macrophages, dendritic cells, mast cells Binds to single stranded viral RNA (ssRNA)
TLR9–?? a Monocytes, macrophages, dendritic cells, B cells Binds to bacterial and viral DNA
TLR10–?? a Monocytes, macrophages, B cells Unknown

a Currently, TLR partner is unknown.

TLR pairs recognize various pathogens by their specific recurring molecular signatures, known as pathogen-associated molecular patterns ( PAMPs ). TLRs located on the cell membrane distinguish PAMPs belonging to bacteria, fungi, and protozoa, whereas intracellular TLRs recognize PAMPs of pathogens that are capable of entering the cytoplasm. All TLRs (with the exception of TLR3) associate with and activate the NF-κB ( nuclear factor kappa-light chain enhancer of activated B cells ) pathway that acts through several cytosolic proteins, including MyD88, which induces an intracellular cascade of TLR-specific responses. This sequence of events results not only in the release of cytokines that induce systemic inflammation ( IL-1 , IL-12 , and tumor necrosis factor-α [TNF-α] ) but also in the activation of B and T cells in order to mount a specific adaptive immune response .

NF-κB is held in the inactive state by IκB . However, binding of the TLR to their ligands activates a kinase that phosphorylates IκB and, in turn, permits the activation of NF-κB. The activated NF-κB enters the nucleus, where it and a coactivator factor induce transcription of a target gene, resulting in an inflammatory reaction, the commencement of an innate immune response , and the conscription of NK cells, thereby also initiating an adaptive immune response (see the next section). Therefore, TLRs have the ability to modulate the immune response, suggesting that the innate immune system is not a static, one-size-fits-all type of response but is dynamic in nature and is capable of regulating both the inflammatory and immune responses equally.

Clinical Correlations

  • 1.

    Hypoactivity of TLRs can result in greater susceptibility to pathogens, whereas their hyperactivity may be responsible for some autoimmune diseases, such as systemic lupus erythematosus, cardiovascular diseases, and rheumatoid arthritis.

  • 2.

    High levels of TLR4 are expressed in mice that are sleep deprived. When injected with malignant cells, the tumors that developed in sleep-deprived animals were larger, more aggressive, and grew at a more rapid rate than in mice that were permitted to sleep normally. Additionally, instead of eliminating the tumor cells, the macrophages that the sleep-deprived animals recruited to the site of the tumor elicited the development of a vascular supply that encouraged tumor growth.

The Adaptive Immune System

The adaptive immune system responds slower than the innate immune system, has immunological memory, and depends on B and T lymphocytes to mount an immune response.

The adaptive immune response exhibits four distinctive properties: specificity , diversity , memory , and self/nonself recognition —that is, the ability to distinguish between structures that belong to the organism, self , and those that are foreign, nonself . Additional characteristics of the adaptive immune system include clonal expansion , the ability to increase the number of cells that can react to a renewed antigenic challenge, and contraction and homeostasis , the ability of the immune system to respond simultaneously to multiple antigenic challenges.

T lymphocytes , B lymphocytes , and specialized macrophages known as antigen-presenting cells ( APCs ) function not only in the (adaptive) immune response but also communicate with members of the innate immune system. They communicate by releasing signaling molecules (cytokines) in response to encounters with foreign substances called antigens ( anti body gen erators) and also by the sporting markers on their cell membranes, such as clusters of differentiation molecules (CD molecules), T-cell receptors (TCRs), and surface immunoglobulins (sIgs).

Recognition of a substance as foreign by the immune system stimulates a complex sequence of reactions that result either in the production of immunoglobulins (also known as antibodies ), which bind to the antigen, or in the induction of a group of cells that specialize in killing foreign cells, invading pathogens, or altered self cells (e.g., tumor cells). The immune response that depends on the formation of antibodies is called the humoral immune response , a function of B cells, whereas the cytotoxic response is known as the cell-mediated immune response , a function of T cells.

The cells that constitute the functional components of the innate and adaptive immune systems (T cells, B cells, macrophages, and their subcategory, APCs) are all formed in the bone marrow. B cells become immunocompetent in the bone marrow, whereas T cells migrate to the thymus to become immunocompetent there. Therefore, bone marrow and the thymus are called the primary ( central ) lymphoid organs . After lymphocytes become immunocompetent in the bone marrow or thymus, they migrate to the secondary ( peripheral ) lymphoid organs —diffuse lymphoid tissue (mucosa-associated lymphoid tissue [MALT]), lymph nodes, spleen, and tonsils—where they come into contact with antigens.

Immunogens and Antigens

Immunogens are molecules that always elicit an immune response; antigens are molecules to which antibodies bind but do not necessarily elicit an immune response.

A foreign structure that can elicit an immune response in a particular host is known as an immunogen ; an antigen is a molecule that can react with an antibody irrespective of its ability to elicit an immune response. Although not all antigens are immunogens, in this textbook, the two terms are considered to be synonymous, and only the term antigen is used.

The region of the antigen that reacts with an antibody , or TCR ( T-cell receptor ), is known as its epitope , or antigenic determinant. Each epitope is a small portion of the antigen molecule and consists of only 8 to 12 or 15 to 22 hydrophilic amino acid or sugar residues that are accessible to the immune apparatus. Large foreign invaders such as bacteria have several epitopes, each capable of binding to a different antibody. Although the term is not frequently used, it should be mentioned that the portion of an antibody that has an affinity to epitopes is referred to as a paratope .

Clinical Correlations

The complexity of a foreign substance is also important in determining its antigenicity. Hence, large polymeric molecules that have relatively simple chemical compositions, such as certain human-made plastics, have minimal immunogenicity. Therefore, these substances are used in the manufacture of artificial implants (e.g., hip replacement).

Clonal Selection and Expansion

During embryonic development, an extremely large number of small clusters (clones) of lymphocytes are formed; each clone can recognize one specific foreign antigen (epitope).

The immune system can recognize and combat an astonishing number of different antigens because during embryonic development an enormous number (∼10 15 ) of lymphocyte clones are formed by rearrangement of the 400 or so genes encoding immunoglobulins or TCRs. All of the cells of a particular clone have identical surface markers and can react with a specific antigen, even though they have not yet been exposed to that antigen. The cell-surface proteins that enable lymphocytes to interact with antigens are membrane-bound antibodies ( B-cell receptors or surface immunoglobulins [ sIgs ]) in the case of B cells and TCRs in the case of T cells. Although the molecular structures of antibodies and TCRs differ, they are functionally equivalent in their ability to recognize and interact with specific epitopes.

The first time an organism encounters an antigen, the adaptive immune response is slow to begin and not very robust; this response is called the primary immune response . Subsequent exposures to the same antigen elicit the secondary immune response ( anamnestic response ), which begins rapidly and is much more intense than the primary response. The increased potency of the secondary reaction is due to the process of immunological memory , which is inherent to the adaptive immune system. Both B and T cells are said to be virgin cells ( naїve cells ) before exposure to antigens. After a virgin cell comes in contact with an antigen, it proliferates to form activated cells and memory cells.

Activated cells , also known as effector cells , are responsible for carrying out an immune response. Effector cells derived from B cells are called plasma cells , which produce and release antibodies. Effector cells derived from T cells either secrete cytokines or destroy foreign cells or altered self cells.

Memory cells , similar to virgin lymphocytes, express either B-cell receptors (sIgs) or TCRs, which can interact with specific antigens. Memory cells are not directly involved in the immune response during which they are generated. However, these cells live for months or years and have a much greater affinity for antigens than do virgin lymphocytes. Moreover, formation of memory cells after first exposure to an antigen increases the size of the original clone, a process called clonal expansion . Because of the presence of an expanded population of memory cells with an increased affinity for the antigen, subsequent exposure to the same antigen induces a secondary immune response.

Immunological Tolerance

Macromolecules of the self are not viewed as antigens and, therefore, do not elicit an immune response.

The immune system can recognize macromolecules that belong to the self and does not attempt to mount an immune response against them ( immunological tolerance ). The mechanism of immunological tolerance depends on killing or disabling those cells that would react against the self. During embryonic development, if a lymphocyte encounters the substance to which it is designed to react, the cell is either killed ( clonal deletion ) so that this particular clone does not form or the lymphocyte is disabled ( clonal anergy ) and cannot mount an immune response, even though it is present.

Clinical Correlations

Autoimmune diseases involve a malfunction of the immune system that results in the loss of immunological tolerance. One example is Graves disease, in which the receptors for thyroid-stimulating hormone (TSH) on the follicular cells of the thyroid gland are perceived to be antigens. Antibodies formed against TSH receptors bind to these receptors and stimulate the cells to release an excess amount of thyroid hormone. Patients with Graves disease have an enlarged thyroid gland and exophthalmos (protruding eyeballs).

Immunoglobulins

Immunoglobulins are antibodies (also known as gamma globulins) that are manufactured by plasma cells; a typical immunoglobulin has one pair of heavy and one pair of light chains attached to each other by disulfide bonds.

Immunoglobulins ( antibodies, gamma globulins ) are glycoproteins that inactivate antigens (including viruses) and elicit an extracellular response against invading microorganisms. The response may involve phagocytosis in the connective tissue spaces by macrophages (or neutrophils) or the activation of the blood-borne complement system .

Clinical Correlations

The complement system is composed of 20 plasma proteins that assemble in a specific sequence and fashion on the surface of invading microorganisms to form a membrane attack complex (MAC) that lyses the foreign cell. The key component of the complement system is protein C3. Deficiency of protein C3 predisposes a person to recurring bacterial infections.

Immunoglobulins are manufactured in large number by plasma cells, which release them into the lymph or blood vascular system. There are five classes of antibodies (IgA, IgD, IgE, IgG, and IgM). Members of the various classes of antibodies share certain characteristics and, because IgG is the typical antibody, it will be described as a template for all classes of immunoglobulins ( Table 12.3 ). Each IgG is a Y-shaped molecule, composed of two long identical polypeptides, known as heavy chains (55- to 70-kilodalton [kD]), and two shorter identical 25-kD polypeptides, the light chains . The four chains are bound to each other by several disulfide bonds and noncovalent bonds in such a way that the stem of the Y is composed only of heavy chains and the diverging arms consist of both light and heavy chains ( Fig. 12.1 ).

TABLE 12.3
Properties of Human Immunoglobulins
Class Cytokines a No. of Units b Ig in Blood (%) Crosses Placenta Binds to Cells Biological Characteristics
IgA TGF- β 1 or 2 10–15 No Temporarily to epithelial cells during secretion Also known as secretory antibody because it is secreted into tears, saliva, the lumen of the gut, and the nasal cavity as dimers; individual units of the dimer are held together by J protein manufactured by plasma cells and protected from enzymatic degradation by a secretory component manufactured by the epithelial cell; combats antigens and microorganisms in the lumen of gut, nasal cavity, vagina, and conjunctival sac; secreted into milk, thus protecting neonates with passive immunity; monomeric form in bloodstream; assists eosinophils in recognizing and killing parasites
IgD 1 < 1 No B-cell plasma membrane Surface immunoglobulin; assists B cells in recognizing antigens for which they are specific; functions in the activation of B cells subsequent to antigenic challenge to differentiate into plasma cells
IgE IL-4, IL-5 1 < 1 No Mast cells and basophils Reaginic antibody; when several membrane-bound antibodies are cross-linked by antigens, IgE facilitates degranulation of basophils and mast cells, with subsequent release of pharmacological agents, such as heparin, histamine, eosinophil and neutrophil chemotactic factors, and leukotrienes; elicits immediate hypersensitivity reactions; assists eosinophils in recognizing and killing parasites
IgG IFN- γ , IL-4, IL-6 1 80 Yes Macrophages and neutrophils Crosses placenta and, thus, protects fetuses with passive immunity; secreted in milk and, thus, protects neonates with passive immunity; fixes complement cascade; functions as opsonins, that is, by coating microorganisms, facilitates their phagocytosis by macrophages and neutrophils, cells that possess Fc receptors for the Fc region of these antibodies; also participates in antibody-dependent cell-mediated cytotoxicity by activating NK cells; produced in large quantities during secondary immune responses
IgM 1 or 5 5–10 No B cells (in monometric form) Pentameric form is maintained by J-protein links, which bind Fc regions of each unit; activates cascade of the complement system; is the first isotype to be formed in the primary immune response
Fc, Crystallizable fragment; IFN, interferon; Ig, immunoglobulin; IL, interleukin; NK, natural killer; TGF, tumor growth factor.

a Cytokines responsible for switching to this isotype.

b A unit is a single immunoglobulin composed of two heavy and two light chains; thus, IgA exists as both a monomer and as a dimer.

Fig. 12.1, Schematic diagram of an antibody, indicating its regions.

The region in the vicinity of the disulfide bonds between the two heavy chains, the hinge area , is flexible and permits the arms to move away from or toward each other. The distal regions on the tips of the arms (the amino-terminal segments) are responsible for binding to the epitope; hence, each antibody molecule can bind two identical epitopes.

The enzyme papain cleaves the antibody molecule at its hinge areas (see Fig. 12.1 ), forming three fragments: one Fc fragment composed of the stem of the Y and containing equal parts of the two heavy chains, and two Fab fragments , each composed of the remaining part of one heavy chain and one entire light chain. Fc fragments are easily crystallized (hence, the c designation), whereas the Fab fragment is the antigen-binding region of the antibody (hence, the ab designation).

The amino acid sequence of the Fc fragment is mostly constant in its class; thus, the stem of an antibody has the ability to bind to Fc receptors of many different cells. The amino acid sequence of the Fab region is variable; the alterations of that sequence determine the specificity of the antibody molecule for its particular antigen.

Each antibody is specific against a particular epitope; thus, the Fab regions of all antibodies against that particular epitope are identical. It is believed that there are 10 6 to 10 9 different types of antibodies in a person, each specific against one particular antigen. Each type of antibody is manufactured by members of the same clone . Thus, there are 10 6 to 10 9 clones whose members discern and react to a particular epitope (or a small number of very similar epitopes).

As noted earlier, small amounts of immunoglobulins are made by B cells and inserted into their plasmalemmae; these are known as sIgs ( surface immunoglobulins ) or B-cell receptors ; they function as antigen-receptor molecules. They are slightly different from antibodies in that they possess a membrane-binding component composed of two pairs of membrane-spanning chains, Igβ and Igα , which bind the heavy chains of the antibody molecule to the cell membrane.

Classes of Immunoglobulins

There are five classes (isotypes) of immunoglobulins in humans: IgG, IgM, IgA, IgD, and IgE.

Humans have five isotypes (classes) of immunoglobulins: IgG , the monomeric form of immunoglobulin described earlier; IgM , which resembles five IgG molecules bound to each other (pentameric form of immunoglobulin); IgA , which resembles two IgG molecules bound to each other (dimeric form of immunoglobulin); IgD , present in very low concentration in the blood but found on the B-cell surface as a monomeric form of immunoglobulin known as surface IgD (sIgD); and IgE , a monomeric form of immunoglobulin present on the surface of basophils and mast cells.

The classes of immunoglobulins are also determined by the amino acid sequences of their heavy chains. The various heavy chains are designated by the Greek letters α, δ, γ, ε, and μ and are associated with IgA, IgD, IgE, IgG, and IgM, respectively. The characteristics of the five isotypes of immunoglobulins are detailed in Table 12.3 .

Cells of the Adaptive Immune Systems

The cells of the adaptive immune system are B lymphocytes (and plasma cells), T lymphocytes, and antigen-presenting cells (macrophages and dendritic cells).

B Lymphocytes

B lymphocytes originate and become immunocompetent in the bone marrow; they are responsible for the humorally mediated immune system.

B lymphocytes , also known as B cells , are small lymphocytes (see Chapter 10 ) that both originate and become immunocompetent in the bone marrow. However, in birds, in which B cells were first identified, they become immunocompetent is a diverticulum of the cloaca, known as the bursa of Fabricius (hence, the designation “B” cells). During the process of becoming immunocompetent, each cell goes from an immature pre–B cell stage to a transitional B cell , which manufactures a series of identifying immunoglobulin chains. Transitional B cells migrate to the spleen to be killed or to be permitted to develop into a mature B cell . Each mature B cell manufactures 50,000 to 100,000 IgM and IgD immunoglobulins and inserts these in its plasma membrane so that the epitope-binding sites of the antibodies face the extracellular space. The Fc region of the antibody is embedded in the phospholipid bilayer by the assistance of two pairs of transmembrane proteins, Ig β and Ig α , whose carboxyl termini are in contact with certain intracellular protein complexes. Every member of a particular clone of B cells has antibodies that bind to the same epitope. When the surface immunoglobulin reacts with its epitope, the Ig β and Ig α transduce (relay) the information to the intracellular protein complex with which they are in contact, initiating a chain of events that results in activation of that particular B cell.

Types of B Cells

There are a number of different types of B cells: B-1 B cells, B-2 B cells, B memory cells, spleen follicular B cells, and spleen marginal zone B cells.

During the ensuing presentation of B-cell types, various T-cell types have to be mentioned even though they and their functions have not as yet been discussed. B cells are considered to be members of the APC population because they are able to complex epitopes with class II MHC molecules and present them to T H 1 cells. It is believed that they present epitopes only during an anamnestic response, not the primary immune response. When they act as APCs, not only do they synthesize and secrete IL-12, a cytokine that prompts T H 1 cells to proliferate and induce NK cells to become active, but they also differentiate into plasma cells and increase their population of B memory cells.

  • B-1 B cells are derived from hemopoietic stem cells that develop in the fetal liver. They arise early in development of the individual and populate the mucosae of the respiratory and gastrointestinal systems, and the peritoneum. They manufacture IgM that they place on their plasmalemmae. They have a limited ability to produce antibody diversity and respond mostly to carbohydrates of the most common microorganisms without the need to interact with T cells. They constitute approximately 50% of the mucosal B cells but do not form memory B-1 B cells. They do not have CD40 molecules on their cell membranes.

  • B-2 B cells ( referred to simply as B cells in this textbook ) are the most numerous of the B cell population. They possess CD40 molecules on their cell membrane with which they contact and signal T H 2 cells. In response, the T H 2 cells release signaling molecules that inhibit T H 1 cells from entering the cell cycle and prompt B cells to form plasma cells and B memory cells. The T H 2 cells release additional cytokines that allow the B cell to manufacture a different class of immunoglobulin, a process known as class switching ( isotype switching ). The cytokines that are released by T-helper cells depend on the type of pathogens present:

    • During parasitic worm invasion, T cells release IL-4 and IL-5; B cells differentiate into plasma cells and, after class switching, form IgE to elicit mast cell degranulation on the surface of the parasites.

    • During bacterial and viral invasions, T cells release IFN- γ and IL-6; B cells switch to forming IgG, which opsonizes bacteria, fixes complement, and stimulates NK cells to kill virally altered cells (antibody-dependent cell-mediated cytotoxicity [ADCC]).

    • During viral or bacterial invasion of mucosal surfaces, T cells release tumor growth factor- β (TGF- β ), and B cells switch to IgA formation, which is secreted onto the mucosal surface.

  • B memory cells are long-lived cells that not only increase the size of the clone that is specific against a particular antigen but also react faster and more vigorously than the cells comprising the original clone.

  • Splenic B cells are of two types, follicular B cells and marginal zone B cells:

    • Follicular B cells are the most populous of the B cells of the primary and secondary follicles of the spleen. These are almost mature cells, and they express IgM, IgD, and CD21 molecules on their cell membranes. These cells are T-cell dependent, and they migrate in and out of the various lymphoid organs, where they are always located in the B cell follicles. Because they migrate, they are also known as recirculating B cells .

    • Marginal zone B cells have a limited range of antibody diversity, are T-cell independent, and are located very close to marginal sinuses of the spleen. They can migrate to lymph nodes in humans and have the ability to react to self antigens as well as to bacterial polysaccharide antigens. They possess IgM, CD1, CD9, and CD21 molecules on their cell membranes; during an antigenic challenge, they differentiate into plasma cells that release IgM.

  • Plasma cells are B cells that have undergone differentiation into antibody-forming cells that possess no surface antibody. All antibodies manufactured by plasma cells that are derived from a single clone of B cells manufacture the identical antibodies that are specific against one particular antigen (or to antigens that are very similar to that specific antigen). Because plasma cells release the antibodies that they manufactured into connective tissue from where the antibodies enter blood vessels or lymph vessels, B cells are responsible for the humorally mediated immune response.

As naїve B cells first become activated, they make IgM, which, when bound to the surface of an invading pathogen, is able to activate the complement system ( complement fixation ). IgM molecules can also bind to viruses, preventing them from contacting the cell surface, thus protecting the cells from viral invasion.

Certain antigens (e.g., polysaccharides of microbial capsules) can elicit a humoral immune response without a T-cell intermediary. These are known as thymic-independent antigens . They cannot induce formation of B-memory cells and can elicit only IgM-antibody formation. However, most antigens require participation of a T-cell intermediary before they can induce a humoral immune response (see section on humoral immune response).

T Lymphocytes

T lymphocytes originate in the bone marrow and migrate to the thymus to become immunocompetent; they are responsible for the cellularly mediated immune response.

T lymphocytes ( T cells ) are also formed in the bone marrow, but they migrate to the thymic cortex, where they become immunocompetent by expressing specific molecules on their cell membranes that permit them to perform their functions. The process whereby T cells become immunocompetent is discussed later.

Although histologically T cells appear to be identical to B cells, there are important differences between them:

  • T cells have TCRs rather than sIgs on their cell surfaces.

  • Although TCRs belong to the immunoglobulin superfamily, they are never secreted.

  • T cells, except for NKT cells, respond to protein antigens only.

  • For T cells to respond to antigens, the epitopes have to be presented to them bound to MHC molecules present on the surface of APCs.

  • Because of the MHC constraint, T cells are said to be MHC restricted (see the later section on MHC restriction and T cells).

  • T cells perform their functions at short distances only.

T cells express clusters of differentiation proteins ( CD molecules or CD markers ) on their plasmalemmae. These accessory proteins bind to specific ligands on target cells. Although almost 300 CD molecules are known, Table 12.4 lists only those that are immediately pertinent to the subsequent discussion of cellular interactions in the immune process. The membrane-bound portion of the TCR associates with the membrane proteins, CD3 , and either CD4 or CD8 , forming the TCR complex . Several other membrane proteins play roles in signal transduction and in strengthening the interaction between the TCR and an epitope, thus facilitating antigen-stimulated T-cell activation.

TABLE 12.4
Selected Surface Markers Involved in the Immune Process
Protein Cell Surface Ligand and Target Cell Function
CD3 All T cells None Transduces epitope–MHC complex binding into intracellular signal, activating T cell
CD4 T-helper cells MHC II on APCs Coreceptor for TCR binding to epitope–MHC II complex, activation of T-helper cell
CD8 Cytotoxic T cells and T reg cells MHC I on most nucleated cells Coreceptor for TCR binding to epitope–MHC I complex; activation of cytotoxic T cell
CD28 T-helper cells B7 on APCs Assists in the activation of T-helper cells
CD40 B cells CD40 receptor molecule expressed on activated T-helper cells Binding of CD40 to CD40 receptor permits T-helper cell to activate B cells to proliferate into B memory cells and plasma cells
APC, Antigen-presenting cell; MHC, major histocompatibility complex; TCR, T-cell receptors.

Similar to sIgs on B cells, TCRs on the plasmalemma of T cells function as antigen receptors. The constant regions of the TCR are membrane bound, whereas the variable amino-terminal regions containing the antigen-binding sites extend from the cell surface. There are two types of TCRs, depending on their protein chain compositions: gamma and delta ( γ and δ ), known as γ/δ T cells , and alpha and beta ( α and β ), known as α/β T cells . There is yet another category of T cells, known as natural killer T cells .

  • γ/δ T cells form a small population. They reside mostly in the mucosa of the gastrointestinal tract, react typically to microbial pathogenic invasion, and have a very fast reaction time. Unlike their α/β counterparts, they do not form memory T cells and are not MHC restricted. It is believed that γ/δ T cells recognize microbial nonprotein antigens, and these antigens do not require APCs to present them. Although these cells become “educated” in the cortex of the thymus to become immunocompetent, they spend considerably less time there than do their α/β T-cell counterparts.

  • Natural killer T cells ( NKT cells ) spend very little time in the thymus and possess some α/β TCRs on their surfaces that are designed to recognize lipid antigens bound to CD1 molecules (similar to class I MHC molecules) presented to them by APCs. Therefore, NKT cells are said to be CD1 restricted (rather than MHC restricted). NKT cells secrete IL-4, IL-10, and IFN- γ. It is believed that these cells kill bacteria whose cell walls are rich in lipids.

  • The majority of T cells are α/β Τ cells ; they have the ability to form memory T cells. Although they react much slower than their γ/δ counterparts, they are the most common T cells to respond to antigenic challenges. Maturation of these cells is described in the following section.

Maturation of α/β T Cells

Because α / β Τ cells spend a considerable amount of time in the thymus, only their maturation is presented in this textbook. While in the thymus, the α/β Τ cells are exposed to various signaling molecules and growth factors produced by reticular epithelial cells of the thymus that control their development into immunocompetent T cells.

  • 1.

    Progenitor T lymphocytes formed in the bone marrow are immunoincompetent (i.e., they are unable to participate in an immune response). From the bone marrow, these cells travel to the medulla of the thymus, where they leave the postcapillary venule at the corticomedullary junction and enter the thymic cortex, where they are known as thymocytes. The thymocytes migrate to the outer region of the cortex. These thymocytes possess Notch-1 receptors on their surfaces; however, because they have neither CD4 nor CD8 molecules, they are referred to as double-negative T cells. The thymus possesses various types of epithelial reticular cells (see the section on the thymus), some of which release signaling molecules that are recognized by the Notch-1 receptors. Double-negative T cells do not express CD3 or TCR molecules on their cell membranes.

  • 2.

    The signaling molecules activate Notch-1 on the surface of the double-negative cells, inducing these cells to manufacture both CD4 and CD8 molecules and place them on their plasma membranes. Because both CD4 and CD8 molecules are present on these cells, they are now referred to as double-positive T cells , which begin to express TCRs and CD3 molecules on their surfaces. As double-positive cells proliferate, they go through gene rearrangement , forming a large number of cells, each expressing a different variable region in their α/β TCR molecules.

  • 3.

    Various self epitope–MHC complexes are presented to the double-positive T cells by epithelial reticular cells of the thymic cortex. Double-positive T cells that bind very weakly to self peptides presented by self MHC molecules are preserved, whereas those that make a strong bond with them are killed. Therefore, this is a positive selection of thymocytes because they have to demonstrate only a weak recognition to self epitope–MHC molecule complexes. An amazing 90% of double-negative T cells are killed in the thymic cortex. The reason why the killing of these cells is essential is that only those T cells may be allowed to survive that recognize only foreign epitopes presented by self MHC molecules.

  • 4.

    There are two types of MHC molecules, MHC I and MHC II. The epithelial reticular cells present either self epitope–MHC I or self epitope–MHC II complexes to the double-positive T cells. The double-positive T cells that are exposed to MHC I molecules cease to express CD4 molecules on their surfaces but continue to express CD8 molecules and are referred to as single-positive CD8 T cells (also known as CD 8 cells ). Similarly, the double-positive T cells that are exposed to MHC II molecules cease to express CD8 molecules on their surfaces but continue to express CD4 molecules and are referred to as single-positive CD4 T cells (also known as CD 4 cells ).

  • 5.

    The single-positive T cells ( I T cells ) that are not forced into apoptosis are immunocompetent; they leave the thymic cortex and migrate into the medulla of the thymus. These I T cells also possess CD45RA molecules on their cell membranes.

  • 6.

    Once in the medulla, medullary epithelial reticular cells present self epitope–MHC II complexes to these I T cells. The I T cells that show a strong response to these complexes are also forced into apoptosis to prevent the mounting of an immune response by these cells to the self (i.e., to prevent an autoimmune response). Therefore, this is a negative selection of thymocytes because they do not recognize the epitope–MHC complex as self. But not all of these I T cells that show a strong response to the self epitope–MHC complex are forced into apoptosis. In an unknown fashion, some of these I T cells escape the “death sentence” and differentiate into regulatory T cells ( T reg cells ) that suppress an immune response (see the section on effector T cells).

  • 7.

    Epithelial reticular cells of the medulla possess the capability to force those I T cells into apoptosis that would mount an immune response against tissue-specific antigens , such as insulin. The epithelial reticular cells are able to do this because they release autoimmune regulator ( AIRE ), a transcription factor that permits these tissue-specific antigens to be expressed in the thymus and thus be presented to the T cells.

  • 8.

    The I T cells that remain alive use the vascular system to leave the thymic medulla and enter the various lymphoid organs located throughout the body. After they leave the thymic medulla, they are referred to as naïve T cells.

Clinical Correlations

Mutations in the AIRE gene are responsible for the autoimmune polyendocrine syndrome type 1 that damages various endocrine glands, as well as counters the function of T H 17 T cells as a result of immune intolerance. Because the thymus was unable to delete (i.e., kill) I T cells that would mount an immune response against tissue-specific antigens —such as insulin, parathormone, IL-17, and IL-22—the affected patients may suffer from autoimmune parathyroidism, hypogonadism, adrenalitis, and chronic mucocutaneous candidiasis. The patient’s candidiasis is caused by the autoantibodies formed against IL-17 and IL-22, the interleukins produced by T H 17 T cells, the body’s primary defense against fungal infections.

A TCR can recognize an epitope only if the epitope is a polypeptide (composed of amino acids) and if the epitope is bound to an MHC complex molecule , such as those in the plasmalemma of an APC. There are two classes of these glycoproteins: MHC class I and MHC class II molecules (although in humans they are known as HLA class I and HLA class II molecules, these terms are used only infrequently [HLA= human leukocyte antigen]). Most nucleated cells express MHC I molecules on their surfaces, whereas APCs can express both MHC I and MHC II on their plasmalemmae. The MHC molecules are unique in each individual (except for identical twins); to be activated, T cells must recognize not only the foreign epitope but also the MHC molecule as self. If a T cell recognizes the epitope but not the MHC molecule, it does not become stimulated; hence, the T cell’s capacity to act against an epitope is said to be MHC restricted .

There are three types of T cells, some with two or more subtypes:

  • Naïve T cells

  • Memory T cells

  • Effector T cells

Naïve T Cells

Naïve T cells possess CD45RA molecules on their cell surfaces and leave the thymus programmed as immunologically competent cells, but they must become activated T cells in order to be able to function. To do that, naïve T cells have to contact their specific antigen after they leave the thymic medulla . When a T lymphocyte becomes activated, it will undergo cell division and will form both memory T cells and effector T cells.

Memory T Cells

Memory T cells are of two types: central memory T cells and effector memory T cells. They are responsible for the immunological memory of the adaptive immune system.

Memory T cells express CD45R0 molecules on their cell membranes; they form the immunological memory of the adaptive immune system because they form a clone whose members are identical and have the capability of combating a particular antigen. These memory cells can become activated and express effector capabilities. There are two types of memory T cells: those that express CR7 molecules on their surfaces and are known as central memory T cells ( TCM ; CR7 + cells ) and those that do not express CR7 molecules on their surface and are known as effector T memory cells ( TEM ; CR7 – cells ). TCMs populate and remain in the T cell–rich zones of lymph nodes (in the paracortex). They are incapable of immediate effector function; however, when they recognize the epitope presented to them by APCs, they stimulate the APCs to release IL-12. This signaling molecule binds to IL-12 receptors of TCMs and stimulates them to differentiate into TEMs . TEMs express receptors that permit these cells to migrate to regions of inflammation, where they have immediate effector function by proliferating and differentiating into effector T cells .

Effector T Cells

Effector T cells are able to respond to an immunological challenge. There are three types of effector T cells: T helper cells, cytotoxic T lymphocytes, and regulatory T cells.

Effector T cells are derived from TEMs. They are immunologically competent cells that are capable of responding to and mounting an immune response. There are three types of effector T cells: T helper cells, T killer cells (cytotoxic T lymphocytes [CTLs]), and T reg cells; T helper and T reg cells have their own cell subtypes.

T Helper Cells

There are several subtypes of T helper cells, all of which display CD4 molecules on their cell membranes. They are responsible for the recognition of foreign antigens and for mounting an immunological response against them.

T helper cells possess CD4 molecules (in addition to the CD3 and TCR) as their cell membrane markers. They interact with other cells of the innate and adaptive immune systems, they synthesize and release various cytokines, and they have the ability to activate cells of the cell-mediated immune system to mount a response against invading pathogens and eliminate them. T helper cells also play a major role in stimulating the humorally mediated immune system by interacting with B cells and stimulating them to differentiate into antibody-producing plasma cells. There are a number of subtypes of T helper cells: T H 0, T H 1, T H 2, T17, and T H αβ. An additional subtype, the T H 3 cell, has been reclassified as the inducible T reg cell (see later discussion).

T H 0 Cells

T H 0 cells are precursor cells that have the capability of manufacturing and releasing a large number of cytokines. These cells can differentiate into T H 1, T H 2, T17, or T H αβ cells, depending on the signaling molecules that they receive from APCs. Then, their repertoire of cytokine release becomes limited.

T H 1 Cells

T H 1 cells are crucial for the control of intracellular pathogens and are also responsible for the induction of the cell-mediated immune response, as in acute allograft rejection and in the cases of multiple sclerosis. These cells secrete IFN-γ, TNF-α, and IL-2.

  • IL-2 stimulates proliferation of activated T cells and B cells as well as cytotoxicity of CD8 T cells (CTLs).

  • IFN-γ stimulates macrophages to become activated so that they can phagocytose pathogens, such as mycobacteria, protozoa, and fungi. This cytokine also activates cytotoxic T cells to kill altered or foreign cells.

  • TNF-α stimulates activated macrophages to produce oxygen radicals in order to be able to kill the phagocytosed pathogens within their endosomes.

    • Macrophages release IL-12, which induces the proliferation of T H 1 cells and inhibits the proliferation of T H 2 cells; it also activates NK cells.

    • Macrophages that phagocytose bacteria express CD40 molecules on their surfaces, and T H 1 cells express CD40 ligand, whose interaction not only increases the macrophage’s phagocytic capability but also induces the macrophage to release TNFα, IL-1, and IL-12.

T H 2 Cells

T H 2 cells elicit a response against a parasitic (IgE) or mucosal (IgA) infection. They secrete IL-4, IL-5, IL-6, IL-9, IL-10, and IL-13, and many of these interleukins facilitate the production of antibodies by plasma cells.

  • IL-4 stimulates B cells to proliferate and differentiate into plasma cells and to switch from IgM production to IgG and IgE synthesis. Thus, it plays an important role in allergic reactions.

  • IL-5 stimulates B cells to proliferate, differentiate into plasma cells, and to switch from IgM production to IgE synthesis.

  • IL-6 stimulates B cells to proliferate, differentiate into plasma cells, and to switch from IgM production to IgG synthesis.

  • IL-9 prompts T H 2 cells to proliferate and enhances mast cell activity.

  • IL-10, acting in concert with IL-4, suppresses the differentiation of T H 0 cells to T H 1 cells.

  • IL-13 suppresses the differentiation of T H 0 cells to T H 1 cells and enhances the functions of IL-4.

T H 17 Cells

T H 17 cells secrete IL-17, a cytokine that not only attracts neutrophils to the site of antigenic attack but also boosts their ability to phagocytose and destroy the bacterial pathogens. Additionally, T H 17 cells secrete IL-21 and IL-22.

  • IL-21 stimulates the activities of B cells, T cells, and NK cells.

  • IL-22 facilitates the inflammatory response and enhances the integrity of the epithelial barrier.

T H αβ Cells

T H αβ cells secrete IL-10 and IFN-ß (or IFN-ß) to provide immunity against viruses. When overly exuberant in combating autoantigens, these cells are responsible for the initiation of a type 2 hypersensitivity.

  • IL-10 activates NK cells which force virally infected cells into apoptosis.

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