Two of the main functions of T cells are (1) to provide cytotoxic activity against facultative intracellular pathogens (mycobacteria, fungi) and virally infected cells or tumor
cells, and (2) to provide cytokines (Table 15-2) to help B cells make antibodies. For the T cell to carry out these functions, it first must bind to the target cell or to the antigen-presenting cell (APC), respectively. For high-affinity binding of T cells to target cells or APCs, several molecules on T cells in addition to TCRs bind to molecules on their respective target cells (Fig. 15-2). CD8 molecules on cytotoxic T cells bind to MHC class I molecules on target cells. CD4 molecules on helper T cells bind to MHC class II molecules on APCs. Lymphocyte function antigen 1 (LFA-1) molecules on T cells bind to intracellular adhesion molecule 1 (ICAM-1 or CD54) on APCs. CD2 molecules on T cells bind to LFA-3 or CD58 on APCs. With the adhesion of cytotoxic T cells to their targets, they are stimulated to kill the target; and with the adhesion of helper T cells to APCs, they are stimulated to produce cytokines, which stimulate B cells and other cells. Many other adhesion pairs participate in these important cell–cell interactions.

In the primary antibody response, native antigen is carried to a lymph node draining the site of entry, taken up by specialized cells called follicle-stimulating cells (FSCs), and expressed on their surfaces. Virgin B cells bearing surface immunoglobulin specific for that antigen then bind to the antigen; if the affinity of the B-cell surface immunoglobulin for the antigen present on the FSCs is high, and if other signals are provided by activated helper T cells, the B cell develops into an antibody-producing plasma cell. If the affinity is not high enough, or if T-cell signals are not received, the B cell dies by apoptosis. The signals provided by activated helper T cells include those from cytokines they secrete (IL-4, IL-5, IL-6, IL-10, and IL-13) (1); (Table 15-2) and the signal from a surface T-cell molecule, CD154, which binds to CD40 on the B-cell surface (5) (Fig. 15-2). Cross-linking of CD40 on B cells or allowing CD40 to interact with CD154 in the presence of certain cytokines causes the B cells to undergo proliferation and to initiate immunoglobulin synthesis. In the primary immune response, usually only IgM antibody is made, and most of it is of relatively low affinity. Some B cells become memory B cells during the primary immune response. These cells have switched their immunoglobulin genes so IgG, IgA, or IgE antibodies of higher affinity are formed on a secondary exposure to the same antigen. The secondary immune response occurs when these memory B cells again encounter that antigen. Plasma cells form, just as in the primary response; however, many more cells are rapidly generated, and IgG, IgA, and IgE antibodies of increased affinity are produced. The exact pattern of isotype response to antigen varies, depending on the type of antigen and the cytokines present in the microenvironment.

NK lymphocytes are derived from bone marrow stem cells and are defined by their functional capacity to mediate nonantigen-specific cytotoxicity. NK cell activity has been found in human fetal liver cells by 8 to 11 weeks’ gestation. Unlike T and B cells, NK cells do not rearrange antigen-receptor genes during their development. All NK cells express CD56, and most also bear CD16 [Fcγ receptor III (FcγRIII)] on their cell surfaces. Because NK cells share surface antigens with T and myeloid cells, the lineage relation of NK cells is still unclear. NK cells have been found in the thymus, but most experimental studies suggest that thymic processing is not necessary for NK cell development. After release from bone marrow, NK cells enter the circulation or migrate to the spleen; there are few NK cells in lymph nodes. The percentage of NK cells in cord blood is usually lower than in the blood of children and adults (constituting 10% of lymphocytes), but the absolute number of NK cells is about the same, owing to a higher lymphocyte count. The capacity of cord blood NK cells to mediate target lysis in either NK cell assays or antibody-dependent cell-mediated cytotoxity assays is roughly two-thirds that of adults (4).

At the time of birth, lymphoid organs are proportionally small but microscopically well developed; they mature rapidly during the postnatal period. The neonate’s thymus is about two-thirds its mature weight, and it reaches that weight by the end of the first year of life. Most lymphoid structures also appear to be mature histologically by the end of the first year. Peripheral blood absolute lymphocyte counts reach a peak by 9 months of age. All lymphoid tissues continue to enlarge and even exceed adult dimensions during the prepubertal years, then all except the spleen undergo involution coincident with puberty. The spleen gradually increases in size during maturation and does not reach full weight until adulthood. The mean number of Peyer patches is one-half the adult number at birth and gradually increases until the adult mean number is exceeded during adolescent years (4).

The principal circulating phagocyte is the neutrophil, whereas the predominant phagocytic cell in tissues is the macrophage. Monocytes are derived from the bone marrow; subsequently, they can differentiate into tissue macrophages. Bone marrow neutrophil maturation is influenced by several factors secreted by stromal cells, monocytes, and T lymphocytes (1). These cytokines include IL-7, IL-3, granulocyte colony-stimulating factor, and granulocyte-monocyte colony-stimulating factor. Mature neutrophils migrate from the bone marrow into the circulation. To carry out their roles, phagocytes must be produced in adequate numbers and mobilized at the appropriate time. To perform their functions, neutrophils must marginate from the intravascular compartment, be deformable enough to undergo diapedesis, migrate along a chemotactic gradient to the site of inflammation, phagocytose, and have adequate lysosomal constituents and oxidative metabolism to kill microorganisms. A defect in any of these characteristics can lead to increased susceptibility to infection (6).

Phagocytosis is the process by which cells ingest particles encountered in their microenvironment so as to contain or destroy them (6). It is facilitated by a variety of substances known as opsonins. The most important opsonins are heat-stable IgG antibodies and the heat-labile complement components C3 and C5. Particles, such as bacteria, are coated with these substances; interaction with phagocytic cell membrane receptors for the opsonins (IgG and C3b) initiates ingestion of the particles. They then enter

a phagocytic vacuole that ultimately fuses with specific and azurophilic granules. Destruction of microorganisms requires generation of reactive oxygen molecules through a phagocytic cell respiratory burst. These oxygen radicals interact with myeloperoxidase and a halide ion to generate hypochlorite, which is extremely toxic to organisms. Azurophilic granules contain lytic enzymes, including acid hydrolase, lysozyme, and myeloperoxidase. Specific granules contain lysozyme and lactoferrin. Movement and fusion of granules is dependent on the microtubular system. The combination of these aerobic and anaerobic neutrophil bactericidal systems effects destruction of the bacterium.

The complement system consists of more than 20 native serum proteins, 12 of which act sequentially to amplify the effects of antibody-mediated immunity, cell-mediated immunity, and phagocytosis, and to generate elements of the inflammatory response (Fig. 15-3) (7). This system is one of the major effector arms in host defense. It can effect a primitive nonantigen-specific defense against invading microorganisms, but it can also be triggered by antibody to provide antigen-specific host defense. The molecular weights of the 12 serum proteins that act sequentially in the complement cascade vary from 24,000 to 400,000 kd. Their serum concentrations vary from about 150 mg/dL to nanogram amounts. The gene encoding properdin is on the short arm of the X chromosome, but the genes encoding all the other complement proteins are on autosomal chromosomes.

Three major known functions of the complement system are to (1) cause lysis of organisms and cells; (2) promote opsonization of particles by coating them with peptides recognized by specific receptors on phagocytic cells; and (3) generate inflammatory peptides, which cause smooth muscle dilatation, immigration of inflammatory cells (chemotaxis), and histamine release. Two major pathways of complement activation are known. The more primitive pathway, termed the alternative pathway because of its discovery after the original pathway, is important as a first line of defense against invasion. This pathway functions in the absence of antibody, but it can also function more rapidly in the presence of antibody.

Most boys afflicted with X-linked agammaglobulinemia (XLA) are well during the first 6 to 9 months of life owing to protection by maternally transmitted IgG antibodies (8). Thereafter, they frequently develop infections with high-grade extracellular pyogenic organisms, such as pneumococci, streptococci, and Haemophilus sp, unless given antibiotics or immunoglobulin therapy. Mycoplasma infections are also frequent. Chronic fungal infections are not usually present, and Pneumocystis carinii pneumonia does not usually occur unless there is an associated neutropenia. Viral infections are self-limiting, except for hepatitis viruses and enteroviruses. The latter susceptibility suggests a primary role for secretory IgA antibody in host defense against hepatitis and enteroviruses because normal T-cell function has been present in all XLA patients with persistent enterovirus infections reported thus far.

The diagnosis of XLA is confirmed when serum concentrations of IgG, IgA, IgM, and IgE are very low and there is a family history of similarly affected lateral maternal male relatives (8). Tests for antibodies to blood group substances and to diphtheria, tetanus, H. influenzae, or pneumococcal vaccine antigens are useful in distinguishing this disorder from transient hypogammaglobulinemia of infancy. Hypoplasia of adenoids, tonsils, and peripheral lymph nodes is the rule; germinal centers are not found, and plasma cells are rare. Pre-B cells are present in the bone marrow, but blood B lymphocytes are usually absent. The abnormal gene in XLA was mapped to q22 on the long arm of the X chromosome and found to encode a B-cell protein-tyrosine kinase, now named Bruton tyrosine kinase (BTK) in honor of the discoverer of this condition (11). Carriers can be detected by the finding of nonrandom X-chromosome inactivation in B cells or by mutation analysis (11).