Complement activation.

Complement proteins are activated in a specific sequence or “cascade” via one or more of three pathways: the classical pathway, the alternative pathway, and the more recently described MBL pathway, as shown in Fig. 2.1 . These pathways converge at C3, and the complement cascade downstream from C3 proceeds identically, irrespective of the pathway by which activation occurs. The C3 convertases, C4b2a for the classical and MBL pathways and C3bBb for the alternative pathway, cleave the C3 molecule at exactly the same location, producing C3b, which binds to the target surface, and C3a, which is released into the fluid phase. Cleavage and activation of C3 lead to a conformational change in C3b that transiently renders its reactive thioester group capable of forming covalent ester or amide bonds with acceptor molecules on the target surface. Surface-bound C3b can act as an opsonin to promote phagocytosis, or it can bind with the classical and alternative pathway C3 convertases to form the C5 convertases C4b2a3b and C3bBb3b, respectively. C5 convertases bind and then cleave C5, with release of the chemoattractant C5a fragment into the fluid phase. The bound C5b fragment then can initiate formation of the membrane attack complex by the sequential incorporation of the remaining terminal components, C6, C7, C8, and multiple molecules of C9. The membrane attack complex can insert into the outer membrane of target cells, such as erythrocytes or gram-negative bacteria, and cause cell lysis and death.

The complement cascade. The initial binding events of the classical, mannan-binding lectin (MBL) and alternative pathways are indicated by a starburst. These pathways intersect at the conversion of C3 to C3b. This is followed by activation of the terminal components, beginning with the binding and cleavage of C5, releasing C5a and leaving bound C5b to initiate assembly of the remaining components to form the membrane attack complex (C5b6789). Enzymatically active proteases of the classical and alternative pathways that cleave and activate subsequent components are, by convention, shown with an overbar. The alternative pathway C3 and C5 convertases are shown associated with properdin (P), which increases their stability. B, Complement factor B; D, complement factor D; MASP, MBL-associated serine proteases.

Effector functions of complement in host defense.

The principal complement effector functions in host defense include opsonization via bound fragments of C3; phagocyte recruitment, especially via release of C5a; lysis of microorganisms, especially gram-negative bacteria, via the membrane attack complex (C5b–C9); and immune regulation via interactions with host cells involved in adaptive immunity. Complement sometimes may be activated and bound to microbial surfaces but unable to carry out these functions if it is bound at a disadvantageous location; for example, C3b bound to a pneumococcal cell wall beneath a thick polysaccharide capsule or C5b–C9 bound to long lipopolysaccharide molecules distant from the gram-negative bacterial outer membrane.

Phagocyte recruitment to infected sites.

Activation of endothelial cells that line the microvessels of acutely infected tissue occurs via locally produced cytokines, eicosanoid compounds, and microbial products. As a result, the endothelial cells rapidly upregulate their surface expression of P-selectin from preformed intracellular storage pools and, subsequently, of E-selectin by new synthesis. These selectins interact with the fucosylated tetrasaccharide moiety sialyl Lewis X, which is presented on constitutively expressed glycoproteins on PMNs including L-selectin and P-selectin glycoprotein ligand–1 (PSGL-1). These early interactions slow the PMNs in this first adhesive phase of leukocyte recruitment, sometimes described as “slow rolling.” Within several hours, newly synthesized ICAM-1 is expressed at the endothelial surface. The slowly rolling PMNs are activated by transient selectin-mediated interactions and locally produced mediators, especially endothelium-derived chemokines such as IL-8. These chemokines are most effective in PMN activation when they are bound by complex proteoglycans at the endothelial cell surface. The activated PMNs then signal the conformational activation of binding function of their surface β ₂ integrins LFA-1 and Mac-1, as well as translocating an additional large quantity of Mac-1 from intracellular storage pools to the cell surface. This newly translocated Mac-1 also may undergo conformational activation as the PMN is exposed to increasing concentrations of mediators. These activated β ₂ integrins interact with the endothelial cell ICAM-1 in this second, firm adhesion phase, which is necessary for transendothelial migration of the PMNs. Other chemoattractants, such as C5a, N-formyl bacterial oligopeptides, and leukotrienes (e.g., LTB ₄ ) that diffuse from the site of infection further activate PMNs and provide a chemotactic gradient for PMN migration into tissue. The receptors for these chemoattractants, like the chemokine receptors, are G-protein coupled and have a seven-transmembrane-domain structure. They constitute important sensory mechanisms of the PMNs for activating adhesion, directional orientation, and the contractile protein-dependent lateral movement of adhesion sites in the PMN membrane necessary for cell locomotion. A scheme for PMN recruitment from the microcirculation into infected tissue is presented in Fig. 2.2 . Although the specific stimuli and adhesion molecules may vary, this general scheme applies to the local recruitment of virtually all circulating cells of the immune system.

Events during leukocyte (polymorphonuclear leukocytes [PMNs]) recruitment to infected sites. Interactions between microorganisms in infected tissue and host cells and proteins result in elaboration of mediators that diffuse to the local microcirculation and stimulate the endothelial cells. This induces new surface expression of P-selectin and E-selectin, release of interleukin-8 and other chemokines, and new surface expression of intercellular adhesion molecule 1 (ICAM-1). The endothelial selectins bind to constitutively expressed carbohydrate ligands on circulating PMNs and slow the passage of the PMNs through the microvessels. As the PMNs slow further, they become activated by interaction with chemokines bound to complex glycopeptides on the endothelial surface. This activation of PMNs increases their expression and binding activity of the β ₂ (CD11/CD18) integrins, Mac-1 and lymphocyte function–associated antigen–1 (LFA-1). Interactions between these integrins and ICAM-1 (and ICAM-2 in the case of LFA-1) lead to tight adhesion and spreading on the endothelial surface. These latter adhesive interactions also are used for migration between endothelial cells and through the subjacent extracellular matrix in response to the gradient of chemoattractants, such as C5a, chemokines, and bacterial peptides, released at the infected site. Homophilic interactions between PECAM-1 on the PMNs and endothelial cells (not diagrammed) also appear to contribute to transendothelial migration.

(Courtesy Scott Seo, MD.)

Phagocytosis.

After PMNs reach the site of infection, they must recognize and ingest, or phagocytose, the invading bacteria. Opsonization, especially with IgG and fragments of C3, greatly enhances phagocytosis. Although nonopsonic phagocytosis may occur, only opsonin-mediated phagocytosis is considered here. CR1 and CR3 are the main phagocytic receptors for opsonic C3b and iC3b, respectively. When PMNs are activated by chemoattractants or other stimuli, CR1 and CR3 are rapidly translocated to the cell surface from intracellular storage compartments, thus increasing surface expression up to 10-fold. Note that CR3 is identical to the adhesion-mediating integrin Mac-1. CR1 and CR3 act synergistically with receptors for the Fc portion of antibodies, especially IgG. Phagocytic cells may express up to three different types of IgG Fc receptors, or FcγRs, all of which can mediate phagocytosis. FcγRI (CD64) is a high-affinity receptor that is expressed mainly on mononuclear phagocytes. The two FcγRs ordinarily expressed on circulating PMN are FcγRII (CD32) and FcγRIII (CD16). FcγRII is conventionally anchored in the cell membrane, exhibits polymorphisms that determine preferences for binding of certain IgG subclasses, and can directly activate PMN oxidative burst activity. FcγRIII is expressed on PMNs as a glycolipid-anchored protein, although it is anchored conventionally on NK cells and macrophages. Many phagocytes also express IgA FcRs, which promote phagocytosis and killing of IgA-opsonized bacteria.

The engagement of phagocyte receptors with microbial opsonins on microbes locally activates cytoskeletal contractile elements, leading to engulfment of the microbe within a sealed phagosome. This is followed by fusion of the phagosome with lysosomal compartments containing the phagocyte’s array of microbicidal products.

Phagocyte microbicidal mechanisms.

Intracellular killing by phagocytes, usually within the fused phagolysosome, involves microbicidal weapons that can be categorized as either oxygen-dependent or oxygen-independent. The oxygen-dependent microbicidal mechanisms of phagocytes depend on a complex enzyme, reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, which catalyzes the conversion of molecular oxygen (O ₂ ) to superoxide anion (O ₂ ⁻ ), the reaction that is deficient in chronic granulomatous disease (see later discussion). As the name suggests, the reaction catalyzed by this enzyme requires a supply of NADPH, which is supplied in turn by reactions of enzymes of the hexose monophosphate shunt. The NADPH oxidase is assembled at the plasma or phagolysosomal membrane of activated cells from six known components that include a cytochrome (α- and β-subunits, designated gp91 ^phox and p22 ^phox , respectively) and at least three cytosolic proteins, p40 ^phox , p47 ^phox , and p67 ^phox (“phox” refers to phagocyte oxidase), along with a Rac-1 GTPase, which assemble with the membrane-associated components to form the active enzyme complex ( Fig. 2.3 ). Each of the main oxidant products derived from this enzyme’s activity exhibits microbicidal activity, including the earliest products, O ₂ ⁻ and H ₂ O ₂ , and the more potent downstream products hypochlorite (OCl ⁻ ) and chloramines (NH ₃ Cl, RNH ₂ Cl), with chloramines being the most stable.

The phagocyte reduced nicotinamide adenine dinucleotide phosphate (NADPH)-oxidase enzyme complex and the major reactions in the evolution of oxygen-dependent PMN microbicidal activity. The diagram depicts the six main components of the NADPH oxidase complex: the 91-kDa and 22-kDa subunits of the membrane-bound cytochrome; the 40-kDa, 47-kDa, and 67-kDa cytosolic components; and a Rac-1 signaling molecule. After assembly at the plasma or phagolysosome membrane, the enzyme catalyzes the conversion of molecular oxygen (O ₂ ) to superoxide anion (O ₂ ⁻ ), the initial step in the sequence of production of oxidant antimicrobial products. This reaction requires a supply of NADPH, most of which is derived from activity of enzymes of the hexose monophosphate shunt (not shown). Shown in sequence are subsequent reactions for the spontaneous formation of hydrogen peroxide (H ₂ O ₂ ), the myeloperoxidase-catalyzed formation of hypochlorite (OCl ⁻ ), and formation of chloramines (RNH ₂ Cl).

The oxygen-independent microbicidal activity of PMNs resides mainly in a group of proteins and peptides stored within their primary (azurophilic) granules and, to a lesser extent, in their secondary (specific) granules. Lysozyme is contained in both the primary and the secondary (specific) granules of PMN. It cleaves important linkages in the peptidoglycan of bacterial cell walls and is most effective when it can act in concert with the complement MAC. The primary granules contain several cationic proteins with important microbicidal activity. A 59-kDa protein, bactericidal/permeability-increasing protein, is active against only gram-negative bacteria. Smaller arginine- and cysteine-rich peptides, the α-defensins, similar to the β-defensins of epithelial cells, are active against a range of bacteria, fungi, chlamydiae, and enveloped viruses; other related molecules include cathelicidin and a group of peptides called p15s. Some of these PMN proteins and peptides interact with each other synergistically to enhance overall antimicrobial activity.

Class I major histocompatibility complex.

Virtually all human cells except neurons express class I MHC. The class I MHC molecule presents antigenic peptides to CD8 ⁺ cytotoxic T lymphocytes. It consists of a heavy chain that contains both the peptide-binding domain and a transmembrane domain and a smaller extracellular subunit, β ₂ -microglobulin. The three major types of class I MHC heavy chains in humans, human leukocyte antigen (HLA)-A, HLA-B, and HLA-C, have at least 22, 31, and 12 different alleles, respectively. This polymorphism permits a great diversity in the peptide-binding repertoire in individuals and within populations. A restricted degree of MHC genetic polymorphism has been invoked as a possible explanation for the predisposition of certain populations to develop infections. Class I MHC molecules within the cell ordinarily bind peptides derived from recently synthesized proteins, either of self-origin or of infecting viruses. A portion of newly synthesized proteins is processed into peptides at a cytoplasmic site, the proteasome. These peptides are actively transported into the endoplasmic reticulum, where they are bound in the peptide-binding cleft of MHC class I. Suitable peptides usually are restricted to 8 to 10 amino acids in length, and they must contain certain amino acids at specific “anchor” positions on the peptide to bind. Allelic variants of MHC class I may require different amino acids at these anchor positions. The other amino acids of the peptide constitute the specific antigenic determinant. After trafficking of the MHC-peptide complex to the cell surface, the peptide antigen is recognized and bound by a specific T-cell receptor on CD8 ⁺ cytotoxic T cells, which concurrently bind the heavy chain of MHC class I via CD8.

Class II major histocompatibility complex.

Mononuclear phagocytes, B lymphocytes, and dendritic cells, including specialized tissue-specific dendritic cells, such as the Langerhans cells of the skin, serve the immune system as “professional” APCs. Dendritic cells, the most efficient APCs for primary activation of naïve T cells, are macrophage-like cells of a distinct lineage that take up and process antigens in tissues and migrate to local lymph nodes or to the spleen, where they are likely to encounter T cells specific for the presented antigens. A defining feature of these professional APCs is their expression of class II MHC molecules in addition to class I MHC. Class II MHC molecules consist of an α and a β chain, which together form a peptide-binding cleft. Class II MHC molecules present peptides, 13 to 17 amino acids in length, derived from proteins that are internalized by endocytosis or during phagocytosis of microorganisms. The three major types of class II MHC α and β chains are HLA-DR, HLA-DP, and HLA-DQ, each exhibiting a high degree of polymorphism. MHC class II, bound to a separate smaller molecule known as the “invariant chain,” traffics via the Golgi to endosomal/lysosomal compartments, where it must dissociate from the invariant chain to bind antigenic peptides derived from internalized proteins. The class II MHC–peptide complexes then move to the cell surface, where the peptide antigens are bound by specific T-cell receptors of CD4 ⁺ T cells, which concurrently bind class II MHC via CD4.

Fig. 2.7 depicts the essential features of the conventional antigen presentation pathways that involve class I and class II MHC molecules, as described earlier. Alternative mechanisms have been documented by which class I MHC can present peptides derived from internalized exogenous proteins, and class II MHC may present peptides derived from newly synthesized proteins. The importance of these unconventional pathways of antigen presentation in the immune response is not fully understood, but evidence indicates that such “cross-presentation” may be important for generation of CD8 ⁺ cytotoxic T-cell response against some viruses or fungi taken up via endocytosis by antigen-presenting cells.

Conventional pathways for peptide antigen presentation by class I and class II major histocompatibility complex (MHC) molecules. In the antigen-presenting cell, a proportion of newly synthesized proteins, whether of viral or host origin, undergo proteolysis into peptides by enzymes that constitute the “proteasome.” The peptides are transported actively into the endoplasmic reticulum (ER), where those with the appropriate length and sequence bind to MHC class I molecules. MHC class II cannot bind peptides in the ER because of interference by the associated “invariant (inv.) chain.” The class I MHC/peptide complex is transported via the Golgi to the cell surface, where it may be recognized by CD8 ⁺ lymphocytes. Class II MHC molecules pass via the Golgi to a lysosomal compartment, where conditions favor the release of the invariant chain. This permits class II MHC to bind peptides derived from internalized proteins that have entered the lysosomal compartment via fusion of endosomes or phagosomes with the lysosome. The lysosome translocates to the cell surface, where the class II MHC/peptide complex may be recognized by CD4 ⁺ lymphocytes.

CD1 family of antigen-presenting molecules.

The CD1 family includes proteins with significant homology and structural similarity to that of the MHC class I heavy chain but that present lipid and glycolipid antigens. All mammalian species express one or more members of the CD1 family, principally on professional antigen-presenting cells. Four human CD1 proteins, CD1a, CD1b, CD1c, and CD1d, have been identified, each tightly associated with a β ₂ -microglobulin subunit. Mycolic acid, lipoarabinomannans, and other related components of mycobacteria are the best-documented foreign antigens presented by CD1 molecules, and both internalized antigens and antigens synthesized within the antigen-presenting cells by ingested mycobacteria may be presented via distinct trafficking patterns of the CD1-antigen complexes. Antigens presented on antigen-presenting cells by CD1 molecules are recognized by a specialized subset of CD1-restricted T cells that usually lack CD4 and CD8; these are known as NK T cells. These cells share characteristics of both NK cells and T cells and exhibit a limited range of T-cell receptor specificity. Greater detail regarding the structure, function, phylogeny, trafficking, expression, and T-cell interactions for members of the CD1 family may be found in a recent review.

Plasmacytoid dendritic cells.

A specialized class of dendritic cells known as “plasmacytoid” dendritic cells plays a multifactorial role in both innate and adaptive immune responses. These cells are early responders to viral infections by virtue of their expression of TLR7/9 and their ability to produce large amounts of type 1 interferons that disrupt viral replication. Additionally they can play an auxiliary role in the adaptive immune response by providing help to conventional dendritic cells during antigen presentation, apparently by helping to sustain IL-12 production by the latter in response to IFN-γ released by interacting T cells.

Regulatory T cells.

The existence of T suppressor cells was long a subject of debate among immunologists. Within the past decade solid evidence has been developed to support the existence of suppressor T cells, now referred to as regulatory T cells, or T-regs. These cells were discovered when thymectomized mice were noted to develop autoimmune disease. Transfer of T cells that expressed CD25, the α chain of the IL-2 receptor, from normal adult mice to thymectomized mice prevented autoimmune disease. This population of CD4 ⁺ CD25 ⁺ T-regs can suppress the activity of other immune cells and has been shown to prevent graft-versus-host disease and allograft rejection. The mechanism of suppression by T-regs is uncertain but may involve direct contact with other cells or secretion of inhibitory cytokines, including IL-10. These inhibitory cytokines can interfere with T-cell proliferation and inhibit the ability of antigen-presenting dendritic cells to promote T-cell activation. The role of T-regs in immunity to infection is only beginning to be studied, but some current evidence suggests that the action of T-regs with specificity for microbial antigens may suppress protective immune responses to some infections but may also suppress excessive or injurious host responses.

T-cell memory.

Some proportion of activated CD4 ⁺ and CD8 ⁺ T cells become endowed with the capacity for long-term antigenic memory and can rapidly become effectors on re-exposure to specific antigen. Whether these cells develop directly from naïve T cells or previously have been effector cells, or both, is uncertain, and the mechanisms by which they become memory T cells are poorly understood. Among the features of memory T cells are high-level expression of CD45RO, the ability to suppress activation of naïve T cells of the same specificity, and a homeostatic level of ongoing proliferation in bone marrow and peripheral lymphoid organs.

T-cell activation by superantigens.

The term superantigen describes a class of proteins, mainly microbial exotoxins, including most staphylococcal enterotoxins, staphylococcal toxic shock syndrome toxin–1 (TSST-1), and related streptococcal TSST-1–like toxins. These bacterial toxins are potent pyrogens, can induce a potentially lethal toxic shock syndrome, and contain binding domains for both T-cell receptor V regions and MHC class II molecules. Superantigens bypass normal antigen-processing and presentation pathways by binding directly to class II MHC molecules on antigen-presenting cells and to specific variable regions on the β-chain of the T-cell antigen receptor. Through these interactions, superantigens induce a polyclonal activation of T cells at orders of magnitude above levels induced by antigen-specific activation, resulting in massive release of cytokines from T cells and antigen-presenting cells, including TNF-α and TNF-β, IL-1, IL-2, and IFN-γ, that are believed to be responsible for the most severe features of toxic shock syndromes.

B lymphocytes.

B lymphocytes (B cells) are the source of humoral immunity in the form of specific immunoglobulin. The earliest recognizable marrow precursors of B cells are pro-B cells whose surfaces bear the pan-B marker CD19. Further differentiation produces pre-B cells and then mature B cells, the latter expressing cell-surface immunoglobulin by which they recognize and bind antigen. B lymphocytes constitute approximately 20% of the lymphocytes in the circulation and peripheral lymphoid tissues, including the lymph nodes, spleen, bone marrow, tonsils, and intestines, and they are identified by the presence of surface immunoglobulin and the pan-B differentiation markers CD19 and CD20.

B-cell activation is initiated by recognition and binding of specific antigens to B-cell surface immunoglobulins. Early activation leads to increased expression of receptors that either bind cytokines (e.g., IL-2, IL-4, and IL-6) or interact with T cells, leading in turn to clonal proliferation and differentiation into memory B cells and plasma cells in the germinal centers of peripheral lymphoid tissue. Some data suggest that B-cell differentiation into memory B cells is favored by exposure to the CD40 ligand on dendritic cells in lymphoid organs, whereas differentiation into plasma cells is favored by exposure to CD23, IL-1α, IL-6, and IL-10. The plasma cells, later found in bone marrow and liver as well as peripheral lymphoid tissue, are responsible for most free immunoglobulin production.

The B-cell response to protein antigens depends on T-cell help. B cells can process and present antigen to CD4 ⁺ T _FH cells they encounter in the lymph nodes and spleen. In the typical sequence of events, B-cell surface immunoglobulin binds to a protein antigen, which is internalized, processed, and presented to the T cell via class II MHC molecules. B cell–mediated activation of T cells during antigen presentation is much more effective for memory T cells, whereas naïve T cells are more likely to be turned off or rendered tolerant. T-cell help is provided for B-cell proliferation and production of antibody against the specific protein antigen. This is mediated by signaling via CD40-ligand interactions with CD40 on the B cell and by the release of cytokines, which also can induce isotype switching. Most B-lymphocyte responses to polysaccharide antigens proceed largely without formal T-cell help, although antibody responses to some such antigens may be enhanced in the presence of T cells.

Immunoglobulin.

Immunoglobulin molecules may be bound at the surface of B cells or free in the circulation, mucosal secretions, or tissues. Free immunoglobulins function in host defense against infection by binding to microbial surfaces to prevent microbial attachment, activating complement via the classical pathway, neutralizing viruses and toxins, and participating in the formation of immune complexes.

Ig molecules are composed of two identical heavy and two identical light chains, as diagrammed in Fig. 2.8 . The carboxyl terminus of the immunoglobulin molecule is the heavy chain constant, or Fc, region. The amino acid sequence of this region determines the immunoglobulin isotype. The heavy chain is encoded by V, (D), J, and constant (C) regions on chromosome 14. Each immunoglobulin molecule has a pair of either κ or λ light chains, defined by distinct constant regions. The variable region of the immunoglobulin molecule contains the antigen-binding site. Like the T-cell receptor, the Fab region consists of two identical heavy and light chain pairs; similarly, broadly diverse antigen specificity results from the variable nature of recombinase-mediated DNA rearrangements of the three hypervariable, or complementarity-determining, regions (CDR1, CDR2, and CDR3) and the four framework regions during B-cell development. The imprecision inherent in this rearrangement, involving mechanisms similar to those described for the T-cell receptor, leads to the generation of more than 10 ¹² potential antigenic specificities. Somatic hypermutation of variable regions after gene rearrangement adds to the repertoire, and further diversity results from differences in approximation of the three CDRs in relation to each other, affecting the three-dimensional structure of the antigen recognition site. Thus unlike most T-cell receptors, which recognize specific peptide sequences, the antigen-binding domain of an immunoglobulin molecule recognizes the three-dimensional structure of its respective antigen.

Structure of an immunoglobulin molecule. The schematic structure of immunoglobulin G (IgG) is shown, depicting the variable (V) and constant (C) regions of both the heavy (H) and light (L) chains, the disulfide bonds that link the two heavy chains at the hinge region and the CL region with CH ₁ , and the antigen-binding sites formed by the complementarity-determining regions of VH and VL.

All immunoglobulin is derived from B cells expressing surface IgM. B cells may change immunoglobulin isotype when they differentiate into plasma cells, which produce only one class or subclass of immunoglobulin each. Isotypes other than IgM are the result of isotype switching by replacing a part of the constant region of the immunoglobulin heavy chain with another isotype-specific segment. As already noted, isotype switching primarily depends on specific B-cell interactions with cytokines and T cells. The variable region remains unchanged during isotype switching; thus there is no change in antigen specificity. However, important features of immunoglobulins, including half-life, localization in tissues, ability to activate complement, and interactions with cellular IgG receptors, are directly determined by isotype.

In addition to isotype switching, immunoglobulins undergo the process of “affinity maturation.” As B cells proliferate in lymphoid tissue in response to persistent or repeated antigen exposure and T-cell help, they undergo V-region somatic hypermutation. When this mutation results in a reduced or absent affinity for antigen, B cells are less able to become activated and elicit T-cell help. Such B cells die by apoptosis, removing lower affinity immunoglobulin from the repertoire. Alternatively, B cells that undergo a mutation resulting in increased affinity for antigen are better able to bind antigen, present antigenic peptides to T cells, receive T-cell help, and survive to give rise to plasma cells, which in turn will produce immunoglobulin with higher affinity. This is a process that occurs as a result of booster doses of vaccines or during persistent infections, as with cytomegalovirus, for example.

Immunoglobulin isotypes.

IgG accounts for about 80% of circulating immunoglobulin and includes the subclasses IgG1, IgG2, IgG3, and IgG4. The half-life of IgG ordinarily is about 21 days (7 days for IgG3). Initial exposure to most microbial protein antigens first induces IgM and then an IgG response consisting of IgG1 and IgG3. IgG2 and IgG4 usually are produced during the secondary immune response. IgG1 usually is made in response to protein antigens. In adults, the main antibody response to polysaccharides is IgG2, whereas in infants IgG1 predominates. The functions of IgG in host defense include blocking microbial attachment, opsonization, complement activation, toxin and virus neutralization, and promoting antibody-dependent cell cytotoxicity. IgG1, IgG2, and IgG3, but not IgG4, can trigger complement activation via the classical pathway by binding to C1q.

Free IgM usually exists as an immunoglobulin pentamer that has a molecular weight of approximately 950,000 and is stabilized by a single J chain. Present mainly in the circulation, its half-life is approximately 8 to 10 days. The IgM response is the earliest of the isotype responses, appearing within the first few days of infection, but it is transient. The formation of an IgM response in the absence of an IgG response to infection is not associated with the formation of memory B cells. The main direct action of IgM in host defense is the activation of complement via the classical pathway.

IgA exists in monomeric circulating and polymeric secretory forms and has a half-life of about 7 days. Both forms are produced mainly by plasma cells that have migrated to mucosal sites. Secretory IgA is made up of two or three IgA molecules joined by a stabilizing J segment that is secreted by plasma cells and a secretory component produced by mucosal epithelial cells. The secretory component permits delivery of IgA to mucosal surfaces. There are two subclasses, IgA1 and IgA2, that differ in the composition of their heavy chains. Most IgA in the circulation is IgA1, whereas most IgA in secretions is IgA2. IgA1 may be cleaved at mucosal sites by bacterial proteases. IgA neutralizes viruses at mucosal sites, may block bacterial adhesion, and can act directly as an opsonin to promote phagocytosis and via Fcα receptors.

The IgE molecule has a molecular weight of 200,000 and a half-life of only 2.3 days. Most IgE is produced by plasma cells in lymphoid tissue near gastrointestinal and respiratory mucosal surfaces and released into the circulation. IgE acts via Fcε receptors to trigger activation and degranulation of mast cells and basophils, leading to immediate hypersensitivity reactions. Persons with intestinal metazoan parasites often have elevated serum levels of IgE, and IgE may have a role in protecting against parasitic disease by stimulating mediator release from mast cells that can recruit eosinophils and cause intestinal smooth muscle contraction and expulsion of parasites.

IgD has a molecular weight of approximately 180,000 and a half-life of 3 days. It is expressed along with IgM on surfaces of naïve B cells but is present in normal adult serum and secretions in very low concentrations. Some antigenic specificity for IgD has been demonstrated, and although its function in host defense is unclear, it may serve as a secondary antigen receptor on B cells, where it may regulate the development of B-cell antibody responses.

B cells.

Pre-B cells are found in the fetal liver and omentum by 8 weeks’ gestation and in the fetal bone marrow by 13 weeks’ gestation. Pre-B cells with surface IgM have been detected as early as 10 weeks’ gestation. After 30 weeks’ gestation and delivery, pre-B cells are seen only in the bone marrow. Mature B cells are present in the circulation by the eleventh week and have reached adult levels in the bone marrow, blood, and spleen by the twenty-second week of gestation.

Fetal B cells express only IgM, whereas most adult B cells express both IgM and IgD. Neonatal B cells may express three immunoglobulin isotypes (e.g., different combinations of IgG, IgA, IgM, and IgD) on their surfaces.

Although germinal centers are not present in lymphoid tissue at birth, they begin to develop in the first few months of life concomitant with the infant’s exposure to antigens. Despite conflicting in vitro data, neonatal T-cell help for B cells probably is comparable to that of adult T cells, as is reflected by the excellent T-dependent antibody response of the newborn to immunization with protein antigens. In contrast to B cells of older individuals, B cells of neonates and young infants cannot respond to pure polysaccharide antigens. The recruitment of T-cell help to enhance this immature response to polysaccharides has been achieved with the advent of protein-polysaccharide conjugate vaccines. Such vaccines elicit help from T cells specific for peptides derived from the protein component as presented by polysaccharide-specific B cells that have internalized the protein-polysaccharide complex, allowing peptide-specific T cells to activate polysaccharide-specific B cells.

Antibody.

Maternal IgG accounts for the great majority of the newborn’s circulating immunoglobulin because almost none is made by the healthy fetus and IgG is the only isotype of maternal immunoglobulin that crosses the placenta. Maternal transport of IgG can be detected as early as 8 weeks’ gestation, and the newborn’s IgG level is directly proportional to gestational age, reaching 100 mg/dL by 17 to 20 weeks’ gestation and 50% of the maternal level by 30 weeks’ gestation ( Fig. 2.9 ). Maternal IgG is transported both passively and actively via trophoblast Fc receptors. Trophoblast Fc receptors have higher affinity for IgG1 and IgG3 than for IgG2 and IgG4, and thus more of those subclasses are transported from the mother.

Immunoglobulin (IgG, IgM, and IgA) levels in the fetus and infant in the first year of life. The IgG of the fetus and newborn infant solely is of maternal origin. The maternal IgG disappears by 9 months of age, by which time endogenous synthesis of IgG by the infant is well established. The IgM and IgA of the neonate are synthesized entirely endogenously because maternal IgM and IgA do not cross the placenta.

(From Braun J, Stiehm ER. The B-lymphocyte system. In: Stiehm ER, editor. Immunologic Disorders in Infants and Children. 4th ed. Philadelphia: WB Saunders; 1996:67.)

The concept of passive transfer of protective IgG is the basis for development of vaccines for maternal immunization before or during pregnancy so that passive transfer of vaccine-induced antibody will result in protection during the neonatal period. Examples of organisms for which such strategies have been investigated include group B streptococcus, H. influenzae type b, meningococcus, pneumococcus, rotavirus, and respiratory syncytial virus.

By about 2 months of chronologic age, approximately half of the term infant’s quantitative IgG is of maternal and half is of infant origin. The physiologic nadir of IgG in all infants is about 3 to 4 months of age and ranges from less than 100 mg/dL in preterm infants with very-low-birth weight to about 400 mg/dL in term infants (see Fig. 2.9 ). Maternal IgG usually has waned completely by about 12 months of age, at which time infant levels are approximately 60% of adult levels. Production of IgG1 and IgG3 matures more rapidly than that of IgG2 and IgG4, reaching adult levels by approximately 8 years of age, versus 10 and 12 years of age, respectively.

Little IgM, IgA, IgE, or IgD normally is produced by the fetus, and none is transported from the mother. The presence of total IgM levels greater than 20 mg/dL at birth suggests an intrauterine infection, and documentation at birth of specific serum IgM or IgA against relevant organisms, such as T. gondii and others, would be diagnostic. Serum IgA levels at birth in both preterm and term infants usually are less than 5 mg/dL and consist of both IgA1 and IgA2. Secretory IgA is not detectable until after birth but usually is present within the first few weeks of life. IgM and IgA reach approximately 60% and 20% of adult levels by 1 year of age, respectively (see Fig. 2.9 ). Secretory IgA reaches adult levels by 6 to 8 years of age.

It has been documented that the fetus can respond to antigenic stimulation in the form of maternal immunization with tetanus toxoid vaccine and be primed for a secondary antibody response to repeat immunization after birth. The amount of fetal antibody produced in response to intrauterine antigenic stimulation is proportional to gestational age.

Maternal antibody inhibits the infants’ ability to respond to live-virus vaccines against certain organisms, such as measles, but it does not prevent them from mounting protective immune responses to most childhood vaccine antigens, such as tetanus, diphtheria, polio, hepatitis B, and protein-conjugated polysaccharide vaccines. In general, neonates have protective responses to T-dependent antigens even though they may produce less antibody to some antigens than do older infants and adults.

The newborn infant’s response to T-independent antigens, such as polysaccharides, is poor. The antibody response to most such antigens, including the polysaccharide capsules of group B streptococci, pneumococci, and H. influenzae type b, is not mature until 18 to 24 months of age. In contrast, in the first few weeks of life, infants mount excellent antibody responses to T-independent polysaccharide antigens that have been rendered T-dependent by covalent conjugation of the polysaccharide to a protein carrier, as noted earlier.

The response of premature infants to most routine childhood vaccines by 2 months of age, including diphtheria, tetanus, pertussis, and oral and inactivated polio, is comparable to that of 2-month-old term infants. However, premature infants may not respond as well to hepatitis B vaccine for reasons that are unclear.

X-linked agammaglobulinemia.

X-linked agammaglobulinemia (XLA), first described by Bruton, is a primary immunodeficiency disorder of the B-cell lineage and is the most serious disorder of humoral immunity. It is characterized by absent or severely decreased numbers of circulating B lymphocytes and absent or extremely low levels of all classes of circulating immunoglobulins. It is caused by several different mutations in the gene encoding for a B-cell–specific tyrosine kinase, Btk, which maps to the long arm of the X chromosome at Xq22. This abnormality in kinase activity results in an arrest in the development of B cells, usually at the pre-B stage, and thus few B cells or their progeny (e.g., plasma cells) are in the circulation or lymphoid tissues.

Most persons with XLA develop chronic or recurrent pyogenic bacterial respiratory or gastrointestinal tract infections, and some may have recurrent skin infections. Sepsis and serious focal infections resulting from bacteremia do not occur as frequently but are more common and more severe than in normal hosts. The causative agents of most of these infections are Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis , but Staphylococcus aureus and Pseudomonas aeruginosa, as well as other gram-negative organisms, may be implicated. The most troublesome gastrointestinal tract infections in XLA are caused by Salmonella, Campylobacter, and chronic infestation with G. lamblia. These patients have been found to have unusually severe or chronic enterovirus infections that can be manifested by chronic arthritis, meningoencephalitis, dermatomyositis, hepatitis, or a combination thereof, and several patients with XLA have developed vaccine-related paralytic poliomyelitis after receiving the live oral polio vaccine.

The only typical abnormality on physical examination in XLA that is not related directly to infections is the absence or a paucity of normal B-cell–containing lymphoid tissues, such as tonsils, adenoids, and peripheral lymph nodes.

The diagnosis of XLA can be confirmed by studying lymphocyte markers and demonstrating a lack of circulating cells that stain for surface immunoglobulin or with B-cell–specific monoclonal antibodies against CD19, CD20, or both. The number and function of T lymphocytes are normal in XLA. It may be difficult to establish the diagnosis based on immunoglobulin levels in the newborn period because of the presence of maternally derived IgG. However, if suspected, the diagnosis can be made in the newborn period by documenting a paucity of circulating B cells by flow cytometry.

Although individuals with XLA ordinarily are thought of as having a “pure” B-cell disorder, recent evidence reveals that the absence of B cells in XLA is associated with a contracted T-cell receptor repertoire and that mice that lack B cells are unable to prime CD4 ⁺ T cells for their effector function in clearing Pneumocystis infection, findings that are consistent with the important role of B cells in presenting antigen to CD4 ⁺ T cells.

In contrast to carriers of some other X-linked diseases examined later (see discussion of chronic granulomatous disease), circulating B lymphocytes of XLA carriers express only one population of B cells, those with the normal allele on the X chromosome, presumably because B cells with the mutant allele are at a selective disadvantage and do not develop. Advances in genetic techniques have enabled detection of maternal carriers of XLA. Prenatal diagnosis can be made by genetic studies of amniotic fluid cells or quantitation of fetal circulating B cells.

The prognosis for patients with XLA has improved markedly with earlier diagnosis, high-dose intravenous immunoglobulin (IVIG) therapy, and aggressive use of antibiotics. Before the availability of IVIG, most patients who survived to the third decade of life had chronic lung disease from recurrent pulmonary infections and hearing loss from recurrent otitis media.

IgG subclass deficiency.

Persons with IgG subclass deficiencies have levels of one or more IgG subclass that are more than two standard deviations below normal for age, normal to slightly decreased total IgG, normal levels of other immunoglobulin isotypes, and, often, a poor antibody response to certain antigens. *

* References .

The most common kinds of infections in patients with any clinically significant IgG subclass deficiency include otitis media, sinusitis, and pneumonia. Ordinarily, these patients do not have life-threatening systemic infections.

Deficiency of IgG1 is likely to be associated with subnormal levels of total IgG because this subclass accounts for about 60% of total IgG, and it often is associated with other subclass deficiencies.

IgG2 deficiency usually is associated with normal total serum IgG levels and is more likely to be clinically significant if accompanied by IgG4 or IgA deficiency. Patients with IgG2 deficiency typically have poor antibody responses to polysaccharide antigens but normal responses to protein antigens. Like most patients with deficiencies of humoral immunity, their infections primarily are due to encapsulated bacteria and are localized to the respiratory tract.

IgG3 deficiency has been associated with low total levels of serum IgG and recurrent respiratory infections, which also may lead to chronic pulmonary disease.

IgG4 deficiency is difficult to diagnose because many normal persons have low serum levels of IgG4, and most normal infants have no detectable IgG4. IgG4 deficiency appears to be of clinical significance, however, if it is associated with IgG2 and IgA deficiency.

The treatment for children with IgG subclass deficiency typically is individualized according to the frequency and severity of symptoms. Noninvasive infections usually can be treated successfully with appropriate antibiotics. Patients with more severe presentations may benefit from regular IVIG therapy, but those who also are completely IgA-deficient should be treated only with IgA-depleted IVIG preparations.

IgA deficiency.

IgA deficiency is the most common immunodeficiency, occurring as frequently as 1/400. This disorder appears to occur sporadically, but familial cases have been described. Most of the functions of serum IgA can be performed by IgG and IgM. Thus, although deficiencies of secretory IgA may lead to recurrent respiratory or gastrointestinal tract infections, deficiency of serum IgA alone usually is not associated with increased susceptibility to systemic infections. IgA deficiency has been associated with many other conditions, including recurrent infections, IgG2 deficiency, autoimmune disorders, and malignancy. Recurrent infections are most likely to occur in the subset of IgA-deficient patients who also have IgG2 deficiency. The infections usually are relatively mild and involve the upper respiratory and gastrointestinal tracts. Chronic gastrointestinal tract disease in these patients can be caused by G. lamblia infestations, nodular lymphoid hyperplasia, lactose intolerance, malabsorption, or inflammatory bowel disease. Other autoimmune diseases associated with IgA deficiency include rheumatoid arthritis, systemic lupus erythematosus, thyroiditis, myasthenia gravis, and vitiligo. About 20% of IgA-deficient patients have allergy, and many have elevated levels of IgE. Food allergy is common and may be the result of abnormal processing of antigen at mucosal surfaces.

Rare patients with serum IgA levels less than 5 mg/dL who receive transfusions may make antibody against donor IgA and have severe reactions when transfused again. IVIG reactions also may occur because IVIG preparations contain varying amounts of IgA. IgA-depleted preparations are available and usually are well tolerated.

Transient hypogammaglobulinemia of infancy.

The syndrome of transient hypogammaglobulinemia of infancy can be differentiated from the physiologic hypogammaglobulinemia in infants because immunoglobulin levels of normal infants begin to rise by about 6 months of age, whereas those of infants with transient hypogammaglobulinemia of infancy do not begin to increase until between 18 and 36 months of age. Infants suspected of having this syndrome should be evaluated for XLA and CVID (see later discussion) and followed closely until their immunoglobulin levels normalize for age.

Antibody deficiency with normal or elevated levels of immunoglobulins.

Some persons with normal levels of all circulating immunoglobulin isotypes are at increased risk for infections similar to those seen in specific deficiencies of immunoglobulin levels described earlier. As in other forms of humoral immunodeficiency, the most common infections in these patients are recurrent bacterial respiratory tract infections, although a few patients have developed pneumococcal sepsis. Such persons can be identified by their inability to make antibody in response to stimulation with specific antigens. A good way to test for this disorder is to immunize with protein antigens, such as tetanus and diphtheria toxoids, and with polysaccharide antigens, such as pneumococcal and H. influenzae type b capsular polysaccharide vaccines. Patients who can respond to protein but not to polysaccharide antigens usually will respond to protein-polysaccharide conjugates. Treatment with IVIG may help prevent recurrent infections in these patients, although their normal overall levels of immunoglobulin can pose difficulties in determining the appropriate doses of IVIG and intervals between infusions.

Severe combined immunodeficiency disease.

Severe combined immunodeficiency (SCID) describes a heterogeneous group of heritable immunodeficiencies that involve serious impairments of both cellular and humoral immunity, thus leading to recurrent severe infections by a wide range of viral, bacterial, and fungal organisms. SCID has multiple forms, which have been reviewed in greater detail elsewhere. At this writing, at least 10 genes have been identified with abnormalities known to result in SCID. X-linked SCID, the most common form, is due to a mutation in the common γ chain of the receptor for IL-2 and several other cytokines (γ _c ). The other known forms of SCID are either known or presumed to be autosomal recessive. These include a deficiency of adenosine deaminase, a purine salvage pathway enzyme; a deficiency in Janus kinase 3 (Jak3), a cytokine receptor signaling molecule; and a defect in the α chain of the IL-7 receptor, IL-7Rα. Mutation of one of at least six different genes whose products play a role in T-cell receptor or immunoglobulin gene recombination or T-cell receptor signaling, including RAG1, RAG2, Artemis, DNA ligase IV, CD3-δ, and CD3-ε, also results in SCID. Additionally, SCID is caused by a mutation in CD45, a phosphatase that regulates signaling thresholds in immune cells. Flow cytometry analysis of lymphocyte markers reveals very low to absent B- and T-cell numbers in patients with most forms of SCID.

Long-term management of patients with SCID involves modalities employed in both B- and T-cell disorders, including prophylaxis against P. jiroveci pneumonia, avoidance of live viral vaccines, and immunoglobulin replacement therapy. Bone marrow transplantation from HLA-matched siblings has corrected the defect successfully in some cases and is considered the current treatment of choice. Adenosine deaminase deficiency is of historical interest in that it is the first heritable disorder for which gene therapy was attempted, although early success was limited. Approaches using retroviral-based gene therapy for X-linked SCID initially appeared to be successful. However, at least three patients developed lymphoproliferative disorders similar to lymphocytic leukemia, with malignant cells demonstrating insertion of the vector into the promoter or first intron of a proto-oncogene, LMO2.

Because the earliest possible treatment with stem cell transplantation often is the key to meaningful survival in patients with SCID, newborn screening programs for SCID based on assays of bloodspots have been introduced in several states and in some countries. These assays are based on quantitation of T-cell receptor excision circles—circular fragments of DNA that are a by-product of T-cell receptor rearrangement during fetal development.

Common variable immunodeficiency.

CVID is a heterogeneous group of combined immunodeficiencies that differ from most other primary immunodeficiencies in that they often present in the second or third decade of life, although they may present at any age. Patients with CVID characteristically have normal or only modestly decreased numbers of circulating B cells; low, but not absent, levels of IgG, IgM, and IgA; poor responsiveness to antigens; and abnormal T-lymphocyte function.

Although both T- and B-cell abnormalities often can be demonstrated, the clinical presentation usually is most like that in patients with humoral or B-cell defects (i.e., recurrent bacterial otitis media and sinopulmonary infections). Occasionally, these patients also have infections with organisms more common in persons with T-lymphocyte abnormalities, such as Pneumocystis, recurrent herpes simplex virus, and herpes zoster virus infections. Chronic gastrointestinal problems may be due to G. lamblia or other intestinal pathogens. CVID patients are prone to nodular lymphoid hyperplasia, autoimmune diseases, and malignancies.

Several gene mutations have been found in patients with CVID. These include the genes encoding for CD19, transmembrane activator and CAML interactor (TACI), receptor for B-cell activating factor of the TNF receptor family (BAFF-R), and inducible costimulatory molecule (ICOS).

Patients with CVID usually can benefit from therapy with IVIG, which reduces the incidence of acute infections. However, most patients with CVID, even some of those who undergo long-term treatment with IVIG, develop chronic sinopulmonary disease.

Hyper–immunoglobulin M syndrome.

Immunoglobulin deficiency with increased IgM is characterized by low levels of IgG, IgA, and IgE but normal to increased levels of IgM in the circulation and normal numbers of circulating B cells. The disorder is caused by an intrinsic T-cell abnormality that impairs class switching from IgM to other isotypes. The basis for the various genetic forms of this defect is in one of several possible defects that involve interactions between CD40 on B cells and CD40 ligand (CD40L) on T cells. B cells from patients with the hyper-IgM syndrome only make IgM antibody, and their B cells only express surface IgM and IgD. The originally described and most common form of the defect is X-linked recessive and results from a mutation in the gene encoding CD40L, a protein expressed transiently on activated T cells. More recently described autosomal recessive forms of this disorder involve mutations either in CD40 itself or in a CD40-activated RNA editing enzyme, activation-induced cytidine deaminase. Other cells express surface CD40, thus neutropenia and the increased incidence of infections caused by Pneumocystis and of malignancies in patients with hyper-IgM syndrome also may be the result of impaired cell interactions via CD40.

Clinically, hyper-IgM syndrome is manifested by recurrent bacterial infections, especially of the respiratory tract. Such persons are susceptible to the same kinds of recurrent pyogenic infections associated with other immunoglobulin deficiencies, as well as to infections with organisms more commonly encountered in patients with T-cell defects (e.g., P. jiroveci ). Some patients with this syndrome have recurrent diarrhea as a result of G. lamblia and Cryptosporidium infection that is severe enough to require parenteral nutrition. About half of patients have persistent or recurrent neutropenia. Those with autoantibodies may have thrombocytopenia, hemolytic anemia, nephritis, hypothyroidism, or arthritis.

The diagnosis of X-linked hyper-IgM syndrome may be established by using immunofluorescence to document absent expression of CD40L on activated T cells, absent CD40 expression on B cells, or demonstrating a mutation in one of the genes encoding CD40, CD40L, or the enzyme activation-induced cytidine deaminase.

Treatment of patients with the hyper-IgM syndrome with IVIG usually results in significant clinical benefit.

Wiskott-Aldrich syndrome.

Wiskott-Aldrich syndrome is a rare X-linked disorder characterized by thrombocytopenia, small platelets, eczema, recurrent infections, autoimmune disease, and hematologic malignancy. Although both T- and B-cell compartments are affected, it presents phenotypically more like a B-cell or humoral deficiency, with recurrent otitis media, sinusitis, and pneumonia. The defect involves a mutation in the gene encoding a signaling molecule, Wiskott-Aldrich syndrome protein, which regulates “immune synapse” formation and IL-2 production.

Ataxia-telangiectasia.

Ataxia-telangiectasia is a rare autosomal recessive disorder characterized by progressive cerebellar dysfunction with ataxia, oculocutaneous telangiectasias, recurrent bacterial respiratory infections such as those seen in humoral deficiencies, and a predilection to hematologic malignancy and breast cancer. Serum immunoglobulins often are low, as are lymphocyte counts. The disorder is due to a mutation in the ATM gene, located on chromosome 11. This gene encodes a serine-threonine kinase that is important in cell cycle regulation and double-stranded DNA repair, and it influences expression of BRCA1 genes associated with breast cancer. The risk for breast cancer in patients with ataxia-telangiectasia is increased 15- to 20-fold over that in the general population. Heterozygotes for missense mutations of the ATM gene can be affected because copies of the abnormal protein can interfere with function of the wild-type protein.

General features of phagocyte disorders.

The most frequently encountered reminder of the importance of an adequate supply of well-functioning phagocytes comes from patients who develop chemotherapy-associated neutropenia and are thus at high risk for bacterial and fungal infections. The qualitative disorders of phagocyte function discussed in this section result in similar susceptibilities to these infections, either because the circulating cells are unable to migrate to an infected site or because, once having migrated to the infected tissue, they are unable to effect normal microbicidal activity. There is some overlap among the types of infectious complications associated with disorders of migration versus killing. However, as a rule, defects of neutrophil migration tend to be associated with infections at skin, subcutaneous tissue, and mucous membrane sites. In contrast, killing defects are more likely to result in infections of deeper soft tissues and internal organs, although skin infections are not uncommon.

Intrinsic disorders of cell migration

Extrinsic or secondary defects of polymorphonuclear leukocyte migration

Defects in phagocyte microbicidal activity.

As described earlier, the broad array of available phagocyte microbicidal mechanisms may be divided into oxygen-dependent and oxygen-independent mechanisms. To date, no specific deficiency of any oxygen-independent microbicidal mechanism has been described. Thus this section is concerned mainly with the known deficiencies of oxygen-dependent microbicidal mechanisms of phagocytes, especially chronic granulomatous disease, the prototypical defect in this group. PMNs, monocytes, and the fixed phagocytes of the reticuloendothelial system generally share in the deficient microbicidal activity observed.

Chronic granulomatous disease.

Chronic granulomatous disease (CGD) was one of the earliest syndromes of phagocyte dysfunction to be characterized. It is recognized now to be a family of biochemically and genetically heterogeneous disorders of distinct components of the phagocyte NADPH oxidase complex (see Fig. 2.3 and related text) that result in the inability of phagocytes to generate superoxide anion and other reactive oxygen species. Organisms that produce catalase pose a special problem for patients with this disease. This encompasses a broad range of pathogens, including staphylococci, gram-negative enteric bacteria, Pseudomonas spp., yeast, fungi, Nocardia spp., and numerous other pathogenic species. Most microorganisms produce H ₂ O ₂ , which might be used, even by the CGD phagocyte, as an effective microbicidal weapon because it feeds into the sequence of oxidant reactions downstream from the defective oxidase enzyme (see Fig. 2.3 ). Organisms that produce catalase are able to survive within these deficient cells because catalase is an enzyme that degrades H ₂ O ₂ to oxygen and water. Infections with catalase-negative bacteria, such as Streptococcus, Haemophilus, and Neisseria spp., do not occur with increased frequency in CGD patients, and these organisms are killed normally in vitro by CGD phagocytes. Phagocyte functions not directly related to oxidative mechanisms of intracellular killing, including adherence, chemotaxis, phagocytosis, and degranulation, usually are normal.

The genetic defect in CGD may be inherited by either X-linked recessive or autosomal recessive mechanisms. In the report of a registry of 368 patients with CGD in the United States, more than two-thirds of the patients had the X-linked recessive form with absent gp91 ^phox , the larger subunit of the cytochrome b ₅₅₈ ; about 12% had an autosomal recessive form with absent cytosolic p47 ^phox ; and fewer than 5% each had autosomal recessive disease with absent cytosolic p67 ^phox or absence of p22 ^phox , the smaller subunit of the cytochrome b ₅₅₈ . Approximately 12% had an unknown genetic form of the disease. A single individual with an autosomal recessive form of CGD due to mutations in the cytosolic p40 ^phox has been reported. About 5% of patients with CGD have normal levels of an abnormal protein that is inactive, and at least 410 different mutations have been reported to result in CGD. These genetically diverse defects all result in defective function of the oxidase and the characteristic CGD phenotype. In the female obligate carriers of X-linked CGD, the proportion of cells that express the defect usually is between 35% and 65%, depending on the proportion of cells in which random inactivation of the normal versus the affected X chromosome occurs. Overall, patients with X-linked disease have more severe courses and experience higher yearly death rates than patients with autosomal recessive forms of the disease.

Patients with CGD experience recurrent serious bacterial and fungal infections, usually beginning in the first few months of life. S. aureus and gram-negative bacilli, especially Serratia marcescens and Burkholderia cepacia, are the most common causes of infection in patients with CGD. Fungi, especially Aspergillus spp., also are prominent etiologic agents, and infections caused by Aspergillus are the most common cause of death in these patients. Granuloma formation at infected sites is one of the histologic hallmarks of this disorder. Pulmonary infections and their complications have been the reported cause of death in up to 50% of these patients in some series, and Aspergillus predominates. These infections often are protracted and respond slowly to appropriate antibiotic therapy. Progression to lung abscess, empyema, or both occurs in about 20% of patients with CGD with pneumonia. Liver abscesses occur in about half of patients and may be recurrent. The hepatosplenomegaly common in CGD may result from these infections but more likely results from chronic infections at various sites with systemic lymphoid hyperplasia. Osteomyelitis occurs in about one third of patients. In contrast to normal children, in whom this infection usually involves the metaphyseal area of long bones, patients with CGD more often develop infections of the small bones of the hands and feet. In normal children, S. aureus is the most common etiologic agent and causes a significant proportion of cases in CGD. However, gram-negative bacilli and Aspergillus appear to be the predominant etiologies, and other agents, including Nocardia, also may be important etiologic agents of bone infection in CGD. Skin infections in this disorder may include pyoderma, purulent dermatitis, and cutaneous or subcutaneous abscesses and often are preceded by a chronic eczematoid skin rash.

Although localized infections are the rule in patients with CGD, these patients also may develop septicemia. The most common cause of septicemia in most series has been Salmonella, but other gram-negative enteric bacilli also have been prominent. Of note, S. aureus is a proportionally less common cause of septicemia in these patients.

Granuloma formation adjacent to hollow viscera in patients with CGD can produce clinically significant obstruction, including obstruction of the gastric outlet, esophagus, small intestine, and ureters. This complication usually responds to treatment with corticosteroids.

CGD should be suspected in patients with a history of recurrent indolent infections caused by catalase-positive organisms such as those described earlier, especially if granulomas are found in biopsy specimens of lymph nodes or other tissues. Confirmation of the diagnosis usually rests on the demonstration of an absent or nearly absent oxidative metabolic burst in the patient’s phagocytes. This can be detected classically by the slide NBT test or by various other measurements of oxidative burst activity, most recently by flow cytometry of PMNs loaded with oxidant-sensitive fluorescent dyes. Fig. 2.10A is an example of the slide NBT test in an X-linked carrier; Fig. 2.10B is an idealized set of flow cytometry histograms with typical patterns for a normal control, a patient with CGD, and both X-linked and autosomal recessive carriers. Prenatal diagnosis has been achieved by the use of the slide NBT test with blood from placental vessels obtained at fetoscopy.

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