Introduction to the Immune System (The Immune System in Health and Disease) (Rheumatology) Part 5

Molecular Basis of T Cell Recognition of Antigen

The TCR for antigen is a complex of molecules consisting of an antigen-binding heterodimer of either aß or γδ chains noncovalently linked with five CD3 subunits (γ, δ, ε, ζ, and η) (Fig. 1-7). The CD3 ζ chains are either disulfide-linked homodimers (CD3^2) or disulfide-linked heterodimers composed of one ζ chain and one η chain. TCRaß or TCRγδ molecules must be associated with CD3 molecules to be inserted into the T cell surface membrane, TCRa being paired with TCRß and TCRγ being paired with TCRδ. Molecules of the CD3 complex mediate transduction of T cell activation signals via TCRs, while TCRa and -ß or -γ and -δ molecules combine to form the TCR antigen-binding site.

The a, ß, γ, and δ TCR for antigen molecules have amino acid sequence homology and structural similarities to immunoglobulin heavy and light chains and are members of the immunoglobulin gene superfamily of molecules. The genes encoding TCR molecules are encoded as clusters of gene segments that rearrange during the course of T cell maturation. This creates an efficient and compact mechanism for housing the diversity requirements of antigen receptor molecules. The TCRa chain is on chromosome 14 and consists of a series ofV (vari-able),J (joining), and C (constant) regions.The TCRß chain is on chromosome 7 and consists of multiple V, D (diversity),J, and C TCRß loci. The TCRγ chain is on chromosome 7, and the TCRδ chain is in the middle of the TCRa locus on chromosome 14.Thus, molecules of the TCR for antigen have constant (framework) and variable regions, and the gene segments encoding the a, ß, γ, and δ chains of these molecules are recombined and selected in the thymus, culminating in synthesis of the completed molecule. In both T and B cell precursors (see below), DNA rearrangements of antigen receptor genes involve the same enzymes, recombinase activating gene (RAG)1 and RAG2, both DNA-dependent protein kinases.


TCR diversity is created by the different V, D, and J segments that are possible for each receptor chain by the many permutations ofV, D, and J segment combinations, by “N-region diversification” due to the addition of nucleotides at the junction of rearranged gene segments, and by the pairing of individual chains to form a TCR dimer.As T cells mature in the thymus, the repertoire of antigen-reactive T cells is modified by selection processes that eliminate many autoreactive T cells, enhance the proliferation of cells that function appropriately with self-MHC molecules and antigen, and allow T cells with nonproductive TCR rearrangements to die.

TCRaß cells do not recognize native protein or carbohydrate antigens. Instead, T cells recognize only short (—9—13 amino acids) peptide fragments derived from protein antigens taken up or produced in APCs. Foreign antigens may be taken up by endocytosis into acidified intracellular vesicles or by phagocytosis and degraded into small peptides that associate with MHC class II molecules (exogenous antigen-presentation pathway). Other foreign antigens arise endogenously in the cytosol (such as from replicating viruses) and are broken down into small peptides that associate with MHC class I molecules (endogenous antigen-presenting pathway). Thus, APCs proteolytically degrade foreign proteins and display peptide fragments embedded in the MHC class I or II antigen-recognition site on the MHC molecule surface, where foreign peptide fragments are available to bind to TCRaß or TCRγδ chains of reactive T cells. CD4 molecules act as adhesives and, by direct binding to MHC class II (DR, DQ, or DP) molecules, stabilize the interaction of TCR with peptide antigen (Fig. 1-7). Similarly, CD8 molecules also act as adhesives to stabilize the TCR-antigen interaction by direct CD8 molecule binding to MHC class I (A, B, or C) molecules.

Signaling through the T cell receptor. Activation signals are mediated via immunoreceptor tyrosine-based activation (ITAM) sequences in LAT and CD3 chains (blue bars) that bind to enzymes and transduce activation signals to the nucleus via the indicated intracellular activation pathways. Ligation of the T-cell receptor (TCR) by MHC complexed with antigen results in sequential activation of LCK and g-chain-associated protein kinase of 70 kDa (ZAP70). ZAP70 phos-phorylates several downstream targets, including LAT (linker for activation of T cells) and SLP76 [SCR homology 2 (SH2) domain-containing leukocyte protein of 76 kDa]. SLP76 is recruited to membrane-bound LAT through its constitutive interaction with GADS (GRB2-related adaptor protein). Together, SLP76 and LAT nucleate a multimolecular signaling complex, which induces a host of downstream responses, including calcium flux, mitogen-activated protein kinase (MAPK) activation, integrin activation, and cytoskeletal reorganization.

FIGURE 1-7

Signaling through the T cell receptor. Activation signals are mediated via immunoreceptor tyrosine-based activation (ITAM) sequences in LAT and CD3 chains (blue bars) that bind to enzymes and transduce activation signals to the nucleus via the indicated intracellular activation pathways. Ligation of the T-cell receptor (TCR) by MHC complexed with antigen results in sequential activation of LCK and g-chain-associated protein kinase of 70 kDa (ZAP70). ZAP70 phos-phorylates several downstream targets, including LAT (linker for activation of T cells) and SLP76 [SCR homology 2 (SH2) domain-containing leukocyte protein of 76 kDa]. SLP76 is recruited to membrane-bound LAT through its constitutive interaction with GADS (GRB2-related adaptor protein). Together, SLP76 and LAT nucleate a multimolecular signaling complex, which induces a host of downstream responses, including calcium flux, mitogen-activated protein kinase (MAPK) activation, integrin activation, and cytoskeletal reorganization.

Antigens that arise in the cytosol and are processed via the endogenous antigen-presentation pathway are cleaved into small peptides by a complex of proteases called the proteasome. From the proteasome, antigen peptide fragments are transported from the cytosol into the lumen of the endoplasmic reticulum by a heterodimeric complex termed transporters associated with antigen processing, or TAP proteins. There, MHC class I molecules in the endoplasmic reticulum membrane physically associate with processed cytosolic peptides. Following peptide association with class I molecules, peptide-class I complexes are exported to the Golgi apparatus, and then to the cell surface, for recognition by CD8+ T cells.

Antigens taken up from the extracellular space via endocytosis into intracellular acidified vesicles are degraded by vesicle proteases into peptide fragments.

Intracellular vesicles containing MHC class II molecules fuse with peptide-containing vesicles, thus allowing peptide fragments to physically bind to MHC class II molecules. Peptide-MHC class II complexes are then transported to the cell surface for recognition by CD4+ T cells (Chap. 2).

Whereas it is generally agreed that the TCRαß receptor recognizes peptide antigens in the context of MHC class I or class II molecules, lipids in the cell wall of intracellular bacteria such as M. tuberculosis can also be presented to a wide variety of T cells, including subsets of CD4, CD8 TCRαß T cells, TCRyδ T cells, and a subset of CD8+ TCRαß T cells. Importantly, bacterial lipid antigens are not presented in the context of MHC class I or II molecules, but rather are presented in the context of MHC-related CD1 molecules. Some yδ T cells that recognize lipid antigens via CD1 molecules have very restricted TCR usage, do not need antigen priming to respond to bacterial lipids, and may actually be a form of innate rather than acquired immunity to intracellular bacteria.

Just as foreign antigens are degraded and their peptide fragments presented in the context of MHC class I or class II molecules on APCs, endogenous self-proteins also are degraded and self-peptide fragments are presented to T cells in the context of MHC class I or class II molecules on APCs. In peripheral lymphoid organs, there are T cells that are capable of recognizing self-protein fragments but normally are anergic or tolerant, i.e., nonresponsive to self-antigenic stimulation, due to lack of selfantigen upregulating APC co-stimulatory molecules such as B7-1 (CD80) and B7-2 (CD86) (see below).

Once engagement of mature T cell TCR by foreign peptide occurs in the context of self-MHC class I or class II molecules, binding of non-antigen-specific adhesion ligand pairs such as CD54-CD11/CD18 and CD58-CD2 stabilizes MHC peptide-TCR binding, and the expression of these adhesion molecules is upregu-lated (Fig. 1-7). Once antigen ligation of the TCR occurs, the T cell membrane is partitioned into lipid membrane microdomains, or lipid rafts, that coalesce the key signaling molecules TCR/CD3 complex, CD28, CD2, LAT (linker for activation of T cells), intracellular activated (dephosphorylated) src family protein tyrosine kinases (PTKs), and the key CD3ζ-associated protein-70 (ZAP-70) PTK (Fig. 1-7). Importantly, during T cell activation, the CD45 molecule, with protein tyrosine phosphatase activity, is partitioned away from the TCR complex to allow activating phosphorylation events to occur. The coalescence of signaling molecules of activated T lymphocytes in microdomains has suggested that T cell-APC interactions can be considered immunologic synapses, analogous in function to neuronal synapses.

After TCR-MHC binding is stabilized, activation signals are transmitted through the cell to the nucleus and lead to the expression of gene products important in mediating the wide diversity of T cell functions such as the secretion of IL-2.The TCR does not have intrinsic signaling activity but is linked to a variety of signaling pathways via immunoreceptor tyrosine-based activation motifs (ITAMs) expressed on the various CD3 chains that bind to proteins that mediate signal transduction. Each of the pathways results in the activation of particular transcription factors that control the expression of cytokine and cytokine receptor genes. Thus, antigen-MHC binding to the TCR induces the activation of the src family of PTKs, fyn and lck (lck is associated with CD4 or CD8 co-stimulatory molecules); phosphorylation of CD3ζ chain; activation of the related tyrosine kinases ZAP-70 and syk; and downstream activation of the calcium-dependent calcineurin pathway, the ras pathway, and the protein kinase C pathway. Each of these pathways leads to activation of specific families of transcription factors (including NF-AT, fos and jun, and rel/NF-KB) that form heteromultimers capable of inducing expression of IL-2, IL-2 receptor, IL-4,TNF^, and other T cell mediators.

In addition to the signals delivered to the T cell from the TCR complex and CD4 and CD8, molecules on the T cell such as CD28 and inducible co-stimulator (ICOS) and molecules on dendritic cells such as B7-1 (CD80) and B7-2 (CD86) also deliver important co-stimulatory signals that upregulate T cell cytokine production and are essential for T cell activation. If signaling through CD28 or ICOS does not occur, or if CD28 is blocked, the T cell becomes anergic rather than activatedm.

T Cell Superantigens

Conventional antigens bind to MHC class I or II molecules in the groove of the αβ heterodimer and bind to T cells via the V regions of the TCRα and -β chains. In contrast, superantigens bind directly to the lateral portion of the TCRß chain and MHC class II β chain and stimulate T cells based solely on the Vß gene segment utilized independent of the D,J, and να sequences present. Superantigens are protein molecules capable of activating up to 20% of the peripheral T cell pool, whereas conventional antigens activate <1 in 10,000 T cells.T cell superantigens include staphylococcal enterotoxins and other bacterial products. Superantigen stimulation of human peripheral T cells occurs in the clinical setting of staphylococcal toxic shock syndrome, leading to massive overproduction of T cell cytokines that leads to hypotension and shock.

B Cells

Mature B cells constitute 10-15% of human peripheral blood lymphocytes, 20-30% of lymph node cells, 50% of splenic lymphocytes, and ~10% of bone marrow lymphocytes. B cells express on their surface intramembrane immunoglobulin (Ig) molecules that function as B cell receptors (BCRs) for antigen in a complex of Ig-associ-ated α and β signaling molecules with properties similar to those described in T cells (Fig. 1-8). Unlike T cells, which recognize only processed peptide fragments of conventional antigens embedded in the notches of MHC class I and class II antigens of APCs, B cells are capable of recognizing and proliferating to whole unprocessed native antigens via antigen binding to B cell surface Ig (sIg) receptors. B cells also express surface receptors for the Fc region of IgG molecules (CD32) as well as receptors for activated complement components (C3d or CD21, C3b or CD35).The primary function of B cells is to produce antibodies. B cells also serve as APCs and are highly efficient at antigen processing. Their antigen-presenting function is enhanced by a variety of cytokines. Mature B cells are derived from bone marrow precursor cells that arise continuously throughout life (Fig. 1-6).

B lymphocyte development can be separated into antigen-independent and antigen-dependent phases.

B cell receptor (BCR) activation results in the sequential activation of protein tyrosine kinases, which results in the formation of a signaling complex and activation of downstream pathways as shown. Whereas SLP76 is recruited to the membrane through GADS and LAT, the mechanism of SLP65 recruitment is unclear. Studies have indicated two mechanisms: (a) direct binding by the SH2 domain of SLP65 to immunoglobulin (Ig) of the BCR complex or (b) membrane recruitment through a leucine zipper in the amino terminus of SLP65 and an unknown binding partner. ADAP, adhesion-and degranulation-promoting adaptor protein; AP1, activator protein 1; BTK, Bruton’s tyrosine kinase; DAG, diacylglyc-erol; GRB2, growth-factor-receptor-bound protein 2; HPK1, haematopoietic progenitor kinase 1; InsP3, inositol-1,4,5-trisphosphate; ITK, interleukin-2-inducible T-cell kinase; NCK, noncatalytic region of tyrosine kinase; NF-B, nuclear factor B; PKC, protein kinase C; PLC, phospholipase C; PtdIns(4,5)P2, phosphatidylinositol-4,5-bisphosphate; RAS-GRP, RAS guanyl-releasing protein; SOS, son of sevenless homologue; SYK, spleen tyrosine kinase.

FIGURE 1-8

B cell receptor (BCR) activation results in the sequential activation of protein tyrosine kinases, which results in the formation of a signaling complex and activation of downstream pathways as shown. Whereas SLP76 is recruited to the membrane through GADS and LAT, the mechanism of SLP65 recruitment is unclear. Studies have indicated two mechanisms: (a) direct binding by the SH2 domain of SLP65 to immunoglobulin (Ig) of the BCR complex or (b) membrane recruitment through a leucine zipper in the amino terminus of SLP65 and an unknown binding partner. ADAP, adhesion-and degranulation-promoting adaptor protein; AP1, activator protein 1; BTK, Bruton’s tyrosine kinase; DAG, diacylglyc-erol; GRB2, growth-factor-receptor-bound protein 2; HPK1, haematopoietic progenitor kinase 1; InsP3, inositol-1,4,5-trisphosphate; ITK, interleukin-2-inducible T-cell kinase; NCK, noncatalytic region of tyrosine kinase; NF-B, nuclear factor B; PKC, protein kinase C; PLC, phospholipase C; PtdIns(4,5)P2, phosphatidylinositol-4,5-bisphosphate; RAS-GRP, RAS guanyl-releasing protein; SOS, son of sevenless homologue; SYK, spleen tyrosine kinase.

Antigen-independent B cell development occurs in primary lymphoid organs and includes all stages of B cell maturation up to the sIg+ mature B cell. Antigen-dependent B cell maturation is driven by the interaction of antigen with the mature B cell sIg, leading to memory B cell induction, Ig class switching, and plasma cell formation. Antigen-dependent stages of B cell maturation occur in secondary lymphoid organs, including lymph node, spleen, and gut Peyer’s patches. In contrast to the T cell repertoire that is generated intrathymically before contact with foreign antigen, the repertoire of B cells expressing diverse antigen-reactive sites is modified by further alteration of Ig genes after stimulation by antigen—a process called somatic mutation—which occurs in lymph node germinal centers.

During B cell development, diversity of the antigen-binding variable region of Ig is generated by an ordered set of Ig gene rearrangements that are similar to the rearrangements undergone by TCR a, ß, γ, and δ genes. For the heavy chain, there is first a rearrangement of D segments to J segments, followed by a second rearrangement between a V gene segment and the newly formed D-J sequence; the C segment is aligned to the V-D-J complex to yield a functional Ig heavy chain gene (V-D-J-C). During later stages, a functional κ or λ light chain gene is generated by rearrangement of a V segment to a J segment, ultimately yielding an intact Ig molecule composed of heavy and light chains.

The process of Ig gene rearrangement is regulated and results in a single antibody specificity produced by each B cell, with each Ig molecule comprising one type of heavy chain and one type of light chain. Although each B cell contains two copies of Ig light and heavy chain genes, only one gene of each type is productively rearranged and expressed in each B cell, a process termed allelic exclusion.

There are —300 VK genes and 5 JK genes, resulting in the pairing ofVK and JK genes to create >1500 different light chain combinations. The number of distinct κ light chains that can be generated is increased by somatic mutations within the VK and JK genes, thus creating large numbers of possible specificities from a limited amount of germ-line genetic information. As noted above, in heavy chain Ig gene rearrangement, the VH domain is created by the joining of three types of germ-line genes called VH, DH, and JH, thus allowing for even greater diversity in the variable region of heavy chains than of light chains.

The most immature B cell precursors (early pro-B cells) lack cytoplasmic Ig (cIg) and sIg (Fig. 1-6). The large pre-B cell is marked by the acquisition of the surface pre-BCR composed of μ heavy (H) chains and a pre-B light chain, termed ψLC. "LC is a surrogate light chain receptor encoded by the nonrearranged V pre-B and the λ5 light chain locus (the pre-BCR). Pro- and pre-B cells are driven to proliferate and mature by signals from bone marrow stroma—in particular, IL-7. Light chain rearrangement occurs in the small pre-B cell stage such that the full BCR is expressed at the immature B cell stage. Immature B cells have rearranged Ig light chain genes and express sIgM. As immature B cells develop into mature B cells, sIgD is expressed as well as sIgM. At this point, B lineage development in bone marrow is complete, and B cells exit into the peripheral circulation and migrate to secondary lymphoid organs to encounter specific antigens.

Random rearrangements of Ig genes occasionally generate self-reactive antibodies, and mechanisms must be in place to correct these mistakes. One such mechanism is BCR editing, whereby autoreactive BCRs are mutated to not react with self-antigens. If receptor editing is unsuccessful in eliminating autoreactive B cells, then autoreactive B cells undergo negative selection in the bone marrow through induction of apoptosis after BCR engagement of self-antigen.

After leaving the bone marrow, B cells populate peripheral B cell sites, such as lymph node and spleen, and await contact with foreign antigens that react with each B cell’s clonotypic receptor. Antigen-driven B cell activation occurs through the BCR, and a process known as somatic hypermutation takes place whereby point mutations in rearranged H- and L-genes give rise to mutant sIg molecules, some of which bind antigen better than the original sIg molecules. Somatic hypermutation, therefore, is a process whereby memory B cells in peripheral lymph organs have the best binding, or the highest-affinity antibodies. This overall process of generating the best antibodies is called affinity maturation of antibody.

Lymphocytes that synthesize IgG, IgA, and IgE are derived from sIgM+, sIgD+ mature B cells. Ig class switching occurs in lymph node and other peripheral lymphoid tissue germinal centers. CD40 on B cells and CD40 ligand on T cells constitute a critical co-stimulatory receptor-ligand pair of immune-stimulatory molecules. Pairs of CD40+ B cells and CD40 ligand+ T cells bind and drive B cell Ig switching via T cell-produced cytokines such as IL-4 and TGF-ß. IL-1, -2, -4, -5, and -6 synergize to drive mature B cells to proliferate and differentiate into Ig-secreting cells.

Humoral Mediators of Adaptive Immunity: Immunoglobulins

Immunoglobulins are the products of differentiated B cells and mediate the humoral arm of the immune response. The primary functions of antibodies are to bind specifically to antigen and bring about the inactivation or removal of the offending toxin, microbe, parasite, or other foreign substance from the body. The structural basis of Ig molecule function and Ig gene organization has provided insight into the role of antibodies in normal protective immunity, pathologic immune-mediated damage by immune complexes, and autoantibody formation against host determinants.

All immunoglobulins have the basic structure of two heavy and two light chains (Fig. 1-8). Immunoglobulin isotype (i.e., G, M,A, D, E) is determined by the type of Ig heavy chain present. IgG and IgA isotypes can be divided further into subclasses (G1, G2, G3, G4, and A1, A2) based on specific antigenic determinants on Ig heavy chains. The characteristics of human immunoglobulins are outlined in (Table 1-11).The four chains are covalently linked by disulfide bonds. Each chain is made up of a V region and C regions (also called domains), themselves made up of units of—110 amino acids. Light chains have one variable (VL) and one constant (CL) unit; heavy chains have one variable unit (VH) and three or four constant (CH) units, depending on isotype. As the name suggests, the constant, or C, regions of Ig molecules are made up of homologous sequences and share the same primary structure as all other Ig chains of the same isotype and subclass. Constant regions are involved in biologic functions of Ig molecules. The CH2 domain of IgG and the CH4 units of IgM are involved with the binding of the C1q portion of C1 during complement activation. The CH region at the carboxy-terminal end of the IgG molecule, the Fc region, binds to surface Fc receptors (CD16, CD32, CD64) of macrophages, dendritic cells, NK cells, B cells, neutrophils, and eosinophils.

Variable regions (VL and VH) constitute the antibody-binding (Fab) region of the molecule.Within the VL and VH regions are hypervariable regions (extreme sequence variability) that constitute the antigen-binding site unique to each Ig molecule. The idiotype is defined as the specific region of the Fab portion of the Ig molecule to which antigen binds. Antibodies against the idiotype portion of an antibody molecule are called antiidiotype antibodies. The formation of such antibodies in vivo during a normal B cell antibody response may generate a negative (or “off”) signal to B cells to terminate antibody production.

TABLE 1-11

PHYSICAL, CHEMICAL, AND BIOLOGIC PROPERTIES OF HUMAN IMMUNOGLOBULINS

PROPERTY

IgG

IgA

IgM

IgD

IgE

Usual molecular form

Monomer

Monomer,

dimer

Pentamer,

hexamer

Monomer

Monomer

Other chains

None

J chain, SC

J chain

None

None

Subclasses

G1, G2, G3, G4

A1, A2

None

None

None

Heavy chain allotypes

Gm (=30)

No A1, A2m (2)

None

None

None

Molecular mass, kDa

150

160, 400

950, 1150

175

190

Sedimentation constant, Sw20

6.6S

7S, 11S

19S

7S

8S

Carbohydrate content, %

3

7

10

9

13

Serum level in average adult, mg/mL

9.5-12.5

1.5-2.6

0.7-1.7

0.04

0.0003

Percentage of total serum Ig

75-85

7-15

5-10

0.3

0.019

Serum half-life, days

23

6

5

3

2.5

Synthesis rate, mg/kg per d

33

65

7

0.4

0.016

Antibody valence

2

2, 4

10, 12

2

2

Classical complement activation

+(G1, 2?, 3)

-

++

-

-

Alternate complement activation

+(G4)

+

-

+

-

Binding cells via Fc

Macrophages, neutrophils, large granular lymphocytes

Lymphocytes

Lymphocytes

None

Mast cells, basophils, B cells

Biologic properties

Placental transfer, secondary Ab for most antipathogen responses

Secretory

immunoglobulin

Primary Ab responses

Marker

for

mature B cells

Allergy,

antiparasite

responses

IgG constitutes ~75-85% of total serum immunoglobulin. The four IgG subclasses are numbered in order of their level in serum, IgG1 being found in greatest amounts and IgG4 the least. IgG subclasses have clinical relevance in their varying ability to bind macrophage and neutrophil Fc receptors and to activate complement (Table 1-11). Moreover, selective deficiencies of certain IgG subclasses give rise to clinical syndromes in which the patient is inordinately susceptible to bacterial infections. IgG antibodies are frequently the predominant antibody made after rechallenge of the host with antigen (secondary antibody response).

IgM antibodies normally circulate as a 950-kDa pentamer with 160-kDa bivalent monomers joined by a molecule called the J chain, a 15-kDa nonimmunoglobulin molecule that also effects polymerization of IgA molecules. IgM is the first immunoglobulin to appear in the immune response (primary antibody response) and is the initial type of antibody made by neonates. Membrane IgM in the monomeric form also functions as a major antigen receptor on the surface of mature B cells (Fig. 1-8). IgM is an important component of immune complexes in autoimmune diseases. For example, IgM antibodies against IgG molecules (rheumatoid factors) are present in high titers in rheumatoid arthritis, other collagen diseases, and some infectious diseases (subacute bacterial endocarditis).

IgA constitutes only 7-15% oftotal serum immunoglobulin but is the predominant class of immunoglobulin in secretions. IgA in secretions (tears, saliva, nasal secretions, gastrointestinal tract fluid, and human milk) is in the form of secretory IgA (sIgA), a polymer consisting of two IgA monomers, ajoining molecule, again called theJ chain, and a glycoprotein called the secretory protein. Of the two IgA subclasses, IgA1 is primarily found in serum, whereas IgA2 is more prevalent in secretions. IgA fixes complement via the alternative complement pathway and has potent antiviral activity in humans by prevention ofvirus binding to respiratory and gastrointestinal epithelial cells.

IgD is found in minute quantities in serum and, together with IgM, is a major receptor for antigen on the B cell surface. IgE, which is present in serum in very low concentrations, is the major class of immunoglobulin involved in arming mast cells and basophils by binding to these cells via the Fc region. Antigen cross-linking of IgE molecules on basophil and mast cell surfaces results in release of mediators of the immediate hypersensitivity response (Table 1-11).

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