INTRODUCTION — Extracellular fluids of the interstitium, lymphatics (lymph), and circulatory system (plasma) are protected from microbial contamination by an array of soluble molecules comprising humoral immunity. The humoral immune system possesses both innate and adaptive components, although this topic review will focus on antibodies (also called immunoglobulins), one of the principal adaptive elements. Innate humoral elements, which include germline-encoded, pathogen-associated molecular pattern receptors like complement and C-reactive protein, are reviewed in greater detail separately. (See "Overview and clinical assessment of the complement system" and "Complement pathways" and "An overview of the innate immune system".)
Antibody production — During B cell development in the bone marrow, antibodies are first expressed as cell surface B cell receptors (BCRs) (see "Normal B and T lymphocyte development"). Each developing B cell generates a unique BCR through random rearrangement of variable (V) gene segments, diversity (D) gene segments, and a few joining (J) gene segments, similar to the process that generates the T cell receptor. Hence, the BCR repertoire is theoretically capable of recognizing almost any conceivable molecular target (antigen). Also, due to features that are unique to B cell biology, immunoglobulin genes can be further diversified by random mutations within specialized structures called germinal centers (see 'Germinal centers' below). These genetic modifications increase antibody-antigen binding strength and specificity, a process called affinity maturation. (See "Immunoglobulin genetics".)
Throughout maturation, the B cell lineage is defined by cell surface BCR expression until terminal plasma cell differentiation. Instead of expressing antibodies on the cell surface as BCRs, plasma cells secrete them extracellularly in massive quantities.
Primary and secondary phase responses — The adaptive humoral immune response can be divided into primary and secondary phases (figure 1). During the primary phase, naïve BCRs bind an antigen and become activated. Some activated B cells immediately produce polyreactive, low-affinity antibodies that serve as a stopgap measure to limit microbial replication. Other activated B cells begin a longer process of proliferation and subsequent differentiation into memory B cells. Many memory B cells are long lived and allow for more rapid and efficient secondary-phase responses to subsequent microbial challenges. (See 'Plasma cell and memory B cell differentiation' below.)
Role in innate immunity — Although antibodies are part of the adaptive immune system, a primary function of antibodies is the enhancement of innate immunity, including phagocytic killing. In addition, natural antibodies, which are constitutively produced even in the absence of stimulation, have innate-like qualities like polyreactivity and provide protection against encapsulated organisms. (See 'Antibodies in innate immunity' below.)
PASSIVE HUMORAL IMMUNITY — Antibodies produced in one host can be passively transferred to another and convey meaningful immunity. This occurs normally during fetal development and can be leveraged for treatment in the form of immune globulin and hyperimmune globulins.
During fetal development — Transplacental transfer of maternal immunoglobulin (Ig)G into fetal circulation is an example of passive immunity. This physiologic process, which occurs largely during the third trimester of gestation, is mediated by the neonatal Fc receptor (FcRn) . FcRn is IgG specific, so the other immunoglobulin isotypes do not cross the placenta, and neonatal serum levels of IgA, IgM, and IgE are negligible. (See 'Nonopsonic Fc receptors' below.)
After birth — After birth, neonates begin to passively receive IgA and innate humoral elements via oral intake of colostrum and breast milk. Through these mechanisms, breast milk affords mucosal protection to an infant's gut and, to some extent, the upper respiratory tract [2,3]. Breast milk immunoglobulins are not systemically absorbed through the infant's gastrointestinal tract.
Antibody levels in infants and children — Infants develop the ability to respond to an array of microbial challenges in the first years of life. The figure shows the pattern of serum IgG levels in childhood (figure 2) .
●IgG – Since the half-life of passively transferred IgG is 20 to 30 days, maternal IgG is largely cleared from an infant's circulation by six months of age . At the same time, endogenously produced IgG rises gradually during the first year of life. Since these two processes occur simultaneously, serum IgG concentrations reach a physiologic nadir between the third and the eighth month of life (see "Transient hypogammaglobulinemia of infancy"). Since most maternal-fetal IgG transfer occurs in the third trimester, the nadir occurs earlier in preterm infants and is associated with a lower serum IgG concentration.
●IgM and IgA – IgM production begins in utero, increases rapidly during the first month of life, and then slowly rises thereafter to reach about 70 percent of adult serum concentrations by one year of age . Unlike other immunoglobulins, most IgA is enterically secreted and does not enter systemic circulation. Accordingly, serum IgA concentrations do not necessarily predict total body IgA production, especially in children less than four years of age in whom undetectable serum IgA concentrations are common. (See "Selective IgA deficiency: Clinical manifestations, pathophysiology, and diagnosis", section on 'Normal biology of IgA'.)
Therapeutic applications — Therapies based on passive transfer of antibodies include immune globulin and "hyperimmune globulins."
●Immune globulin is a preparation of IgG raised against a broad array of antigens, which is extracted from the pooled plasma of several thousand screened donors. At lower replacement doses (0.5 g/kg), it is used to prophylax antibody-deficient patients against sinopulmonary infections and bacteremia. At higher doses (1 to 2 g/kg), immune globulin has therapeutically useful anti-inflammatory and immunomodulatory effects. (See "Overview of intravenous immune globulin (IVIG) therapy", section on 'Uses for IVIG'.)
●Hyperimmune globulins, some of which are of animal origin, are mono/oligoclonal immunoglobulins derived from plasma of individuals with high titers of specific antibodies to certain pathogens and/or individuals who have been immunized to specific antigens. Hyperimmune globulins are used for postexposure prophylaxis against several infectious diseases. In addition, Rho(D) immune globulin is used to prevent RhD alloimmunization and reduce the risk of hemolytic disease of the fetus and newborn. (See "Overview of intravenous immune globulin (IVIG) therapy", section on 'Uses for hyperimmune globulin'.)
ACTIVE HUMORAL IMMUNITY — After birth, infants begin to generate endogenous humoral responses. Although the initial steps of B cell development begin in the sterile, fetal environment, antibody production requires naïve B cells to differentiate further via activation signals provided by antigenic and nonantigenic stimuli. (See "Normal B and T lymphocyte development".)
The B cell receptor — During pre-B cell development, the pioneer transcription factor PU.1 coordinates expression of the B cell receptor (BCR) complex, a multi-component cell-surface receptor comprised of the immunoglobulin (Ig) heavy, immunoglobulin light, Ig-alpha, and Ig-beta chains . The heavy and light chains mediate antigen binding, whereas Ig-alpha and Ig-beta interact with Src-family tyrosine kinases through intracellular immunoreceptor tyrosine-based activation motifs (ITAMs).
B cell coreceptors — B cell coreceptors can be divided into those that amplify BCR activation and those that inhibit it. The activating B cell coreceptor is formed by the complement receptor CD21, the intracellular signaling molecule CD19, and CD81. The function of CD81 is unknown.
Inhibitory B cell coreceptors CD22 and Fc-gamma-RIIb contain immunoreceptor tyrosine-based inhibition motifs (ITIMs) that intracellularly interact with Src-family tyrosine kinases to recruit inhibitory molecules.
Activation and signaling — Once two or more BCRs are cross-linked by a multivalent antigen, ITAMs are phosphorylated by Src-family kinases, like Lyn (figure 3). Phosphorylated ITAMs recruit the kinase Syk, which phosphorylates the B cell-linker protein (BLNK) to form a scaffold aiding construction of large multiprotein signaling complexes that incorporate Bruton tyrosine kinase (BTK). BTK phosphorylates phospholipase C-gamma-2 (PLC-gamma-2), which can then hydrolyze the membrane phospholipid phosphatidylinositol 4,5-bisphosphate (PIP2) into inositol triphosphate (IP3) and diacylglycerol (DAG). IP3 and DAG lead to downstream calcium influx, protein kinase C activation, and eventual downstream effects that include translocation of activating transcription factors, like NFAT and NFK-beta, to the nucleus and nuclear disintegration of the transcriptional suppressor BCL6 [6,7].
The activating B cell coreceptor augments BCR activation by recruiting phosphoinositide 3-kinases (PI3K) to the Src-family kinase phosphorylated tail of CD19. PI3K generates phosphatidylinositol (3,4,5)-trisphosphate (PIP3) from PIP2. PIP3 recruits BTK, PLC-gamma-2, phosphoinositide-dependent kinase-1, and protein kinase B (also known as AKT) to the plasma membrane, where their proximity facilitates meaningful interactions . Phosphorylated ITIMs of inhibitory B cell coreceptors recruit and activate inhibitory phosphatases like SH2-containing inositol phosphatase (SHIP). SHIP generates PIP2 from PIP3, essentially reversing the activating effects of PI3K.
Defects causing immunodeficiency — The importance of many of the molecules in the BCR and B cell coreceptor complex has been demonstrated by human primary immunodeficiency disorders. As examples:
●Deficiency of PLC-gamma-2, CD21, CD19, CD81, NFK-beta-1, or NFK-beta-2 leads to hypogammaglobulinemia [12-17]. (See "Pathogenesis of common variable immunodeficiency", section on 'Genetics'.)
Types of antigens — B cell antigens were originally divided into those capable of eliciting antibody production in thymectomized mice lacking T cells (thymus-independent or TI) and antigens that cannot and, hence, are dependent on T cell help (thymus-dependent or TD) . Generally, TD antigens are peptides that can be loaded into major histocompatibility complex (MHC) class II molecules, whereas TI antigens cannot.
Type 1 thymus-independent antigens — Historically, thymus-independent (TI) antigens were further subdivided by their ability to elicit antibody production (type 1) or not (type 2) from Btk-deficient murine B cells . Since Btk is required for proper BCR signaling, it was not surprising that molecules originally described as type 1 TI "antigens" like lipopolysaccharide (LPS) and the immunostimulatory unmethylated cytosine guanine dinucleotide (CpG) DNA were later discovered to be potent toll-like receptor (TLR) ligands that do not signal through the BCR. Similarly, laboratory preparations of pokeweed mitogen, a plant lectin long known to be a polyclonal B cell activator, were found to be inert once depleted of contaminating TLR ligands . Accordingly, it may be more accurate to reclassify type 1 TI antigens as nonantigenic stimuli or B cell mitogens.
Type 2 thymus-independent antigens — Type 2 TI antigens possess highly repetitive molecular structures capable of cross-linking specific BCRs. Clinically relevant examples of type 2 TI antigens are Streptococcus pneumoniae and the Haemophilus influenzae capsular polysaccharides. Since polysaccharides cannot be loaded into MHC II, these bacteria evade T cell recognition but still elicit specific antibody responses.
●For reasons that are not fully understood, children younger than two years of age respond poorly to type 2 TI antigens responses. This renders infants and toddlers especially susceptible to invasive infections from encapsulated organisms . To address this, bacterial serotype-specific polysaccharide vaccines for younger children are conjugated to bacterial peptides like inactivated tetanus toxoid or a mutated form of diphtheria toxin. (See "Pneumococcal vaccination in children", section on 'Conjugate vaccines'.)
●B cells from older children and adults are more adept at type 2 TI responses and typically respond to unconjugated polysaccharide vaccines. Although polysaccharide vaccines do not contain TD antigens, they do contain TLR ligands, including bacterial peptidoglycans, and this second activation signal appears to be integral to their efficacy [22-24]. (See "Pneumococcal vaccination in adults".)
Thymus-dependent antigens — Thymus-dependent (TD) antigens are proteins that can be loaded into MHC II molecules and presented to the T cell receptor (TCR) of CD4+ T cells. As the reactivity of each T cell's TCR is unique, the TCR and the antigen it recognizes are considered matched to one another or "cognate." Naïve CD4+ T cells typically first interact with antigen presented by conventional antigen-presenting cells (APCs), although B cells also express MHC II. In addition to presenting antigen, APCs provide B7 coactivation ligands and various cytokines that allow the innate immune system to shape T helper (Th) differentiation. Coactivation of T cells is discussed in more detail elsewhere. (See "The adaptive cellular immune response: T cells and cytokines", section on 'T cell activation via the two-signal model'.)
Several differentiated CD4+ T cell subsets are specialized to promote antibody secretion. Among them are Th2 cells, which secrete interleukin (IL-)4, IL-5, and IL-13. While Th2 cells may confer some protection against parasitic infections, in the developed world they primarily mediate IgE-mediated atopic diseases. (See "The biology of IgE".)
T follicular helper (Tfh) cells drive protective antibody responses to TD antigens in secondary lymphoid tissues like lymph nodes. Early in their differentiation, Tfh cells express chemokine receptor 5 (CXCR5), which allows them to home to CXCL13 B cell follicles along a chemokine gradient . Upon arrival, they interact with activated B cells through inducible T cell costimulator (ICOS). The essential nature of this interaction is evidenced by ICOS-deficient patients who fail to produce Tfh cells and cannot form antibody responses to TD antigens, resulting in one form of common variable immunodeficiency (CVID) .
Mature Tfh cells that are presented their cognate antigen by a follicular B cell will respond to it by producing activation signals, including the cell surface protein CD40 ligand (CD40L) and the secreted cytokines IL-21 and IL-4. Despite distinct roles in the humoral immune response, many actions of Tfh cells and follicular B cells are guided by the same transcription factor, BCL6. One consequence of BCL6 expression is signaling lymphocyte activation molecule (SLAM)-associated protein (SAP) production. SAP physically pulls Tfh and follicular B cells together using SLAM molecule interactions . The prolonged and intimate nature of this activating interaction conveys significant potency, which produces a mass of rapidly dividing B cells, the germinal center (GC). Interestingly, despite a tendency for lymphoproliferation in other tissues, SAP-deficient patients and mice are hypogammaglobulinemic and cannot form GCs, thus demonstrating the importance of intimate, prolonged interactions to TD humoral responses . SAP deficiency is reviewed in detail separately. (See "X-linked lymphoproliferative disease".)
Complement — Complement components deposited upon the extracellular surface of microbes bind to complement receptors including CD21, a component of the activating B cell coreceptor. The coreceptor, which also includes CD81 and CD19, is amplified by PI3K to initiate several downstream signaling cascades . Accordingly, antigens coupled to complement components produce robust antibody responses at concentrations 1/10,000th that of complement-free antigens. In contrast, CD21-deficient, CD19-deficient, and CD81-deficient humans are hypogammaglobulinemic, and their B cells each demonstrate suboptimal responses to BCR activation [13,16,17]. (See "Pathogenesis of common variable immunodeficiency", section on 'Defects in specific molecules'.)
TACI, BAFF, and APRIL — Other bridges between innate and adaptive immunity are three additional receptors found on B cells :
●Transmembrane activator and calcium-modulator and cyclophilin ligand (CAML) interactor (TACI)
●B cell-activating factor of the tumor necrosis factor family receptor (BAFF-R)
●B cell maturation antigen (BCMA)
The ligand, BAFF, is shared by all three receptors, and a second ligand, a proliferation-inducing ligand (APRIL), is shared by BCMA and TACI . Both BAFF and APRIL are produced by innate cells of the myeloid and nonmyeloid lineages [32,33]. TACI, BAFF-R, and BCMA ligation enhances various essential B cell functions including activation, tolerance, class-switching, survival, type 2 TI antigen responses, and terminal differentiation [34,35]. Furthermore, some patients with CVID carry variants of the genes encoding TACI and BAFF-R, although most do not [36-38].
Toll-like receptors — Toll-like receptor ligands can activate B cells in isolation or synergistically with other signals. An important example is unmethylated CpG DNA, which is present in bacterial genomes and binds to TLR9. This ligand can induce activation and isotype-switching in B cells and is being developed as a vaccine adjuvant [39-41]. Bacterial peptidoglycans, which are recognized by TLR2, are essential to formation of type 2 TI immune responses [22-24]. (See 'Type 2 thymus-independent antigens' above.)
Cognate T cell help — Activated Th cells that are presented their cognate antigen by a B cell will respond to it by expressing multiple stimulatory signals. Effective transmission of these signals, which include cytokines (IL-21 and IL-4) and cell-to-cell interactions, especially CD40L, require prolonged intimate contact. (See 'Thymus-dependent antigens' above.)
ANERGY — Without additional nonantigenic stimuli, B cell receptor (BCR) cross-linking is insufficient for many B cells to become sufficiently activated to differentiate beyond the mature naïve stage of development. The term "anergy" describes an unresponsive state resulting from chronic low-level BCR activation . Anergic human B cells are enriched in self-reactive clones and downregulate activating receptors like CD21 and CD40, suggesting that anergy may be an important tolerogenic strategy to prevent autoantibody production . During immunization or infection, anergic B cells expressing self-reactive BCRs may be recruited into germinal centers to participate in immune protection. During a germinal center reaction, the BCRs of anergic B cells are altered by somatic hypermutation to diminish self-reactivity initially and then to enhance recognition of microbial antigens. This process is named clonal redemption [44,45].
GERMINAL CENTERS — Germinal centers (GCs) are temporary, three-dimensional structures formed within secondary lymphoid tissues (ie, lymph nodes, spleen, tonsils, and aggregations of lymphoid tissue located in the gastrointestinal and respiratory tracts). The chief products of GCs are class-switched antibodies that bind TD antigens with high affinity. Class-switching expands the effector functions of antibodies without changing their antigen reactivities. Although GCs were previously thought be the primary site of antibody class-switching and affinity maturation, compelling new data suggest class-switching occurs just prior to GC formation .
Class-switching — During initial interactions between cognate T and B cells, activation-induced cytidine deaminase (AID) is upregulated by B cells. AID induction is dependent upon CD40L expression and cytokine secretion by T helper cells. AID is an enzyme that introduces double-stranded DNA breaks within immunoglobulin encoding genes. Prior to GC formation, AID targets class-switch regions that adjoin immunoglobulin constant region gene segments. DNA breaks permit the excision and replacement of utilized constant regions (eg, Cmu encoding IgM) with more distal ones (eg, C-epsilon encoding IgE) . Class-switched antibodies are specialized and can be used for a diverse array of adaptive functions. (See "Immunoglobulin genetics" and "Overview of therapeutic monoclonal antibodies".)
Although CD40/CD40L interactions induce AID , it is the cytokines produced by T helper cells that influence the selection of specific class isotypes. For instance, IL-4, which is associated with parasitic infections, makes the C-epsilon locus available to AID, resulting in increased switching to IgE [49,50]. In contrast, IL-21 is a broad negative regulator of IgE class-switch recombination . The central importance of IL-21 in controlling IgE secretion is demonstrated by hyperIgE syndrome patients with deficiencies of IL-21 or the IL-21 receptor and patients with altered signaling of STAT3, one of the intracellular signaling molecules that serves the IL-21 receptor [52-55]. (See "Autosomal dominant hyperimmunoglobulin E syndrome".)
Affinity maturation — Affinity maturation is an adaptation that genetically alters follicular B cells in GCs through repeated cycles of extreme evolutionary pressure. Each cycle includes:
●(1) B cell receptor (BCR)-mediated competition for unprocessed antigens
●(2) Antigen processing by B cells and major histocompatibility complex (MHC) II presentation
●(3) Preferential activation and survival of B cells presenting the most antigen to cognate follicular T helper (Tfh) cells
●(4) Rapid proliferation of surviving B cells
●(5) Random mutation of immunoglobulin genes
A key component of follicles is the lattice of follicular dendritic cells (FDCs). FDCs secrete CXCL13 to draw-in activated, chemokine receptor 5 (CXCR5)-expressing B and T cells . Unlike other dendritic cells, FDCs are likely not of hematopoietic origin and do not present processed antigens via MHC II . Instead, FDCs present large unprocessed, native antigens on their cell surface via complement and antibody receptors. Accordingly, FDCs cannot directly present antigens to T helper cells residing within the follicle (Tfh cells) but instead relinquish antigens to a BCR strongly binding one of the antigen's many epitopes.
B cells subsequently process native antigens into several small peptides and present these via MHC II. Accordingly, the epitopes recognized by the BCR and T cell receptor need not be identical but only contained within the same native antigen. This less stringent requirement called linked recognition increases the chances that rare pathogen-specific B cells and T cells will come into physical contact .
In the first days of a TD immune response, activated follicular B cells secrete low-affinity IgM antibodies and proliferate, pushing resting B cells outward to form a follicular mantle . This is the outer margin of the secondary lymphoid follicle (figure 4). The interior of this structure, the GC, contains two functional compartments, the light and dark zones. In the basal light zone, follicular B cells called centrocytes interact with FDCs and Tfh cells. Those centrocytes unable to obtain antigen from FDCs die/apoptose from neglect and are consumed by follicular macrophages. By contrast, centrocytes presenting cognate antigen to Tfh cells are rewarded with activation and survival signals. Activated centrocytes enter the dark zone, downregulate their BCR, and become rapidly dividing centroblasts. After several divisions, centroblasts begin to re-express AID, which introduces random mutations within the antigen-recognizing regions of immunoglobulin genes. This process is called somatic hypermutation .
After some time, centroblasts cease proliferation and re-enter the basal light zone as centrocytes. Due to somatic hypermutation, some re-entering centrocyte BCRs bind native antigens with higher affinity than others. The centrocytes most efficient at obtaining, processing, and presenting these antigens are again rewarded by Tfh cells with activation and survival signals. Successive cycles of re-entry into basal light and dark zones drives the process of affinity maturation. Affinity maturation is the expected outcome of a unidirectional evolutionary pressure that rewards B cells capable of generating BCRs with ever-increasing antigen affinity [61,62].
Despite copious IgM production, CD40L-deficient, CD40-deficient, and AID-deficient patients cannot reap the attendant benefits of immunoglobulin class-switching and somatic hypermutation. Such patients are susceptible to recurrent, life-threatening infections [63-65]. (See "Hyperimmunoglobulin M syndromes".)
Plasma cell and memory B cell differentiation — When follicular B cells have undergone affinity maturation and class-switching, some exit the basal light zone, enter the apical light zone, downregulate BCL6, and begin to express B lymphocyte-induced maturation protein 1 (Blimp1). Blimp1 represses AID expression and promotes post-transcriptional switching from membrane-bound to secreted antibody production . Blimp1-expressing plasmablasts downregulate CXCR5, allowing egress from secondary lymphoid tissues and homing to the bone marrow. Once in the marrow, they terminally differentiate into plasma cells, which generate high-affinity, isotype-switched antibodies. These antibodies also re-enter the very germinal reactions in which they were forged to compete with follicular BCRs for native antigens to further drive affinity maturation . Other affinity-maturated, class-switched follicular B cells exit the basal light zone, enter the apical light zone, and then circulate as memory B cells for extended periods. During a recall response, a memory B cell recognizing its cognate antigen can quickly differentiate into a plasma cell or even enter a newly formed GC reaction to undergo additional affinity maturation .
Regulation of germinal center responses — GCs form to generate high-affinity, class-switched antibodies that remove specific thymus-dependent (TD) antigens from circulation. Once the antigen driving a GC response is cleared, the reaction should terminate . The persistence of excess antigen or an inability to generate high-affinity, isotype-switched antibodies may lead to follicular hyperplasia and lymphadenopathy, features of several primary immunodeficiencies [69,70]. The size and efficiency of GC reactions also appear to be controlled by a subset of T regulatory cells called T follicular regulatory (Tfr) cells. Tfrs, which express CXCR5 and the Treg transcription factor forkhead box protein 3 (FOXP3), can both sharpen affinity maturation to vaccine antigens and limit off-target autoantigens responses [71,72]. In mice, both Tregs and Tfh cells can differentiate into Tfr cells, which may explain their functional heterogeneity [71-73].
ANTIBODIES IN INNATE IMMUNITY — There is significant cross-talk between the humoral and innate immune systems. This includes coating pathogens with IgG and IgA antibodies to enhance phagocytosis (ie, opsonization), use of antibodies as pathogen detectors by innate cells, and antibody-mediated inhibition of activation. Additionally, polyreactive IgM natural antibodies, which are constitutively produced starting in utero, play a vital, protective role very early in immune responses before a more specific humoral immune response can be generated.
Opsonization — Opsonization is a mechanism by which antibodies generated through the humoral immune response can augment phagocytosis, a key mechanism of the innate immune system. Opsonins are host proteins, including antibodies, which bind to the membrane of foreign cells, such as bacteria (ie, opsonize the bacteria), enhancing their phagocytic uptake by leukocytes. In particular, the antigen-binding sites (Fab) of immunoglobulins bind to the bacteria, while opsonic receptors bind to the constant (Fc) portion of the molecule.
The principal immunoglobulin opsonins are IgG1 and IgG3, while IgA1 and IgA2 also serve this function in the respiratory tract . Some complement proteins also have critical opsonic function . Human phagocytic cells do not have an Fc receptor for IgM, but as IgM is extremely efficient at activating opsonic complement, some consider it an opsonin as well.
Opsonic Fc receptors — The Fc-binding site is recognized by several classes of opsonic receptors: Fc-gamma-RI (CD64), Fc-gamma-RIIa and -RIIb (CD32a and CD32b), Fc-gamma-RIIIa (CD16), and Fc-alpha-RI (CD89) (table 1). In addition, there are several nonopsonic Fc receptors, which serve pathogen recognition, regulatory, and transfer roles.
●Fc-gamma-RI – Fc-gamma-RI (designated CD64) is not expressed on quiescent neutrophils or cells in their basal state but is found at 15,000 to 25,000 copies after these cells are exposed to interferon (IFN)-gamma (but not to IFN-alpha or IFN-beta). The protein is a single transmembrane protein receptor that binds IgG1 and IgG3 with high affinity, promoting phagocytosis of particles or bacteria opsonized with IgG .
●Fc-gamma-RII – Fc-gamma-RII (CD32) is a constitutive low-affinity receptor, which binds dimeric but not monomeric IgG. Its expression is low (1000 to 4000 copies per cell). Fc-gamma-RII has the following subclass affinities: IgG1 = IgG3 >> IgG2 = IgG4 [74,76]. Fc-gamma-RII exists in several forms with distinct biologic functions. Fc-gamma-RIIa is an activating receptor, while Fc-gamma-RIIb is an inhibitory receptor. IgG-bound dengue virus exploits Fc-gamma-RIIa and Fc-gamma-RIIb to more easily enter host cells and exacerbate symptomatic infections . This phenomenon is known as antibody-dependent enhancement. (See "Dengue virus infection: Pathogenesis" and "COVID-19: Convalescent plasma and hyperimmune globulin", section on 'Antibody-dependent enhancement'.)
Fc-gamma-RIIa-mediated signaling requires the activation of tyrosine kinases of both Src-family kinases and Syk, resulting in tyrosine phosphorylation of Shc, activation of phospholipase C, and increased intracellular calcium levels . In addition, Fc-gamma-RII engagement leads to mitogen-activated protein kinase phosphorylation and activation, a necessary prerequisite for phagocytosis.
In addition to promoting phagocytosis, the cytoplasmic domain of Fc-gamma-RIIa may play an important role in fusion of phagosomes with lysosomes . A mutant Fc-gamma-RII that lacks tyrosine phosphorylation sites can still mediate phagolysosome formation. Fc-gamma-RII also appears to be a receptor for the acute-phase reactant C-reactive protein .
●Fc-gamma-RIII – Fc-gamma-RIII (CD16) is constitutively expressed on the surface of neutrophils and macrophages, occurring at a frequency of 100,000 to 300,000 molecules per cell. It binds IgG subclasses 1 and 3 with intermediate and low affinity, respectively . CD16 is also expressed on natural killer cells. (See "NK cell deficiency syndromes: Clinical manifestations and diagnosis".)
Fc-gamma-RIIIa and Fc-gamma-RIIIb are the two genetic isoforms of Fc-gamma-RIII. They are structurally similar extracellularly but differ markedly in their transmembrane and cytoplasmic domain because of alternate splicing . On myeloid cells, ligation of Fc-gamma-RIIIa promotes activation. On natural killer cells, Fc-gamma-RIIIa activates antibody-dependent, cell-mediated cytotoxicity. (See "NK cell deficiency syndromes: Clinical manifestations and diagnosis".)
●IgA antibody receptor – Polymeric IgA antibody can function as an opsonin. It is recognized on neutrophils by Fc-alpha-RI (CD89) . Fc-alpha-RI is a 60 kD protein composed of two immunoglobulin-like domains that share homology with Fc-gamma-R. Fc-alpha-RI mediates signal transduction via G-protein linked phospholipase C activation, leading to phagocytosis and stimulation of the respiratory burst [74,84-86].
In addition to Fc receptors, other opsonin receptors include the complement receptors 1 (CR1), CD11b and CD11c .
Nonopsonic Fc receptors — There are several additional Fc receptors that are involved in functions other than opsonization (table 1).
●Fc-gamma-RIIb – Fc-gamma-RIIb contains inhibitory signaling motifs and recruits the Src-homology tyrosine phosphatase and downregulates cells that express it (especially B cells and some mononuclear cells). (See 'B cell coreceptors' above.)
●Fc-gamma-RIIIb – Ligation of Fc-gamma-RIIIb does not promote cellular activation and may instead mediate removal of proinflammatory immune complexes from systemic circulation .
●Fc-epsilon-RI – Classical mast cell activation occurs through the "high-affinity" IgE receptor, Fc-epsilon-RI. Activation occurs when adjacent receptors, occupied by receptor-bound IgE, are crosslinked by a multivalent antigen (see "Mast cells: Surface receptors and signal transduction"). Release of histamine, tryptases, and tumor necrosis factor-alpha, as well as leukotrienes and prostaglandins (LTC4 and PGD2, respectively) are responsible for the signs and symptoms of immediate hypersensitivity allergic responses .
●Fc-epsilon-RII (CD23) – Fc-epsilon-RII, is the "low-affinity" receptor for IgE. Fc-epsilon-RII negatively regulates the activation and differentiation of both IgE- and IgG-expressing B cells into plasma cells, either by CD23-dependent interaction of B cells with other cells or by the interaction of CD23 with the B cell receptor within B cells [89,90].
●FcRn – The neonatal Fc receptor (FcRn) is structurally more similar to major histocompatibility complex II molecules than to other Fc receptors . FcRn mediates maternal/fetal transfer of serum IgG through the placenta and maternal/infant transfer of breast milk IgG through the intestinal epithelium . Enteroviruses exploit FcRn to enter host cells, which may explain neonatal susceptibility to these enteroviral infections including hepatitis, neurological meningitis, and encephalitis [92,93]. In addition, FcRn extends the half-life of serum IgG by reducing its degradation, resulting in a recycling effect .
Natural antibodies — The term "natural antibodies" refers primarily to IgMs that can first be identified during neonatal development before most microbial exposures occur. All vertebrates, even animals bred in germ-free environments, produce natural antibodies. For humans, natural antibodies and placentally transferred maternal IgG together provide vital protections against pathogens during infancy . In contrast to maternal IgG, which degrades after a few months, natural antibody production persists throughout an individual's lifespan.
Natural antibody repertoires differ little between cord blood samples from unrelated infants suggesting the protection they offer may be expectant rather than responsive to antigenic exposures. Indeed, natural antibodies preferentially bind to glycans broadly expressed across fungal and bacterial species . Natural antibodies can also recognize many mammalian glycans including those associated with tumors and apoptotic cell death ; mice deficient in natural antibodies are more susceptible to metastatic cancer and autoimmune disorders [98-100].
In mice, natural antibodies are produced by a distinct subset of B cells that express CD5 known as B-1 cells, which are generated from progenitor cells in the fetal liver . Murine B-1 cells produce natural antibody without any requirement of prior antigenic stimulation but cannot differentiate into memory cells. In humans, it is hypothesized that B-1 cells also exist, although the identity, origin, and underlying biology of these cells are less clear . (See "Normal B and T lymphocyte development".)
●Definition – The humoral immune response denotes immunologic responses that are mediated by antibodies. (See 'Introduction' above.)
●Early passive humoral immunity – Neonates rely heavily on maternal immunoglobulin (Ig)G passed through the placenta and on IgA transferred through colostrum and breast milk. After infancy, the child's immunoglobulins gradually increase as levels of maternal antibodies wane (figure 2). (See 'Passive humoral immunity' above.)
●Active humoral immunity – Antibodies are produced when B cells encounter antigen and respond by undergoing activation, proliferation, and differentiation. (See 'Active humoral immunity' above.)
●Types of antigens – B cell antigens are categorized as thymic-independent (TI) and thymic-dependent (TD) antigens. TD B cell antigens require T cell help to generate antibodies. (See 'Types of antigens' above.)
●Primary and secondary phases – The humoral immune response can be divided into primary and secondary phases (figure 1). During the primary phase, naïve B cell receptors bind an antigen and become activated. Some activated B cells differentiate into memory B cells, which are long-lived. When exposed to microbes again, memory B cells produce antibodies more rapidly and efficiently during the secondary phase responses. (See 'Primary and secondary phase responses' above.)
●B cell activation and anergy – B cells require multiple signals to become activated and begin differentiating into memory or plasma cells (figure 3). If these activating signals are not received, the B cell may respond with anergy to that antigen. (See 'Antigenic stimulation' above and 'Anergy' above.)
●Germinal centers – Germinal centers (GCs) are the areas within secondary lymphoid tissues in which the humoral immune response to TD antigens is refined (figure 4). Within GCs, B cells change their B cell receptors to maximize antigen affinity. Plasma cells and memory B cells formed within GCs provide long-lasting immunity and enable rapid recall immunologic responses upon subsequent antigen exposures. (See 'Germinal centers' above.)
●Class-switching – Activated B cells upregulate activation-induced deaminase (AID), which mediates immunoglobulin class-switching before GC entry. Class-switching serves to change an antibody's effector function without changing the antigen it recognizes. (See 'Class-switching' above.)
●Affinity maturation – AID is also expressed by B cells presenting antigen to T follicular helper cells (Tfh) in the GC light zone. In the GC, AID introduces arbitrary somatic mutations in immunoglobulin encoding genes that alter antigen reactivity. Variants increasing antigen binding strength foster B-cell survival and promote continued somatic hypermutation.
●Roles in innate immunity – Antibodies mediate interactions between the adaptive and innate immune systems, including opsonization, pathogen detection, and antibody-mediated inhibition of activation. Receptors for the Fc region of specific immunoglobulin isotypes provide various effector, regulatory, and transport functions to innate and adaptive immune cells (table 1). (See 'Antibodies in innate immunity' above.)
ACKNOWLEDGMENTS — The UpToDate editorial staff acknowledges Francisco A Bonilla, MD, PhD, and E Richard Stiehm, MD, who contributed to earlier versions of this topic review.
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