Version May 2024
INTRODUCTION — This topic will review the structure, normal serum concentrations, genetics, and biologic properties of immunoglobulin G (IgG) subclasses. Disorders associated with increased or decreased levels of IgG subclasses are mentioned briefly. IgG subclass deficiency is discussed in detail separately. (See "IgG subclass deficiency".)
PROPERTIES OF IgG SUBCLASSES — IgG is composed of four subclasses: IgG1, IgG2, IgG3, and IgG4 [1-9]. The structure, genetics, and function of the IgG subclasses are reviewed in this section. Detailed discussions of these topics as they apply to immunoglobulins in general are presented separately. (See "Structure of immunoglobulins" and "Immunoglobulin genetics".)
Structures and physical properties — The four IgG subclasses are present in the serum in monomeric form. The tertiary structures of the IgG subclasses are similar, although they differ in the location and number of interchain-disulfide bonds (figure 1). All four IgG subclasses cross the placenta (table 1) [10-12].
The determination of immunoglobulin class and/or subclass is based on differences in the heavy chain constant (CH) regions (figure 1). Functional differences among the subclasses arise from structural variation in both the Fc regions and in the hinge regions (the area where the variable or Fab regions are joined to the Fc region) [1].
The Fc region of each IgG subclass has a distinct affinity for phagocyte membrane Fc-gamma-receptors (FcγR) (table 1). The binding of IgG molecules to FcγRs is important for initiating phagocytosis. IgG1 and IgG3 bind FcγRI, FcγRII, and FcγRIII; IgG2 binds FcγRII; and IgG4 binds FcγRI and FcγRII [10-13]. (See 'Biologic functions' below.)
An IgG molecule is composed of two identical heavy (H) chains and two identical light (L) chains, which usually results in two identical antigen-binding sites on the Fab arms. However, IgG4 antibodies have unique structural and functional properties and undergo "half antibody exchange," resulting in recombined antibodies composed of two different binding specificities [14]. A large fraction of IgG4 molecules exchange H-L dimer partners, resulting in a hybrid antibody that contains two different Fab arms with different antigen specificities. Although this antibody can only bind monovalently, it is capable of cross-linking two different antigens [15]. The functional significance of this characteristic is discussed below. (See 'Opsonization' below.)
The hinge regions of antibody molecules allow for rotation and flexion of the Fab arms. The degree of flexibility depends on the amount of inter-heavy chain disulfide bonds present within the hinge [5]. In decreasing order, the relative flexibility of the hinge regions of the IgG subclasses is as follows: IgG3>IgG1>IgG4>IgG2 [16]. In addition, the number of amino acids in the hinge region differs among the subclasses: IgG3 has 62 amino acid residues, IgG1 has 15 amino acid residues, and IgG2 and IgG4 have 12 amino acid residues [17]. This increased flexibility may also account for the increased complement activation and FcR binding affinity. (See 'Biologic functions' below.)
Normal serum concentrations — The IgG subclasses are named according to their abundance in the serum (table 1) [10-12,18]:
●IgG1 comprises 60 to 70 percent of total IgG
●IgG2 comprises 20 to 30 percent
●IgG3 comprises 5 to 8 percent
●IgG4 comprises 1 to 4 percent
Because IgG1 accounts for the majority of total serum IgG, deficiencies in IgG1 often result in overall hypogammaglobulinemia. In contrast, deficiencies of the other subclasses can be accompanied by normal levels of total IgG. (See "IgG subclass deficiency".)
Normal levels of the IgG subclasses are shown in the table (table 2). The measurement of IgG subclass levels is complicated by several factors, including normal variation with age and the use of different methodologies. Although all IgG subclasses are transported through the placenta, IgG2 does not cross the placenta as readily as the other subclasses, so that newborns have lower levels of IgG2 antibodies [19]. The levels of each of the IgG subclasses rise at different rates during development. Adult IgG1 levels are present by five years of age. However, adult levels of IgG2, IgG3, and IgG4 are not achieved until adolescence (figure 2) [20].
Half-lives — The half-life of IgG3 is just 7 to 8 days, due to its relative susceptibility to proteolytic enzymes, whereas the half-lives of IgG1, IgG2, and IgG4 are approximately 21 to 24 days [21].
GENETICS — The heavy chain constant (CH) regions of an immunoglobulin molecule determine its class and subclass. The amino acid sequences of the various IgG subclasses are 90 to 95 percent homologous [22]. The CH regions are encoded by C gene segments clustered on chromosome 14 [23]. (See "Immunoglobulin genetics".)
Each of the four subclasses has a corresponding C gene segment that encodes its CH regions (table 1). As an example, the gene segment C-gamma-2 encodes the CH regions of IgG2 molecules, and C-gamma-3 encodes the corresponding regions of IgG3 molecules.
Allotypes — Mutations in the C genes provide additional amino acid variation in the sequence composition of IgG subclass proteins. These mutations are inherited in an autosomal pattern and can serve as genetic markers or allotypes [24]. Thus, allotyping is used to distinguish an antibody of a particular subclass encoded by allele "a" from an antibody of the same isotype encoded by allele "b." Allotype nomenclature designates these antigenic markers by class, subclass, the letter "m," and then the allele in parentheses. As an example, G2m(n) is the n allele of IgG2 molecule.
There is evidence that IgG subclass levels are influenced by allotypes and allotype combinations under normal conditions [25]. As an example, individuals of IgG allotype G3m(5) have twice the IgG3 levels as those with IgGm(21) [26].
Allotypes can vary markedly among healthy human populations from different geographical regions [27]. It has been hypothesized that antibodies of certain allotypes may confer superior protection to pathogens indigenous to specific regions [26].
BIOLOGIC FUNCTIONS — The biologic functions of the IgG subclasses include neutralization, opsonization, complement activation, and antibody-dependent cellular cytotoxicity.
Neutralization — Neutralization refers to the property of some IgG molecules to block the binding of viruses to host cells and to toxins to their target molecules. An example of viral neutralization is the development of IgG antibody to poliovirus following vaccination to prevent infection. An example of neutralization to toxin is the development of IgG blocking antibody to tetanus toxin following immunization with tetanus toxin to prevent "lockjaw." IgG1 and IgG3 are the predominant subclasses mediating neutralization.
Opsonization — IgG1, IgG2, and IgG3 are important for opsonization of microbes by phagocytes. Opsonization refers to the binding of antibodies to the surfaces of a microbe or foreign particle in order to facilitate phagocytosis by neutrophils or macrophages via Fc-gamma-receptors. Both antibodies and complement proteins can act as opsonins. Immunoglobulin molecules interact with microbes through their Fab portions and bind to phagocytes through the Fc portion.
In contrast to the other subclasses, IgG4 has low affinity for Fc-gamma-receptors and C1q and thus minimal ability to activate cells or initiate complement activation. In addition, IgG4 antibodies may undergo Fab arm exchange resulting in two different antigen-specific antibodies. This results in loss of IgG4 antibodies to cross-link antigens and form immune complexes [14].
Complement activation — The different IgG subclasses differ in their ability to bind C1q and activate the classical complement pathway (table 1). IgG1 and IgG3 fix C1q most effectively, while IgG2 does so weakly. IgG4 does not bind complement at all [5]. (See "Complement pathways", section on 'Classical pathway'.)
Antibody-dependent cellular cytotoxicity — Antibody-dependent cellular cytotoxicity (ADCC) is a mechanism in which Fc-gamma-receptor-bearing effector cells, such a NK cells, bind IgG antibody recognizing antigens on target cells. IgG1 is the predominant IgG subclass displaying ADCC activity. ADCC is discussed in more detail separately. (See "NK cell deficiency syndromes: Clinical manifestations and diagnosis", section on 'Antibody-dependent cellular cytotoxicity'.)
Role in specific types of infections — Antibody responses to certain types of pathogens are predominantly comprised of molecules of a specific IgG subclass, which is referred to as IgG subclass restriction (table 1). Specifically:
●Antibody responses to bacterial polysaccharide antigens, such as the capsular antigens of Streptococcus pneumoniae, are composed mainly of IgG2 molecules [28].
●Antibody responses to protein antigens and viral antigens are composed predominantly of IgG1 and IgG3 [29,30].
●The biologic role of IgG4 is incompletely understood, although the finding that antibody responses to chronic schistosomiasis and filariases are primarily composed of IgG4 molecules suggests that IgG4 may play a role in the immune response against parasitic disease [31,32]. Total and antigen-specific IgG3 and IgG4 were elevated in Indian children with visceral leishmaniasis [33].
DISORDERS WITH ELEVATED SUBCLASS LEVELS — Increased serum IgG4 levels have been reported in several disorders:
●IgG gammopathies – Markedly elevated levels of any of the IgG subclasses, often with diminution of the others, is characteristic of the IgG gammopathies, including multiple myeloma or benign monoclonal IgG paraproteins. These patients should be referred to a hematologist. (See "Diagnosis of monoclonal gammopathy of undetermined significance" and "Multiple myeloma: Clinical features, laboratory manifestations, and diagnosis".)
●IgG4-related disease (IgG4-RD) – IgG4-RD is a rare systemic immune-mediated disorder first described in older Japanese men in the early 2000s but now recognized in other patient populations and in diverse areas of the world. It is characterized by tumor-like swelling of involved organs, elevated serum levels of IgG4 (ie, ≥135 mg/dL), lymphoplasmacytic infiltrates enriched in IgG4-positive plasma cells and variable degrees of fibrosis, and responsiveness to glucocorticoids, particularly in the early stages of disease. IgG4-RD is reviewed in detail separately. These patients should be referred to a rheumatologist.
●Allergic disorders – Patients with allergic disorders, such as atopic dermatitis, may demonstrate elevated levels of IgG4, probably due to prolonged allergen stimulation [34]. In addition, patients receiving allergen immunotherapy develop increased levels of allergen-specific IgG4, although this usually does not impact the total serum IgG4. These patients should be referred to an allergist. (See "Allergen immunotherapy for allergic disease: Therapeutic mechanisms", section on '"Blocking" IgG4'.)
●Idiopathic membranous nephropathy – Increased levels of IgG4 have been described in idiopathic membranous nephropathy, in association with increased interleukin 10 (IL-10) and interleukin 13 (IL-13) mRNA expression [35]. These patients should be referred to a nephrologist. (See "Membranous nephropathy: Pathogenesis and etiology", section on 'Pathogenesis'.)
●Pulmonary disorders – A variety of pulmonary disorders, including Loeffler syndrome, leiomyosarcoma, periarteritis nodosa, and mycosis fungoides, have been associated with elevated IgG4 levels [36-38]. These patients should be referred to a pulmonologist.
●Rheumatoid arthritis – Elevated IgG4 levels have also been reported in rheumatoid arthritis [39]. These patients should be referred to a rheumatologist. (See "Diagnosis and differential diagnosis of rheumatoid arthritis", section on 'Evaluation and diagnosis'.)
DISORDERS WITH REDUCED SUBCLASS LEVELS — Decreased levels of IgG subclasses are seen in the normal population but can also be associated with increased frequency and severity of infections, particularly of the upper and lower respiratory tract. IgG subclass deficiency is considered to be a primary immunodeficiency when reduced levels of one or more IgG subclasses (with normal total IgG) are accompanied by impaired antibody function (usually demonstrated by abnormal vaccine response). This disorder is reviewed separately. These patients should be referred to an immunologist. (See "IgG subclass deficiency".)
SUMMARY
●Immunoglobulin G (IgG) is comprised of four subclasses: IgG1, IgG2, IgG3, and IgG4. All four subclasses are monomeric and have similar structures. All cross the placenta. (See 'Properties of IgG subclasses' above.)
●IgG subclasses are numbered according to their serum concentrations. IgG1 normally comprises 60 to 70 percent of total IgG, such that low levels of IgG1 usually results in overall hypogammaglobulinemia. (See 'Normal serum concentrations' above.)
●The class and subclass of an immunoglobulin molecule are determined by the constant heavy chain (CH) portion. The amino acid sequences of the various IgG subtypes are 90 to 95 percent homologous, with each subtype having a specific CH gene segment that encodes its CH region (eg, gene segment C-gamma-2 encodes the CH regions of IgG2 molecules). (See 'Genetics' above.)
●All four IgG subclasses act as opsonins, binding to microbes and facilitating phagocytosis. They have differing abilities to activate the classical complement pathway: IgG1 and IgG3 fix C1q most effectively activating the classical complement pathway, while IgG2 does so weakly, and IgG4 does not bind complement at all (table 1). (See 'Biologic functions' above.)
●Many IgG antibody responses to pathogens demonstrate "IgG subclass restriction," which means the response is largely composed of certain IgG subtypes. Antibody responses to protein antigens and viral antigens are composed predominantly of IgG1 and IgG3, while responses to polysaccharide antigens are mostly IgG2. (See 'Role in specific types of infections' above.)
●The functions of IgG4 remain incompletely defined. It may play a role in the immune response to parasitic infection, but elevations in IgG4 have also been associated with an array of different disorders. (See 'Disorders with elevated subclass levels' above.)
●Low levels of one or more of the IgG subclasses are found in healthy people but can also be associated with increased infections and poor vaccine response. The latter is considered to be a form of primary immunodeficiency. (See "IgG subclass deficiency".)
ACKNOWLEDGMENTS — The UpToDate editorial staff acknowledges J Keith Lemmon, MD, and E Richard Stiehm, MD, who contributed to earlier versions of this topic review.
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