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Immunoglobulin G
Immunoglobulin G
Immunoglobulin G
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The water-accessible surface area of an IgG antibody

Immunoglobulin G (IgG) is a type of antibody. Representing approximately 75% of serum antibodies in humans, IgG is the most common type of antibody found in blood circulation.[1] IgG molecules are created and released by plasma B cells. Each IgG antibody has two paratopes.

Function

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Antibodies are major components of humoral immunity. IgG is the main type of antibody found in blood and extracellular fluid, allowing it to control infection of body tissues. By binding many kinds of pathogens such as viruses, bacteria, and fungi, IgG protects the body from infection.[citation needed]

It does this through several mechanisms:[citation needed]

IgG antibodies are generated following class switching and maturation of the antibody response, thus they participate predominantly in the secondary immune response. [3]

IgG is secreted as a monomer that is small in size allowing it to easily diffuse into tissues. It is the only antibody isotype that has receptors to facilitate passage through the human placenta, thereby providing protection to the fetus in utero. Along with IgA secreted in the breast milk, residual IgG absorbed through the placenta provides the neonate with humoral immunity before its own immune system develops. Colostrum contains a high percentage of IgG, especially bovine colostrum. In individuals with prior immunity to a pathogen, IgG appears about 24–48 hours after antigenic stimulation.[citation needed]

Therefore, in the first six months of life, the newborn has the same antibodies as the mother and the child can defend itself against all the pathogens that the mother encountered in her life (even if only through vaccination) until these antibodies are degraded. This repertoire of immunoglobulins is crucial for the newborns who are very sensitive to infections, especially within the respiratory and digestive systems.[citation needed]

IgG are also involved in the regulation of allergic reactions. According to Finkelman, there are two pathways of systemic anaphylaxis:[4][5] antigens can cause systemic anaphylaxis in mice through classic pathway by cross-linking IgE bound to the mast cell receptor FcεRI, stimulating the release of both histamine and platelet activating factor (PAF). In the alternative pathway, antigens form complexes with IgG, which then cross-link macrophage receptor FcγRIII and stimulates only PAF release.[4]

IgG antibodies can prevent IgE mediated anaphylaxis by intercepting a specific antigen before it binds to mast cell–associated IgE. Consequently, IgG antibodies block systemic anaphylaxis induced by small quantities of antigen but can mediate systemic anaphylaxis induced by larger quantities.[4]

Structure

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The various regions and domains of a typical IgG

IgG antibodies are large globular proteins made of four peptide chains;[6] two identical γ (gamma) heavy chains of about 50 kDa and two identical light chains of about 25 kDa. The resulting tetrameric quaternary structure, therefore, has a total molecular weight of about 150 kDa.[7] The two heavy chains are linked to each other and to a light chain each by disulfide bonds. The resulting tetramer has two identical halves, which together form a Y-like shape. Each end of the fork contains an identical antigen binding site. The various regions and domains of a typical IgG are depicted in the figure "Anatomy of an IgG."

The Fc regions of IgGs bear a highly conserved N-glycosylation site at asparagine 297 in the constant region of the heavy chain.[8] The N-glycans attached to this site are predominantly core-fucosylated biantennary structures of the complex type.[9] In addition, small amounts of these N-glycans also bear bisecting GlcNAc and α-2,6-linked sialic acid residues.[10] The N-glycan composition in IgG has been linked to several autoimmune, infectious and metabolic diseases.[11]

Subclasses

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There are four IgG subclasses (IgG1, 2, 3, and 4) in humans, named in order of their abundance in serum (IgG1 being the most abundant).[12]

Name Percentage Crosses placenta easily Complement activator Binds to Fc receptor on phagocytic cells Half life[13]
IgG1 66% yes (1.47)* second-highest high affinity 21 days
IgG2 23% no (0.8)* third-highest extremely low affinity 21 days
IgG3 7% yes (1.17)* highest high affinity 7 days
IgG4 4% yes (1.15)* no intermediate affinity 21 days
* Quota cord/maternity concentrations blood. Based on data from a Japanese study on 228 mothers.[14]

Note: IgG affinity to Fc receptors on phagocytic cells is specific to individual species from which the antibody comes as well as the class. The structure of the hinge regions (region 6 in the diagram) contributes to the unique biological properties of each of the four IgG classes. Even though there is about 95% similarity between their Fc regions, the structure of the hinge regions is relatively different.[citation needed]

Given the opposing properties of the IgG subclasses (fixing and failing to fix complement; binding and failing to bind FcR), and the fact that the immune response to most antigens includes a mix of all four subclasses, it has been difficult to understand how IgG subclasses can work together to provide protective immunity. In 2013, the Temporal Model of human IgE and IgG function was proposed.[15] This model suggests that IgG3 (and IgE) appear early in a response. The IgG3, though of relatively low affinity, allows IgG-mediated defences to join IgM-mediated defences in clearing foreign antigens. Subsequently, higher affinity IgG1 and IgG2 are produced. The relative balance of these subclasses, in any immune complexes that form, helps determine the strength of the inflammatory processes that follow. Finally, if antigen persists, high affinity IgG4 is produced, which dampens down inflammation by helping to curtail FcR-mediated processes.[citation needed]

The relative ability of different IgG subclasses to fix complement may explain why some anti-donor antibody responses do harm a graft after organ transplantation.[16]

In a mouse model of autoantibody mediated anemia using IgG isotype switch variants of an anti erythrocytes autoantibody, it was found that mouse IgG2a was superior to IgG1 in activating complement. Moreover, it was found that the IgG2a isotype was able to interact very efficiently with FcgammaR. As a result, 20 times higher doses of IgG1, in relationship to IgG2a autoantibodies, were required to induce autoantibody mediated pathology.[17] Since mouse IgG1 and human IgG1 are not entirely similar in function, and the inference of human antibody function from mouse studies must be done with great care. However, both human and mouse antibodies have different abilities to fix complement and to bind to Fc receptors.[citation needed]

It has been reported that vaccination could be linked to IgG4 levels. In 2025, Japanese researchers showed that total IgG4 levels were increased in the pancreatic cancer patients who got three or more doses of Covid vaccines and their prognoses were worse. Elevated IgG4 levels were correlated with spike-specific IgG4 for pancreatic cancer (R2=0.38) and all cases (R2=0.27), and the probability of finding Foxp3-positive regulatory T cells (Tregs) in tumors was significantly higher in the patients who received Covid booster shots. They argued that future studies would have to show how booster injections worsen pancreatic cancer patients' prognoses, pointing out that Tregs suppress antitumor effects. [18]

Role in diagnosis

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Adalimumab is an IgG antibody.

The measurement of immunoglobulin G can be a diagnostic tool for certain conditions, such as autoimmune hepatitis, if indicated by certain symptoms.[19] Clinically, measured IgG antibody levels are generally considered to be indicative of an individual's immune status to particular pathogens. A common example of this practice are titers drawn to demonstrate serologic immunity to measles, mumps, and rubella (MMR), hepatitis B virus, and varicella (chickenpox), among others.[20]

Testing of IgG is not indicated for diagnosis of allergy, and there is no evidence that it has any relationship to food intolerances.[21][22][23]

See also

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References

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Revisions and contributorsEdit on WikipediaRead on Wikipedia

Immunoglobulin G

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from Grokipedia
Immunoglobulin G (IgG) is the most abundant class of immunoglobulin in human serum, comprising approximately 75–80% of total circulating antibodies and accounting for 10–20% of total plasma protein. It is a Y-shaped monomeric consisting of two identical heavy γ chains and two light chains (either κ or λ), each approximately 50 kDa and 25 kDa in size, respectively, connected by disulfide bonds to form two antigen-binding Fab regions and one Fc region, with a total molecular weight of about 146 kDa. IgG exists in four subclasses—IgG1 (∼65% of total IgG), IgG2, IgG3, and IgG4—differentiated by variations in their regions and constant domains, which influence their biological properties and immune responses. As a key component of the , IgG plays critical roles in host defense by binding to pathogens and through its variable Fab domains, facilitating opsonization for by macrophages and neutrophils, activation of the , and mediation of (ADCC) via interactions with Fcγ receptors on immune cells. These effector functions vary by subclass: IgG1 and IgG3 are potent activators of complement and strong binders to most Fcγ receptors, while IgG2 primarily targets from , and IgG4 exhibits properties by blocking IgG receptors and acting as a monovalent antigen mop. Additionally, IgG neutralizes bacterial endotoxins, viruses, and toxins, contributing to long-term following infection or . IgG is unique among antibody isotypes for its ability to cross the placental barrier, providing essential to the and protecting the newborn during the early months of life when their own is immature. This transplacental transfer is mediated by the neonatal (FcRn) expressed on cells, which actively transports maternal IgG from the maternal circulation into the fetal bloodstream, with transfer efficiency increasing in the third trimester. The long circulatory of IgG, approximately 21 days, is also regulated by FcRn, which recycles IgG after in endothelial cells, preventing lysosomal degradation and enabling sustained immune protection. In clinical contexts, IgG levels and subclasses are measured to diagnose immunodeficiencies, autoimmune diseases, and infections, with therapeutic applications including intravenous immunoglobulin (IVIG) for replacement therapy in primary immunodeficiencies and modulation of inflammatory conditions. Alterations in IgG , particularly in aging or disease states like , can further influence its inflammatory potential and efficacy.

Introduction

Definition and Properties

Immunoglobulin G (IgG) is the most abundant class of in serum, constituting approximately 70-85% of total circulating immunoglobulins and representing about 10-20% of total plasma protein. It exists as a monomeric with a molecular weight of approximately 150 kDa, featuring a characteristic Y-shaped structure that enables binding and effector functions. Key properties of IgG include its notably long serum half-life of 21-23 days, which is longer than that of other immunoglobulin classes and contributes to sustained immune protection. In humans, IgG is divided into four subclasses—IgG1, IgG2, IgG3, and IgG4—each differing in abundance, hinge region flexibility, and effector capabilities, with IgG1 comprising 60-70% of total IgG. A distinctive feature is its ability to cross the placental barrier, mediated by binding to the neonatal (FcRn) on cells, thereby providing to the . In comparison to other immunoglobulin isotypes, IgG predominates in serum with concentrations of 8-16 mg/mL, far exceeding IgA (1-4 mg/mL, mainly secretory), IgM (0.5-2 mg/mL, pentameric and initial responder), IgD (trace amounts), and IgE (minimal, <0.05 mg/mL). This high serum prevalence and monomeric form distinguish IgG as the primary mediator of long-term humoral immunity, in contrast to the multimeric structures of IgM and the mucosal focus of IgA.

Historical Background

The concept of protective serum factors, later identified as antibodies including Immunoglobulin G (IgG), emerged in the late 19th century through pioneering work on antitoxins. In 1890, Emil von Behring and Shibasaburo Kitasato demonstrated that serum from animals immunized against diphtheria and tetanus contained substances capable of neutralizing the respective toxins in other animals, marking the first evidence of humoral immunity and the birth of serum therapy. This discovery, published in the Deutsche Medizinische Wochenschrift, earned Behring the first Nobel Prize in Physiology or Medicine in 1901 for establishing the principles of passive immunization. Advances in protein separation techniques in the early 20th century began to characterize these serum factors. In 1937, Arne Tiselius developed moving-boundary electrophoresis, which separated human serum proteins into distinct fractions: albumin, α-globulin, β-globulin, and γ-globulin, with the γ-globulin fraction later associated with antibody activity due to its enrichment in immune sera. By the 1930s, researchers recognized γ-globulin as the primary carrier of protective antibodies, though its heterogeneity and precise composition remained unclear. The nomenclature evolved alongside biochemical insights, transitioning from "γ-globulin" to the standardized term "Immunoglobulin G." Electrophoretic studies in the 1950s confirmed that the 7S (sedimentation coefficient) component of γ-globulin corresponded to the main antibody class in serum. In 1964, the World Health Organization's expert committee on biological standardization formalized the immunoglobulin nomenclature, designating the subclasses as IgG, IgA, IgM, IgD, and IgE to reflect their electrophoretic mobility and structural distinctions, with IgG representing the predominant serum immunoglobulin. This system resolved prior confusion from terms like "7S γ-globulin." Further elucidation of IgG's structure came in the 1960s, culminating in the 1972 Nobel Prize in Physiology or Medicine awarded to Rodney R. Porter and Gerald M. Edelman for determining the chemical structure of antibodies, primarily through analysis of rabbit and human . Porter's enzymatic fragmentation of IgG into Fab and Fc regions, combined with Edelman's sequencing of polypeptide chains, revealed the Y-shaped molecule's domain organization and variability, providing the molecular basis for antibody diversity and function. Early therapeutic applications of IgG-rich serum highlighted its clinical importance. In the 1930s, during polio outbreaks, convalescent serum containing γ-globulin was administered for passive immunity, with trials in 1934 involving over 2,900 patients showing reduced severity when given early, though efficacy varied and side effects like serum sickness emerged. These efforts, building on diphtheria antitoxin success, spurred the development of purified γ-globulin preparations for prophylaxis against infectious diseases.

Molecular Structure

Overall Architecture

Immunoglobulin G (IgG) exhibits a monomeric quaternary structure composed of two identical heavy chains, designated as γ chains and each weighing approximately 50 kDa, paired with two identical light chains of either the κ or λ isotype, each around 25 kDa. These polypeptide chains assemble into a heterotetramer represented by the formula (H₂L₂), where H denotes the heavy chain and L the light chain, held together by a combination of interchain disulfide bonds and non-covalent interactions such as hydrophobic forces and hydrogen bonding. The overall molecular architecture of IgG forms a characteristic Y-shaped configuration, with dimensions of roughly 14.5 nm in length, 8.5 nm in width, and 4.0 nm in thickness. This shape arises from the bilateral symmetry of the molecule, where the two Fab (fragment antigen-binding) arms extend from the top of the Y, each comprising the amino-terminal domains of one heavy chain and one light chain, and the Fc (fragment crystallizable) region constitutes the base, formed by the intertwined carboxyl-terminal domains of the two heavy chains. Positioned between the Fab and Fc regions is the hinge region, a flexible segment of the heavy chains that imparts mobility to the Fab arms, enabling conformational adaptability. This hinge contains multiple interchain disulfide bonds linking the heavy chains, with the exact number varying across IgG subclasses: two bonds in IgG1 and IgG4, four in IgG2, and eleven in IgG3. A key post-translational modification in IgG's architecture is the presence of a conserved N-linked glycosylation site at asparagine residue 297 (Asn297) in the CH2 domain of each heavy chain within the Fc region, where a biantennary glycan is attached, influencing the molecule's conformational stability.

Domains and Regions

Immunoglobulin G (IgG) molecules are composed of domains that adopt the characteristic immunoglobulin fold, a β-sandwich structure formed by two antiparallel β-sheets packed face-to-face, typically consisting of 7 to 9 β-strands. This Ig fold is conserved across both variable (V) and constant (C) regions of the heavy and light chains, providing structural stability and modularity to the antibody. Each domain spans approximately 70–110 amino acids, with the β-sheets connected by loops that contribute to interdomain interactions. The heavy chain of IgG includes an N-terminal variable domain (VH) followed by three constant domains: CH1, CH2, and CH3. A flexible hinge region, rich in proline and glycine residues, connects CH1 to CH2, allowing mobility between the antigen-binding and effector regions. The light chain, which pairs with the heavy chain, consists of a variable domain (VL) and a single constant domain (CL). These domains associate non-covalently, with VH pairing to VL and CH1 to CL, forming the Fab arms of the molecule. The antigen-binding site, or paratope, is located at the distal tip of each Fab arm and is formed by six hypervariable loops known as complementarity-determining regions (CDRs): three from VH (CDR-H1, CDR-H2, CDR-H3) and three from VL (CDR-L1, CDR-L2, CDR-L3). These CDRs create a surface that interacts specifically with the epitope on the antigen, with CDR-H3 often contributing the most contacts due to its variability in length and sequence. The Fc region is formed by the dimerization of the CH2 and CH3 domains from the two heavy chains, stabilized by non-covalent interactions at the CH2-CH3 interface, which includes hydrophobic contacts and hydrogen bonds primarily involving residues in the AB and EF loops of CH2 and the G-strand of CH3. In IgG1, this region is further secured by two interchain disulfide bonds in the hinge that link the heavy chains, along with intrachain disulfides within each domain. These covalent links ensure the structural integrity of the Fc dimer. Structural variations in IgG domains arise from allotypic polymorphisms, particularly in the constant regions of the heavy chains, such as the Gm allotypes, which are defined by specific amino acid substitutions or deletions (e.g., Gm(1) involving Asp and Leu in CH3). These allotypes occur at multiple positions across CH1, CH2, and CH3, influencing subtle conformational differences without altering the overall fold.

Biosynthesis

Genetic Organization

The immunoglobulin heavy chain locus, which encodes the heavy chains of all immunoglobulins including , is located on the long arm of human at cytogenetic band 14q32.33. This locus spans approximately 1.25 Mb and is organized into distinct regions containing variable (IGHV), diversity (IGHD), joining (IGHJ), and constant (IGHC) gene segments. There are 123-129 IGHV genes, 27 IGHD segments, 9 IGHJ genes, and 11 IGHC genes per haploid genome, with the V, D, and J segments positioned upstream of the constant region cluster. The constant genes are arranged in the order IGHM (μ), IGHD (δ), IGHG3 (γ3), IGHG1 (γ1), IGHA1 (α1), IGHG2 (γ2), IGHE (ε), and IGHA2 (α2), enabling sequential expression during B cell development. The four IGHG genes specific to IgG subclasses each span approximately 18-20 kb within the IGHC cluster, which itself occupies about 300 kb. Each IGHG gene consists of four exons: one encoding the CH1 domain, one for the hinge region (with variable length and structure among subclasses), and two for the CH2 and CH3 domains, respectively. These exons are separated by introns, and the genes share high sequence similarity in their constant domains (>90% identity), reflecting their evolutionary duplication from a common ancestral γ gene. The supports isotype-specific functions while maintaining a modular structure for antibody assembly. Diversity in the variable region of IgG heavy chains is generated through V(D)J recombination, a site-specific recombination process occurring in developing B cells. This mechanism involves the lymphoid-specific RAG1 and RAG2 proteins, which form a transposase-like complex that recognizes recombination signal sequences (RSSs) flanking the IGHV, IGHD, and IGHJ segments. RAG1/RAG2 initiate double-strand DNA breaks at these RSS-gene segment borders, followed by non-homologous end joining (NHEJ) repair to join one D segment to a J segment and then a V segment to the DJ unit, creating a functional VDJ exon upstream of a constant gene. This combinatorial joining, along with junctional diversity from exonuclease trimming and nucleotide additions, produces vast variability in antigen-binding specificity.00675-X) To enable production of IgG instead of the default IgM or IgD, mature s undergo class-switch recombination (CSR), a deletional recombination event that excises intervening DNA between switch (S) regions upstream of the IGHC genes. CSR is initiated by activation-induced deaminase (), which deaminates cytosines to uracils in S regions, leading to double-strand breaks processed by NHEJ to juxtapose the VDJ unit with a downstream IGHG gene (e.g., IGHG1 for IgG1). This irreversible switch occurs during activation in germinal centers, directed by cytokines and CD40 signaling, allowing tailored effector responses without altering specificity.00078-7) Further refinement of IgG affinity occurs via somatic hypermutation (SHM), which introduces point mutations at a high rate (10^{-3} to 10^{-4} per base pair per generation) primarily in the IGHV regions of activated B cells. Like CSR, SHM is triggered by AID, which targets single-stranded DNA in transcription bubbles during Ig gene transcription, generating U:G mismatches that are processed by error-prone repair pathways such as base excision repair or mismatch repair, resulting in transitions and transversions. Mutations cluster in complementarity-determining regions (CDRs) to enhance antigen binding, with positive selection driving affinity maturation in germinal centers.

Production in B Cells

Immunoglobulin G (IgG) production begins with the differentiation of naive B cells, which initially express surface IgM and IgD as part of their . Upon encounter and activation by + helper T cells, these naive B cells proliferate and migrate to germinal centers within secondary lymphoid organs, where they undergo and class-switch recombination (CSR) to switch from IgM/IgD to downstream isotypes including IgG. This CSR process replaces the constant region of the heavy chain from μ/δ to γ, enabling the expression of membrane-bound and secreted IgG, and is dependent on activation-induced cytidine deaminase (AID) that initiates DNA breaks in switch regions. The regulation of CSR to specific IgG subclasses is influenced by cytokines from T cells and innate immune cells. For instance, interleukin-4 (IL-4), primarily from T follicular helper cells, promotes switching to IgG1, IgG4, and IgE subclasses, while interferon-γ (IFN-γ), often produced by T helper 1 cells, directs switching to IgG1 and IgG3 subclasses in humans. Other cytokines, such as transforming growth factor-β (TGF-β), can further modulate subclass preferences, ensuring tailored antibody responses based on the immune challenge. Following CSR, IgG heavy and light chain genes are transcribed into pre-mRNA in activated B cells and their plasmablast descendants. The pre-mRNA undergoes to produce either membrane-bound or secreted forms; for secreted IgG, the site in the γ constant region exon is selected, excluding transmembrane exons. The mature mRNAs are then translated on cytoplasmic ribosomes, with nascent polypeptides bearing N-terminal signal peptides that direct translocation into the (ER) lumen via the Sec61 translocon. In the ER, immunoglobulin chain folding and assembly are tightly coordinated to ensure proper structure. Heavy chains initially bind to the chaperone BiP (an family member) via their CH1 domain, preventing premature secretion until association with light chains displaces BiP and allows folding. Light chains fold independently but facilitate heavy chain release from BiP, enabling the pairing of heavy and light chains through non-covalent interactions in the variable region and the formation of inter-heavy chain disulfide bonds in the hinge region, resulting in the H2L2 tetramer of IgG. Misfolded or unassembled chains are retained by mechanisms, such as the unfolded protein response (UPR), which expands the ER to handle high synthetic loads in differentiating plasma cells. Post-assembly, IgG molecules traffic to the Golgi apparatus, where N-linked occurs on the CH2 domain of the Fc region, adding complex carbohydrates that influence stability, , and effector functions. Fully processed IgG is then packaged into secretory vesicles and exported via at the plasma membrane, with plasma cells capable of secreting up to 2,000–10,000 molecules per cell per second. Terminally differentiated plasma cells, arising from B cells or extrafollicular responses, are the primary producers of circulating IgG, accounting for over 90% of serum levels through their longevity in the niche supported by survival factors like APRIL and BAFF. These long-lived plasma cells maintain high rates of IgG synthesis by upregulating transcriptional factors such as BLIMP1, which represses B cell identity genes and enhances antibody factory machinery, including expanded rough ER and secretory pathways.

Physiological Functions

Role in Adaptive Immunity

Immunoglobulin G (IgG) plays a central role in the by facilitating long-term following primary exposure. Upon re-encounter with the same , the secondary antibody response shifts from the initial production of IgM to a dominant IgG-mediated phase, characterized by higher affinity antibodies due to and class-switch recombination in germinal centers. This transition enables more effective neutralization and opsonization, providing sustained protection against reinfection. Memory B cells, generated during the primary response, are pivotal in this process, as they predominantly express IgG after class switching and persist in lymphoid tissues to enable rapid proliferation and differentiation into plasma cells upon re-exposure. These IgG-secreting memory cells ensure a swift and amplified secondary response, contributing to immunological that underpins efficacy and lifelong immunity. The role of IgG in adaptive immunity is evolutionarily conserved, with the role of class-switched immunoglobulins emerging in jawed vertebrates as key components of humoral defense systems. The specific IgG isotype, traceable to ancestral IgY-like molecules in early mammalian , supports class-switched responses similar to modern IgG.

Effector Activities

Immunoglobulin G (IgG) molecules exert their effector activities primarily through interactions between their Fab and Fc regions with immune components, enabling the elimination of pathogens and toxins. The Fab arms bind specifically to antigens on pathogens or infected cells, while the Fc region recruits and activates various immune effectors, such as , complement proteins, and cytotoxic cells. These mechanisms amplify the adaptive by bridging humoral and cellular immunity. Opsonization is a key effector function where IgG coats or infected cells, enhancing their recognition and uptake by like macrophages and neutrophils. The Fab region binds to microbial antigens, exposing the Fc region, which then ligates activating Fcγ receptors (FcγRI, FcγRIIa, FcγRIIIa) on , triggering intracellular signaling cascades that promote cytoskeletal rearrangement and engulfment of the opsonized target. This process not only facilitates pathogen clearance but also enhances for further immune activation. Complement activation by IgG occurs via the classical pathway, initiated when the Fc region of antigen-bound IgG molecules binds C1q, the recognition subunit of the C1 complex. Multiple IgG Fc regions in close proximity on an immune complex induce a conformational change in C1q, activating C1r and C1s proteases, which cleave downstream complement components to form and initiate the cascade leading to opsonization by C3b, membrane attack complex formation, and . This mechanism is particularly efficient for lysing enveloped pathogens or enveloped cells. Antibody-dependent cellular cytotoxicity (ADCC) involves IgG-coated targets being recognized by effector cells, primarily natural killer (NK) cells, through low-affinity FcγRIIIa receptors on their surface. Upon binding, the FcγRIIIa cross-links with adapter proteins containing immunoreceptor tyrosine-based activation motifs (ITAMs), activating signaling pathways that release perforin and granzymes from cytotoxic granules, inducing in the target cell. This process is crucial for eliminating virus-infected cells and tumor cells without direct . Neutralization by IgG prevents entry or activity through steric hindrance mediated by the Fab region. By binding to critical epitopes on viruses, such as receptor-binding domains on viral spike proteins, IgG blocks attachment to host cells, inhibiting fusion and internalization; similarly, it neutralizes bacterial s by occluding their active sites or receptor-interaction domains, rendering them inert before they can exert damage. This Fab-dependent mechanism provides immediate protection at mucosal surfaces and in circulation. IgG can indirectly contribute to of mast cells and , primarily through immune complex formation that engages FcγRIIa on these cells, leading to cross-talk with FcεRI signaling pathways. This activation promotes calcium influx and release of preformed mediators like and proteases, as well as de novo synthesis of cytokines, enhancing inflammatory responses in contexts such as IgG-mediated . Although less prominent than IgE-driven degranulation, this mechanism amplifies local immunity against certain antigens.

Subclasses

Isotypes and Their Characteristics

Human immunoglobulin G (IgG) exists in four subclasses, designated IgG1, IgG2, IgG3, and IgG4, which differ in their constant regions and exhibit distinct physicochemical properties. These subclasses are the products of closely related but distinct genes within the locus on chromosome 14. In healthy adult serum, the subclasses are present in varying abundances: IgG1 constitutes 60-70%, IgG2 20-30%, IgG3 5-8%, and IgG4 less than 5% (typically 1-4%). Structurally, the subclasses vary notably in the region, which connects the Fab arms to the Fc domain and influences flexibility and stability. The upper and middle regions comprise 15 in IgG1, 12 in IgG2, 62 in IgG3 (due to duplicated exons), and 12 in IgG4. These differences are accompanied by variations in inter-heavy chain bonds within the hinge: IgG1 and IgG4 each have 2 such bonds, IgG2 has 4, and IgG3 has 11, contributing to IgG3's more rigid yet extended conformation. Polymorphisms known as allotypes further diversify the subclasses, arising from genetic variations in the constant regions. For instance, the IgG1m(1) allotype (also denoted Gm(1)) involves a substitution in the CH1 domain that can influence Fc patterns and overall function. These allotypes are serologically defined markers with population-specific frequencies, such as the prevalence of certain G1m variants in different ethnic groups. The γ gene cluster encoding these subclasses evolved through tandem duplication events from an ancestral γ gene, followed by divergence and segmental exchanges, allowing adaptation of humoral immunity across species. In humans, this resulted in four functional γ genes arranged in the order IGHG3, IGHG1, IGHG2, and IGHG4. Regarding stability, the subclasses differ in serum half-life, with IgG3 exhibiting the shortest at approximately 7 days compared to 21 days for the others; this is attributed to structural features in its CH3 domain that impair recycling via the neonatal Fc receptor (FcRn).

Functional Variations

Immunoglobulin G (IgG) subclasses exhibit distinct functional variations that influence their engagement with immune effector mechanisms, such as (ADCC), complement activation, and interactions with Fc gamma receptors (FcγRs) and complement component C1q. These differences arise from structural features in their constant regions, particularly the hinge and CH2 domains, which modulate binding affinities and biological activities. IgG1 and IgG3 generally promote pro-inflammatory responses through strong effector engagements, while IgG2 and IgG4 tend toward more restrained or protective roles in specific contexts. IgG1 demonstrates the highest affinity for activating FcγRs (e.g., FcγRIIa, FcγRIIIa) and C1q, enabling robust ADCC and (CDC), making it dominant in antiviral and cytotoxic immune responses against infected cells. This subclass is particularly effective in recruiting natural killer cells and macrophages to eliminate virus-infected targets via FcγRIIIa-mediated ADCC. In contrast, IgG2 shows lower affinity for FcγRs and C1q, resulting in weak complement that requires high antigen density for efficacy. It predominates in responses to polysaccharide antigens, such as those on bacterial capsules, facilitating opsonization and in antibacterial immunity. IgG2 also contributes to allergic responses alongside IgG4, where it helps modulate allergen-specific immunity during repeated exposure. IgG3 possesses an exceptionally long hinge region that enhances flexibility and accessibility of the C1q-binding site, leading to the most potent complement activation among subclasses and strong ADCC via high FcγR affinity. Despite its functional potency, IgG3 has a short serum half-life due to susceptibility to proteolytic cleavage at the extended , positioning it as a key player in early bacterial defense before subclass switching occurs. IgG4, however, exhibits low binding to FcγRs and negligible complement activation, minimizing pro-inflammatory effector functions and conferring properties. A unique mechanism, Fab-arm exchange, allows IgG4 molecules to swap half-antibodies, forming bispecific, functionally monovalent antibodies that block immune complex formation without triggering effector cells. This is prominent in chronic exposure scenarios, such as venom , where IgG4 promotes tolerance and reduces allergic reactions. The regulation of IgG subclass switching in B cells is influenced by T helper cell cytokines: Th1-associated interferon-gamma (IFN-γ) promotes switching to IgG3, enhancing early pro-inflammatory responses, while Th2 cytokines like interleukin-4 (IL-4) and IL-13 drive switching to IgG1 and IgG4, supporting humoral and tolerogenic activities.

Clinical Applications

Diagnostic Roles

Immunoglobulin G (IgG) plays a central role in clinical diagnostics through the measurement of its total levels, subclass distributions, and antigen-specific antibodies, which help identify immune deficiencies, infections, and autoimmune conditions. Serological assays, particularly , are widely employed to quantify total IgG or detect antigen-specific IgG responses. For instance, ELISA protocols enable the quantitative detection of IgG antibodies against viral antigens, such as the , by coating microtiter plates with the and measuring optical density proportional to bound IgG. These assays demonstrate high for identifying IgG seropositivity in post-infection or post-vaccination scenarios, with clinical performance validated across diverse populations. Quantification of IgG subclasses (IgG1 through IgG4) is essential for diagnosing selective IgG subclass deficiencies, often associated with recurrent sinopulmonary infections, particularly IgG2 deficiency. Nephelometry and turbidimetry are standard automated methods for this purpose, measuring light scattering or transmission caused by antigen-antibody complexes in serum to determine subclass concentrations. These techniques provide precise results from small serum volumes and are recommended for confirming deficiencies when total IgG is normal but specific antibody responses are impaired. IgG1 and IgG2 typically comprise the majority of circulating IgG, with deficiencies in these subclasses indicating heightened infection risk. In hemolytic disease of the fetus and newborn (HDFN) due to Rh incompatibility, detection of maternal anti-D IgG antibodies is critical for . Prenatal screening identifies anti-D IgG via indirect antiglobulin tests, where titers above a threshold (often ≥16) predict severe fetal by quantifying IgG capable of crossing the and binding RhD-positive red blood cells. This approach allows timely monitoring of antibody levels throughout to guide interventions. IgG autoantibodies are key markers in autoimmune diagnostics, including IgG-class rheumatoid factor (RF) and anti-nuclear antibodies (ANA). RF, an IgG autoantibody targeting the Fc portion of IgG, supports rheumatoid arthritis diagnosis when combined with clinical criteria, with specificity around 80%. ANA testing, primarily detecting IgG antibodies to nuclear antigens via immunofluorescence or ELISA, serves as a sensitive screen for systemic lupus erythematosus and other connective tissue diseases, with patterns like speckled or homogeneous informing specificity. Monitoring IgG titers is vital for assessing vaccine-induced immunity, such as anti-hepatitis B surface antigen (anti-HBs) IgG levels following . Quantitative immunoassays measure anti-HBs IgG titers, with levels ≥10 mIU/mL indicating protection and ≥100 mIU/mL conferring robust long-term immunity; post-vaccination testing at 1-2 months verifies rates exceeding 96%. Declining titers over time may prompt booster evaluation to maintain protective thresholds.

Therapeutic Uses and Pathologies

Intravenous immunoglobulin (IVIG) consists of pooled polyclonal IgG derived from thousands of healthy donors and serves as a replacement therapy for primary immunodeficiencies, where it replenishes deficient antibodies to prevent recurrent bacterial infections, administered at doses of 400-600 mg/kg every 3-4 weeks. In autoimmune diseases such as Guillain-Barré syndrome, IVIG exerts immunomodulatory effects by neutralizing pathogenic autoantibodies and altering immune cell function, typically at higher doses of 2 g/kg divided over 2-5 days. These therapies reduce infection severity and autoimmune flares, with IVIG also approved for conditions like and . Monoclonal antibodies engineered from IgG scaffolds enable precise targeting of disease mediators. Rituximab, a chimeric IgG1 anti-CD20 antibody, depletes malignant or autoreactive B cells via antibody-dependent cellular cytotoxicity and complement activation, treating non-Hodgkin's lymphoma, chronic lymphocytic leukemia, and rheumatoid arthritis. Adalimumab, a fully human IgG1 monoclonal antibody, binds soluble and membrane-bound TNF-α to inhibit its proinflammatory signaling, providing relief in autoimmune disorders including rheumatoid arthritis, psoriatic arthritis, and Crohn's disease. Post-2020 developments include COVID-19 therapeutics like casirivimab and imdevimab, recombinant human IgG1 antibodies that neutralize the SARS-CoV-2 spike protein by binding non-overlapping epitopes, though efficacy has waned against later variants, limiting use as of 2025. IgG deficiencies manifest in primary immunodeficiencies, leading to increased susceptibility to infections. results from mutations in the BTK gene, causing absent B cells and profoundly low or undetectable serum IgG levels, with patients experiencing severe, recurrent bacterial infections starting in infancy. involves low IgG (often <400 mg/dL) alongside impaired specific responses, predisposing individuals to sinopulmonary infections, gastrointestinal issues, and , typically diagnosed in adulthood. Conversely, hypergammaglobulinemia with elevated IgG occurs in chronic inflammation, as seen in or , where persistent immune activation drives polyclonal B-cell expansion and production. Pathologically, IgG contributes to reactions through immune complex formation. In , IgG antibodies against foreign proteins (e.g., from antitoxins) form circulating complexes that deposit in vessel walls and tissues, activating complement and neutrophils to cause fever, , arthralgias, and potential organ damage 7-14 days post-exposure. Maternal-fetal alloimmunization involves IgG alloantibodies (e.g., anti-D) crossing the to target fetal antigens, resulting in hemolytic disease of the and newborn with risks of , , and kernicterus. Emerging IgG-based therapies include bispecific antibodies engineered in IgG-like formats to redirect immune effectors against tumors. These molecules simultaneously bind tumor antigens (e.g., ) and immune activators (e.g., CD3 on T cells), enhancing ; examples include , approved in 2023 for relapsed or refractory . In 2025, inebilizumab-cdon (UPLIZNA), a humanized IgG1 targeting , received FDA approval as the first treatment for in adults.

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