Overview
IgG is a monomer (~150 kDa) composed of two identical heavy γ-chains (~50 kDa each) and two identical κ or λ light chains (~25 kDa each), joined by two interchain disulfide bonds at the hinge region. The molecule is divided into two Fab arms (antigen binding, via VH+VL CDRs) and one Fc region (effector functions, via CH2+CH3 domains).
The four subclasses (IgG1–4) are defined by the constant region of the γ heavy chain and differ critically in hinge length, number of interchain disulfide bonds, Fc receptor (FcγR) binding affinity, and complement-activation capacity. IgG1 and IgG3 are the principal complement-activating subclasses; IgG2 is the dominant anti-polysaccharide subclass; IgG4 is anti-inflammatory and does not activate complement.
The extraordinary 21-day half-life of IgG (versus 5–7 days for IgA, IgM, or most plasma proteins) is maintained by the FcRn (neonatal Fc receptor) recycling pathway. In acidic endosomes (pH ~6) of vascular endothelial cells, IgG-Fc binds FcRn with high affinity; the IgG–FcRn complex is transcytosed back to the plasma membrane where, at physiological pH 7.4, affinity drops and IgG is released into circulation — rescuing it from lysosomal degradation. FcRn also mediates IgG transcytosis across syncytiotrophoblasts of the placenta.
IgG Subclasses
| Subclass | Abundance | Hinge / SS bonds | Complement | FcγR binding | Key roles and notes |
|---|---|---|---|---|---|
| IgG1 | ~65% of IgG | 15 aa hinge; 2 interchain SS | Yes (C1q); activates classical pathway | Excellent FcγRI & FcγRIII binding → ADCC, opsonophagocytosis | Anti-protein antigens; dominant response to most vaccine antigens; longest half-life among subclasses; most therapeutic mAb scaffold (adalimumab, trastuzumab, nivolumab, rituximab) |
| IgG2 | ~25% of IgG | 12 aa hinge; 4 interchain SS (rigid hinge) | Weak (reduced C1q binding) | Poor FcγRI/III binding; primarily FcγRIIA on phagocytes | Dominant anti-polysaccharide antibody → critical for immunity to encapsulated bacteria (S. pneumoniae, H. influenzae, N. meningitidis); children have delayed IgG2 development → susceptibility period before PCV13 vaccination |
| IgG3 | ~8% of IgG | 62 aa hinge; 11 interchain SS (longest) | Most potent complement activator (C1q binds best to IgG3 Fc) | Excellent FcγRI & FcγRIII; shorter FcRn binding → shorter half-life (~7 days) | Anti-viral (influenza, RSV, SARS-CoV-2 spike); dominant early IgG response to many viral pathogens; most immunogenic subclass (allotype differences can induce IgG anti-IgG3 antibodies) |
| IgG4 | ~4% of IgG | 12 aa hinge; 2 interchain SS | None (does not activate classical or lectin pathway) | FcγRIIb (inhibitory receptor); minimal activating FcγR binding | Anti-inflammatory; produced in chronic allergen exposure (allergen immunotherapy blocking antibody); undergoes Fab-arm exchange in vivo (half-molecules swap → bispecific monomers); elevated in IgG4-related disease; therapeutic mAb scaffold when effector function is undesirable (pembrolizumab, durvalumab use IgG4 or Fc-silenced variants) |
Fc Receptor Interactions
The IgG Fc region (CH2+CH3 domains) interacts with multiple Fcγ receptors on immune effector cells and with FcRn. Receptor engagement depends on IgG subclass, Fc glycosylation state (especially fucosylation of the Asn297 N-glycan), and local cytokine environment.
| Receptor | CD name / affinity | Cells | Signaling | Function |
|---|---|---|---|---|
| FcγRI | CD64; Kd ~10−8 M (binds monomeric IgG) | Monocytes, macrophages, dendritic cells | ITAM (activating) | Phagocytosis of opsonized targets; antigen uptake for presentation; activated by IFN-γ upregulation |
| FcγRIIA | CD32A; medium affinity (binds immune complexes) | Neutrophils, monocytes, macrophages, platelets | ITAM (activating) | Phagocytosis, respiratory burst, platelet activation; HIT: anti-PF4/heparin IgG binds FcγRIIA on platelets → activation → thrombocytopenia + thrombosis |
| FcγRIIB | CD32B; medium affinity | B cells, mast cells, basophils, macrophages | ITIM (inhibitory) | Maintains B cell tolerance; co-ligation with BCR raises activation threshold; anti-inflammatory; loss of RIIB on B cells → autoantibody production in SLE models |
| FcγRIIIA | CD16A; low–medium affinity (binds immune complexes / IgG-coated cells) | NK cells, macrophages, monocytes | ITAM (activating) | ADCC: NK cells recognize IgG-coated target cells → perforin/granzyme cytotoxicity; therapeutic mAbs with afucosylated Fc (obinutuzumab, benralizumab) bind FcγRIIIA ~10× more avidly → enhanced ADCC efficacy |
| FcγRIIIB | CD16B; GPI-anchored; low affinity | Neutrophils | GPI-linked (no cytoplasmic domain) | Neutrophil-mediated clearance of immune complexes from circulation; trapping on neutrophil surface |
| FcRn | MHC class I-related; pH-dependent (Kd pH 6 << Kd pH 7.4) | Vascular endothelial cells, syncytiotrophoblasts, intestinal epithelium, hepatocytes | No canonical signaling domain | IgG half-life extension via endosomal recycling; placental IgG transfer; oral IgG absorption (?); basis for FcRn-blocking therapy in autoimmune disease |
Complement Activation
IgG1 and IgG3 activate the classical complement pathway by binding C1q at their CH2 domains. C1q is a hexameric bridging protein of the C1 complex (C1q:C1r:C1s = 1:2:2); it requires simultaneous engagement of at least two adjacent Fc regions to trigger conformational changes in C1r/C1s and initiate the cascade.
On an antigen surface, multiple bound IgG molecules can spontaneously form a planar hexameric IgG ring (Fc-Fc contacts via CH2/CH3 interfaces) that optimally presents six Fc regions to the six globular heads of C1q — triggering highly efficient complement activation. This hexamer model explains why high surface IgG density triggers complement far more efficiently than low density: it is not linear, but cooperative.
Complement effector outputs: C3b opsonization → enhanced phagocytosis (CR1, CR3 on macrophages/neutrophils); C3a/C5a anaphylatoxins → mast cell degranulation, vascular permeability, chemotaxis; MAC (C5b-9) → direct lysis of gram-negative bacteria and nucleated target cells.
IgG2: weak classical pathway activation (rigid hinge limits C1q access). IgG4: none (does not bind C1q).
Placental Transfer and Neonatal Immunity
IgG is the only immunoglobulin isotype that undergoes active placental transfer. The mechanism involves FcRn expressed in syncytiotrophoblast cells of the placenta:
- Maternal IgG in intervillous space is endocytosed into syncytiotrophoblast lysosomes (pH ~5.5)
- At low pH, IgG-Fc binds FcRn with high affinity
- The IgG–FcRn complex is transcytosed across the syncytiotrophoblast to the fetal endothelial side
- At fetal plasma pH 7.4, affinity drops and IgG is released into fetal circulation
Transfer efficiency by subclass: IgG1 > IgG4 > IgG3 > IgG2. Transfer begins significantly in the second trimester and accelerates in the third trimester; at term, fetal IgG concentration may exceed maternal concentration (~1.1× maternal level). This passive immunity bridges the gap until infant B-cell-derived IgG appears at ~3–6 months post-birth.
Pathological maternal IgG transfer:
- Anti-Ro/La IgG (maternal SLE/Sjögren) → neonatal lupus (transient rash, hepatitis, complete heart block — the congenital heart block is irreversible)
- Anti-D IgG (Rh incompatibility) → hemolytic disease of the fetus/newborn (HDFN); prevented by Rh-immune globulin (RhoGAM) in Rh-negative mothers
- Anti-TSHR IgG (maternal Graves) → transient neonatal Graves disease; resolves as maternal IgG catabolizes (~3 months)
- Anti-PLA2R IgG (maternal membranous nephropathy) → neonatal nephrotic syndrome (transient)
Therapeutic Applications
Monoclonal antibodies
The vast majority of therapeutic monoclonal antibodies are built on IgG1 scaffolds (for cytotoxic applications requiring ADCC and/or complement: rituximab, trastuzumab, cetuximab, obinutuzumab) or IgG4 scaffolds (where effector function is undesirable: pembrolizumab, nivolumab, durvalumab — checkpoint inhibitors; bispecific antibodies). IgG1 with Fc point mutations (LALA, LALAPG, N297A/Q) are used when antigen blockade alone is desired without effector cell engagement.
IVIG (Intravenous Immunoglobulin)
IVIG is pooled polyclonal IgG from ≥1,000 plasma donors. At immunomodulatory doses (1–2 g/kg), its primary mechanism is FcRn saturation: saturating IVIG doses compete with pathogenic IgG for FcRn binding, accelerating catabolism of all IgG — including autoantibodies. Additional mechanisms include anti-idiotype antibodies, complement consumption, DC tolerization, Treg induction, and FcγRIIB engagement. Indications: CIDP, GBS, MG crisis, dermatomyositis, ITP, Kawasaki disease, primary immunodeficiency replacement.
Subcutaneous immunoglobulin (SCIG)
SCIG allows home administration; slower absorption from SC tissue → steadier serum IgG levels with smaller peak–trough variation; preferred for long-term replacement in primary immunodeficiency. Facilitated SCIG with hyaluronidase enables large volumes (10–20% Ig preparations) once monthly.
Half-life engineering
YTE mutation (M252Y/S254T/T256E) and LS mutation (M428L/N434S) in the CH2/CH3 FcRn-binding interface increase FcRn affinity at pH 6 without affecting pH 7.4 release → extend IgG half-life to 6–8 weeks (vs. ~3 weeks for WT IgG). Used in: motavizumab-YTE (RSV), rozanolixizumab-LS (MG). Inverse approach (FcRn-blocking mutations, e.g., H435A) used in efgartigimod for therapeutic IgG reduction.
Antibody–drug conjugates (ADCs) and bispecifics
ADCs use IgG1 as the targeting scaffold with cytotoxic payload conjugated via engineered cysteines or lysines (trastuzumab emtansine / T-DM1, trastuzumab deruxtecan / T-DXd). Bispecific antibodies most commonly use IgG4 with knob-into-hole CH3 engineering or single-chain Fab fusion to engage two different antigens simultaneously (blinatumomab: CD3×CD19 BiTE; teclistamab: CD3×BCMA).
Pathology
| Condition | IgG involvement | Notes |
|---|---|---|
| Multiple myeloma (IgG subtype) | IgG M-protein (monoclonal IgG) in ~55% of MM cases; IgG kappa > IgG lambda | Clonal plasma cells overproduce structurally intact IgG (whole molecule) or light chain only; serum protein electrophoresis shows M-spike; treat with bortezomib, lenalidomide, daratumumab |
| Warm AIHA | IgG autoantibodies against RBC surface antigens (Rh, Band 3) at 37°C | IgG-coated RBCs detected by direct Coombs (DAT); cleared by splenic macrophages via FcγRIII (extravascular hemolysis); treat with corticosteroids, rituximab, splenectomy |
| HDFN (anti-D) | Maternal IgG anti-D crosses placenta → opsonizes Rh-positive fetal RBCs | Fetal/neonatal hemolytic anemia, jaundice, hydrops fetalis; prevention: Rh(D) immunoglobulin (RhoGAM) given ante/postpartum to Rh-negative sensitized mothers |
| Immune thrombocytopenia (ITP) | IgG autoantibodies against platelet glycoproteins (GPIIb/IIIa = αIIbβ3, GPIb) | Platelet FcγRIIIA / FcγRIIA binding → phagocytosis by splenic macrophages; also direct Fab-mediated platelet destruction; IVIG raises platelet count via FcRn saturation; eltrombopag for chronic ITP |
| Myasthenia gravis | Anti-AChR IgG (IgG1/IgG3) → complement activation at neuromuscular junction | C3b/MAC deposition destroys NMJ postsynaptic membrane; also receptor blocking and accelerated endocytosis by cross-linking; anti-MuSK IgG4 (non-complement-activating; different pathomechanism); FcRn blocker efgartigimod now approved |
| IgG4-related disease | Elevated serum IgG4; IgG4+ plasma cell infiltrates in affected organs | Autoimmune pancreatitis (type 1), sclerosing cholangitis, orbital pseudotumor, retroperitoneal fibrosis; serum IgG4 >135 mg/dL supportive; responds to prednisolone; rituximab for refractory cases |
Cross-Atlas Connections
- Subtype of Antibody (Immunoglobulin) — IgG is one of five Ig isotypes; the IgG entry details the specific subclass biology, Fc receptor pharmacology, and FcRn biology not covered in the generic antibody entry
- Secreted by B cell / Plasma cell — class-switched, affinity-matured B cells differentiate into long-lived bone marrow plasma cells secreting IgG at up to 2,000 molecules per second; short-lived plasmablasts produce IgG acutely
- Activates Complement C3 — IgG1/IgG3 Fc binds C1q → classical pathway → C3 convertase (C4b2a) → C3b opsonization, anaphylatoxins C3a/C5a, MAC assembly
- Engages Macrophage — IgG-opsonized pathogens or cells are cleared by macrophage FcγRI (CD64) and FcγRIIIA (CD16) via phagocytosis and respiratory burst (ADCP)
- Engages Natural killer cell — IgG-coated target cells trigger NK cell FcγRIIIA (CD16A) → ADCC; afucosylated IgG Fc greatly amplifies this interaction; key mechanism of anti-tumor mAbs
- Parent entry Erythropoietin (EPO) — FcRn also recycles albumin and EPO; therapeutic EPO fusion proteins use albumin-FcRn-binding for extended half-life; EPOR-expressing cells can be targeted by IgG bispecific formats
References
- Vidarsson G, Dekkers G, Rispens T. IgG subclasses and allotypes: from structure to effector functions. Front Immunol. 2014;5:520. doi:10.3389/fimmu.2014.00520
- Roopenian DC, Akilesh S. FcRn: the neonatal Fc receptor comes of age. Nat Rev Immunol. 2007;7(9):715–725. doi:10.1038/nri2155
- Nimmerjahn F, Ravetch JV. Fcγ receptors as regulators of immune responses. Nat Rev Immunol. 2008;8(1):34–47. doi:10.1038/nri2206
- Bruhns P, Jorieux S. Solution for a detrimental side effect: FcRn in IgG4-related disorders. Nat Struct Mol Biol. 2021;28:12–14.
- Wang W, Wang EQ, Balthasar JP. Monoclonal antibody pharmacokinetics and pharmacodynamics. Clin Pharmacol Ther. 2008;84(5):548–558. doi:10.1038/clpt.2008.170