IgG3

IgG3 Full Name

immunoglobulin heavy constant gamma 3 (G3m marker)

IgG3 Introduction

Immunoglobulin G3 (IgG3) is one of the four IgG subclasses in human serum. Although its concentration is relatively low compared to total IgG, its unique molecular structure endows it with distinct biological properties that set it apart from the other subclasses. The most striking structural feature of IgG3 is its exceptionally long hinge region. At the genetic level, this extended hinge is encoded by multiple independent exons. The most common allele comprises an initial exon encoding 17 amino acids, followed by three repetitive exons each encoding 15 amino acids. This distinctive genetic and protein architecture grants the IgG3 molecule exceptionally high segmental flexibility, allowing its Fab arms to pivot with a greater range and angle. This theoretically enables more effective bridging of spatially distant antigenic epitopes. Furthermore, the hinge region is rich in cysteine residues, capable of forming up to 11 interchain disulfide bonds. While contributing to its flexibility, this also makes its structure remarkably complex and somewhat rigid. IgG3 has the shortest half-life among all IgG subclasses, typically only about 7 days—far less than the approximately 21 days for IgG1, IgG2, and IgG4. The primary reason for its short half-life is its low binding affinity for the neonatal Fc receptor (FcRn).

Figure 1. Schematic Overview of the Human IgG3 Antibody. (Source: Damelang T, et al. 2019)

The ultra-long hinge region of IgG3 not only enhances antigen-binding flexibility but also significantly optimizes the effector functions mediated by its Fc fragment. Among all IgG subclasses, IgG3 is the most potent activator of the classical complement pathway. Complement activation is a central mechanism of humoral immunity for clearing pathogens and immune complexes. Upon binding its target antigen, the Fc region of IgG3 can bind the initiating complement molecule C1q with high efficiency, triggering the downstream complement cascade, leading to pathogen lysis or opsonophagocytosis. Additionally, IgG3 exhibits high affinity for various Fc gamma receptors (FcγRs) on cell surfaces, particularly showing strong binding to activating FcγRs on immune cells such as macrophages, neutrophils, and natural killer (NK) cells. This potent binding makes it play a critical role in antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP).

Selective IgG3 deficiency is one of the most common IgG subclass deficiencies in clinical practice. Its main clinical manifestation is recurrent infections, particularly bacterial respiratory tract infections. Patients often suffer from chronic sinusitis, pharyngitis, recurrent bronchitis, bronchopneumonia, and acute exacerbations of asthma. This is closely linked to IgG3's central role in clearing common respiratory pathogens. The second category of diseases closely associated with IgG3 is autoimmune disorders. Given its potent pro-inflammatory and effector capabilities, when IgG3 acts erroneously as an autoantibody attacking self-tissues, it can cause severe pathological damage. In systemic lupus erythematosus (SLE), IgG3 subtype autoantibodies targeting self-nucleosome antigens have been strongly correlated with the activity and severity of lupus nephritis. These IgG3 autoantibodies can form immune complexes in the glomeruli, efficiently activate complement, and trigger intense inflammatory responses, leading to kidney injury.

Alternate Names for IgG3

IGHG3; immunoglobulin heavy constant gamma 3 (G3m marker); IgG3;

• 1. Damelang T, et al. Role of IgG3 in Infectious Diseases. Trends Immunol. 2019 Mar;40(3):197-211.
  2. Napodano C, et al. Immunological Role of IgG Subclasses. Immunol Invest. 2021 May;50(4):427-444.