Immunoglobulin GEdit

Immunoglobulin G (IgG) is the most abundant antibody isotype in human serum and a central effector molecule of the adaptive immune system. It is produced by plasma cells derived from B lymphocytes after exposure to antigens, and it coordinates a range of defense mechanisms that protect against bacterial, viral, and toxin-mediated threats. In addition to its role in pathogen neutralization and opsonization, IgG is uniquely capable of crossing the placental barrier, providing passive immunity to the fetus and newborn. Clinically, IgG is collected from healthy donors to produce plasma-derived products used in replacement therapy for immunodeficiency and as an immunomodulatory treatment for various autoimmune and inflammatory diseases.

IgG’s functional versatility arises from its structure and the diversity of its subclasses, which together shape how it interacts with pathogens, cells, and the complement system. The molecule is a Y-shaped immunoglobulin composed of two identical heavy chains (gamma chains in humans) and two light chains, forming two antigen-binding Fab regions and one Fc region that engages cellular receptors and the complement cascade. The Fc region’s interactions with Fc receptors on phagocytes and with components of the complement system determine downstream effects such as phagocytosis, inflammation, and toxin neutralization. IgG’s ability to persist in circulation is aided by the neonatal Fc receptor neonatal Fc receptor (FcRn), which protects IgG from rapid degradation and extends its half-life.

Structure and subclasses

Molecular structure

IgG molecules are monomers with two identical antigen-binding sites. Post-translational glycosylation of the Fc region modulates receptor binding and effector functions. The Fc region’s architecture allows two main pathways of action: engagement of Fc gamma receptors on immune cells and initiation of the classical complement pathway when IgG binds antigen-organized complexes.

IgG subclasses

Humans express four IgG subclasses: IgG1, IgG2, IgG3, and IgG4. Each subclass has distinct serum distributions and effector profiles: - IgG1 and IgG3 are the most potent at activating the classical complement pathway and binding Fc receptors, making them particularly effective against protein antigens and certain bacteria. - IgG2 is more responsive to polysaccharide antigens and often dominates responses to encapsulated bacteria. - IgG4 has anti-inflammatory properties and can undergo Fab-arm exchange, a process that can alter antigen recognition and reduce inflammatory signaling.

Distribution and subclass function can influence susceptibility to infections and the clinical manifestations of certain immunodeficiencies, including selective IgG subclass deficiencies. See Common variable immunodeficiency and Selective IgG deficiency for related conditions.

Fc-mediated functions and placental transfer

IgG operates through several key mechanisms: - Neutralization of viruses and toxins by binding to critical epitopes, preventing cell entry. - Opsonization, which marks pathogens for phagocytosis by macrophages and neutrophils via Fc gamma receptors. - Activation of the classical complement pathway, enhancing inflammation and pathogen clearance. - Placental transfer, enabling maternal IgG to provide passive immune protection to the fetus and newborn, a process mediated by FcRn that also regulates maternal IgG levels in early life.

These properties place IgG at the center of both protective immunity and immune-mediated pathology, making its therapeutic manipulation a mainstay in clinical immunology. Related topics include Humoral immunity and Fc receptor.

Production, pharmacokinetics, and clinical use

Production and pharmacokinetics

Most therapeutic IgG products are derived from pooled human plasma through rigorous purification processes to ensure safety and consistency. After administration, IgG distributes primarily in extracellular fluids and has a half-life of roughly three weeks, varying with subclass and individual factors. The pharmacokinetic profile supports dosing strategies that balance protection against infections with minimizing adverse effects.

Therapeutic forms and indications

The two main clinically used forms are intravenous immunoglobulin (IVIG) and subcutaneous immunoglobulin (SCIG). IVIG delivers a large bolus of IgG, often used for replacement therapy in humoral immunodeficiencies, while SCIG enables more steady, slower absorption suitable for outpatient administration.

Replacement therapy for immunodeficiency: Individuals with humoral immune defects, such as X-linked agammaglobulinemia or Common variable immunodeficiency, rely on IgG replacement to prevent recurrent infections and maintain baseline immune defenses.
Immunomodulatory therapy: IgG products modulate immune responses in various autoimmune and inflammatory diseases, sometimes reducing autoantibody activity, altering cytokine signaling, or dampening pathogenic immune processes.

See also Intravenous immunoglobulin and Subcutaneous immunoglobulin for more detail on indications, dosing, and administration.

Clinical conditions and examples

IgG-based therapies have a broad clinical footprint: - Kawasaki disease: IVIG is a standard therapy to reduce the risk of coronary artery aneurysms in affected children. - Autoimmune and inflammatory diseases: IT P (immune thrombocytopenia), Guillain–Barré syndrome, chronic inflammatory demyelinating polyneuropathy (CIDP), autoimmune myasthenia gravis, and other autoimmune conditions may respond to IVIG or SCIG as part of a broader treatment plan. - Infection-prone populations: Immunoglobulin replacement improves outcomes in patients with poor antibody production, helping to reduce the frequency and severity of infections.

For readers seeking deeper background, see Kawasaki disease, Immune thrombocytopenia, and Guillain–Barré syndrome.

Safety, risks, and controversies

IgG products are generally well tolerated but carry risks typical of plasma-derived therapies. Common adverse effects include infusion-related reactions such as headaches, fever, and mild flu-like symptoms. Rare but more serious risks include thromboembolism, aseptic meningitis, acute kidney injury, and transfusion-associated reactions. Proper product selection, patient monitoring, and individualized dosing help mitigate these risks. Modern manufacturing and donor screening have markedly reduced infectious risks, with careful screening for blood-borne pathogens and nanofiltration steps.

Contemporary debates surrounding IgG therapies center on cost, supply, and clinical value. IVIG, in particular, is a relatively expensive, finite-resource product, and shortages have occurred in various health systems, prompting discussions about prioritization, alternative therapies, and payer policies. While high-level evidence supports IVIG for several approved indications, the magnitude of benefit can vary by condition, patient, and dosing strategy, leading to ongoing discussions about when and how to use IgG therapies most efficiently. See Intravenous immunoglobulin and Subcutaneous immunoglobulin for policy and practice considerations, and Kawasaki disease for condition-specific guidance.