What is Immunoglobulin G (IgG)?

Immunoglobulin G (IgG): Structure, Function, and Clinical Applications

Immunoglobulin G (IgG) is the most abundant antibody isotype in human serum, comprising approximately 60% of total immunoglobulins, and plays a critical role in immune defense through pathogen neutralization, opsonization, complement activation, and immunomodulation. 1, 2

Structure and Subtypes

• IgG is divided into four subclasses (IgG1, IgG2, IgG3, and IgG4) with IgG1 being the most abundant, comprising approximately 60% of total IgG 1
• Each IgG molecule consists of two heavy chains and two light chains, forming a Y-shaped structure with antigen-binding fragments (Fab) and a crystallizable fragment (Fc) that interacts with cell surface receptors and complement 2
• The different IgG subclasses have varying abilities to activate complement and bind to Fc receptors, resulting in different functional properties 2, 3

Physiological Functions

• IgG provides protection against microbial pathogens through multiple mechanisms including neutralization of toxins and viruses, opsonization of bacteria for phagocytosis, and activation of the complement cascade 2, 4
• IgG is the only antibody class that can cross the placenta, providing passive immunity to the developing fetus 5
• IgG has a relatively long half-life (approximately 21 days) compared to other antibody isotypes, allowing for prolonged protection 2
• IgG antibodies play a dual role in immune regulation with both pro-inflammatory and anti-inflammatory properties depending on context, concentration, and glycosylation patterns 3

Clinical Applications and Testing

Diagnostic Applications

• Serum IgG levels are measured as part of the evaluation for suspected immunodeficiency disorders 5
• IgG subclass measurements should only be performed when clinically indicated, particularly when evaluating recurrent infections despite normal total IgG levels 1
• Specific antibody responses to vaccines (both protein and polysaccharide) are often measured alongside IgG levels to assess functional antibody production 5, 1
• IgG antibodies against specific pathogens can be measured to diagnose current or past infections, such as in Q fever where phase I and II IgG antibodies help distinguish between acute and chronic infection 5

Therapeutic Applications

• IgG replacement therapy is indicated for disorders with significantly impaired antibody production, including primary immunodeficiencies like X-linked agammaglobulinemia and Common Variable Immunodeficiency (CVID) 5
• High-dose intravenous immunoglobulin (IVIG) therapy is used as an immunomodulatory treatment for various autoimmune and inflammatory disorders 6
• IgG can be administered through different routes:
  • Intravenous (IVIG): Higher doses possible but more systemic reactions
  • Subcutaneous (SCIG): Fewer systemic reactions but more local reactions
  • Intramuscular (IGIM): Less commonly used 7

Clinical Considerations for IgG Replacement Therapy

• IgG replacement therapy should be initiated based on clinical evidence of impaired antibody function causing recurrent infections, not solely on laboratory values. 1
• The standard dose for IgG replacement therapy is typically 400-600 mg/kg every 3-4 weeks for IVIG or equivalent doses weekly/biweekly for SCIG 5, 1
• IgG therapy can interfere with the immune response to live vaccines; specific waiting periods are recommended between IgG administration and vaccination 5
• Adverse reactions to IgG therapy include:
  • Immediate reactions (within 6 hours): headache, fever, chills
  • Delayed reactions (6 hours to 1 week): persistent headache, aseptic meningitis, renal failure
  • Late reactions (weeks to months): rare but potentially severe 7

Special Considerations

• Patients receiving antibody-containing products (including IgG) should delay measles or varicella vaccination for specific intervals based on the dose received, as passive antibodies can interfere with vaccine response 5
• IgG replacement therapy might be necessary even after definitive therapy such as hematopoietic stem cell transplantation if B-cell function is not restored 5
• The presence of anti-IgA antibodies in IgA-deficient patients is a rare but potential risk factor for anaphylactic reactions to IVIG, though the actual risk is very small 5
• Regular monitoring of IgG trough levels, blood cell counts, and serum chemistry is recommended for patients on IgG replacement therapy 5

Common Pitfalls in IgG Testing and Interpretation

• Normal total IgG does not exclude IgG subclass deficiency; conversely, isolated low subclass levels may not be clinically significant without evidence of impaired antibody function 1
• IgG subclass deficiency may be secondary to medications (antiepileptics, gold, penicillamine, hydroxychloroquine, NSAIDs) 1
• Some patients with IgG subclass deficiency may evolve into more severe phenotypes like Common Variable Immunodeficiency (CVID) over time, requiring ongoing monitoring 1
• Measurement of specific antibody responses to vaccines is often more clinically relevant than isolated IgG subclass measurements 5, 1