What is IgG (Immunoglobulin G) subclasses testing?

IgG Subclass Testing: Purpose and Clinical Significance

IgG subclass testing measures the levels of the four IgG subclasses (IgG1, IgG2, IgG3, and IgG4) to evaluate for potential deficiencies that may contribute to recurrent infections, particularly in patients with normal total immunoglobulin levels. 1

What Are IgG Subclasses?

• IgG is the most common immunoglobulin isotype and is divided into four subclasses (IgG1, IgG2, IgG3, and IgG4), each with unique biological functions 2
• IgG1 comprises approximately 60% of total IgG, while the other subclasses make up smaller proportions 1
• Each subclass has distinct roles in immune defense:
  • IgG1 and IgG3 primarily respond to protein antigens and have strong complement activation properties 2
  • IgG2 is crucial for responses to polysaccharide antigens, particularly bacterial capsular polysaccharides 2, 3
  • IgG4's role is less clear but may have both protective and sensitizing functions 2

Clinical Indications for Testing

• Testing should be considered in patients with recurrent sinopulmonary infections, particularly with encapsulated bacteria, despite normal total immunoglobulin levels 1, 4
• Testing is indicated when infections are resistant to standard medical therapy or negatively affect quality of life 5, 1
• Other indications include:
  • Poor specific antibody responses to vaccines 1, 4
  • Recurrent otitis media, bronchitis, or bronchiectasis 5
  • Infections with organisms of low pathogenicity 5

Interpretation of Results

• Normal IgG subclass values fall within 2 standard deviations of the mean, with approximately 2.5% of healthy individuals naturally having levels below this range for at least one subclass 1, 4
• Abnormal results should be confirmed with repeat testing at least one month apart 1, 4
• Clinical significance of low subclass levels should be evaluated in the context of:
  • Presence of recurrent infections 1
  • Impact on quality of life 1
  • Response to standard antibiotic therapy 1
  • Specific antibody production to vaccines 1, 4

Common Pitfalls and Important Considerations

• Normal total IgG does not exclude subclass deficiency; conversely, isolated low subclass levels may not be clinically significant 1
• IgG subclass deficiency may be secondary to medications (antiepileptics, gold, penicillamine, hydroxychloroquine, NSAIDs) 1, 4
• Some patients with IgG subclass deficiency may evolve into more severe phenotypes like Common Variable Immunodeficiency (CVID) over time 1
• IgG4 is present in very low concentrations in children younger than 10 years, so IgG4 deficiency should not be diagnosed before this age 4
• IgG replacement therapy should not be initiated based solely on laboratory values without clinical correlation 1

Associated Conditions

• IgG subclass deficiencies may be associated with:
  • Other primary immunodeficiencies, particularly IgA deficiency 1, 2
  • Secondary immunodeficiencies (HIV infection, post-HSCT) 1
  • Atopic conditions 1
  • Autoimmune diseases 2, 6
  • Trisomy 21 1

Diagnostic Algorithm

1. First, measure total immunoglobulin levels (IgG, IgA, and IgM) 4
2. If total IgG is normal but clinical suspicion remains high, measure all four IgG subclasses 4
3. Confirm abnormal results with repeat testing at least one month later 1, 4
4. Assess functional antibody production by measuring specific antibody responses to both protein antigens (e.g., tetanus toxoid) and polysaccharide antigens (e.g., pneumococcal vaccines) 4
5. Evaluate clinical significance based on infection history, quality of life impact, and response to standard therapies 1