What are Immunoglobulin G (IgG) subclasses?

Immunoglobulin G (IgG) Subclasses: Structure, Function, and Clinical Significance

IgG subclasses are four distinct variants of IgG (IgG1, IgG2, IgG3, and IgG4) that differ in their structure, biological functions, and serum concentrations, with each subclass having specific roles in immune response and protection against different types of pathogens. 1, 2

Structure and Distribution

• IgG is the most abundant immunoglobulin isotype in human serum and comprises four subclasses that differ in their constant regions, particularly in their hinges and upper CH2 domains 2
• The four subclasses are distributed in different proportions in serum:
  • IgG1 comprises approximately 60% of total IgG 1
  • IgG2, IgG3, and IgG4 make up the remainder, with IgG4 present in very low concentrations, especially in children younger than 10 years of age 3
• Normal IgG subclass values are defined as within 2 standard deviations of the mean, with approximately 2.5% of the healthy population naturally having levels below this range for at least one subclass 1

Biological Functions

• Each IgG subclass has distinct biological functions based on their structure:
  • IgG1 and IgG3 primarily mediate responses to protein antigens 4, 5
  • IgG2 predominantly mediates responses to polysaccharide antigens, particularly from encapsulated bacteria 4, 5
  • IgG4's role is less clear but may have both protective and sensitizing functions 4
• The subclasses differ in their ability to activate complement:
  • IgG1 and IgG3 have the highest complement-activating capacity 6, 2
  • IgG2 has limited complement activation ability 2
  • IgG4 generally does not activate complement via the classical pathway 2
• The subclasses have different affinities for Fc gamma receptors (FcγR):
  • IgG1 has the highest FcγR-binding affinity, followed by IgG3, IgG2, and IgG4 7
  • This affects their ability to trigger effector functions like antibody-dependent cell-mediated cytotoxicity (ADCC) and phagocytosis 7, 2

Development and Class Switching

• IgG subclass switching follows a sequential pattern: IgG3 → IgG1 → IgG2 → IgG4 6
• This process is regulated by interaction with T cells and cytokines 6
• The development of IgG subclasses may follow either:
  • A single lineage model where B cells can successively switch to produce any IgG subclass 5
  • A multi-lineage model where different B cell lineages are committed to producing specific IgG subclasses 5

Clinical Significance

IgG Subclass Deficiency (IGGSD)

• IGGSD is defined as having one or more IgG subclass levels below the 5th percentile with normal total IgG, IgA, and IgM levels 3, 1
• Clinical manifestations typically include:
  • Recurrent respiratory tract infections, particularly with encapsulated bacteria 3, 4
  • Increased susceptibility to sinopulmonary infections 1
  • Possible association with atopic and autoimmune diseases 3, 4
• Secondary causes of IGGSD include:
  • Medications (antiepileptics, gold, penicillamine, hydroxychloroquine, NSAIDs) 3, 1
  • Other immunodeficiencies (HIV, post-HSCT) 3, 1
  • Associated syndromes like Trisomy 21 3

Diagnostic Approach

• Measurement of IgG subclasses should be considered in patients with:
  • Recurrent respiratory infections despite normal total immunoglobulin levels 3, 1
  • Poor vaccine responses suggesting Specific Antibody Deficiency (SAD) 3, 8
• All four subclasses should be measured simultaneously 3
• Abnormal levels should be confirmed by at least one additional measurement at least one month apart 3, 8
• Functional antibody production should be assessed by measuring responses to both protein and polysaccharide vaccines 8

Management

• For asymptomatic individuals with low IgG subclass levels, no specific intervention is needed 1
• For patients with recurrent infections:
  • Aggressive antimicrobial therapy and prophylaxis 3
  • Aggressive treatment of any atopic disease 3
  • Consider IgG replacement therapy in selected cases with:
    • Recurrent infections affecting quality of life 3, 1
    • Failure of or intolerance to antibiotic therapy 3
    • Impaired specific antibody production 3, 1

Important Considerations and Pitfalls

• A one-time low level of one or more IgG subclasses is not sufficient for diagnosis of IGGSD 3
• IgG4 deficiency should not be diagnosed before age 10 years due to naturally low levels in children 3
• Some patients with IGGSD may evolve into more severe phenotypes like Common Variable Immunodeficiency (CVID) over time 1
• IgG replacement therapy should not be initiated based solely on laboratory values without clinical correlation 1
• When IgG replacement therapy is indicated, human normal immunoglobulin contains a distribution of IgG subclasses closely proportional to that in native human plasma 9