What are the different IgG (Immunoglobulin G) subclasses and their functions?

IgG Subclasses: Structure and Function

Human IgG consists of four distinct subclasses (IgG1, IgG2, IgG3, and IgG4), each with unique structural properties, antigen specificities, and biological functions that are critical for effective immune responses.

Subclass Distribution and Proportions

• IgG1 comprises approximately 60% of total IgG and represents the predominant subclass in healthy individuals 1
• IgG2, IgG3, and IgG4 make up the remaining 40% in varying proportions 1
• IgG4 is present in very low concentrations in children younger than 10 years of age, and IgG4 deficiencies should not be diagnosed before age 10 years due to poorly defined normal ranges 2
• IgG levels gradually increase with age, reaching adult-like levels by 59 months 3

Functional Characteristics by Subclass

IgG1 and IgG3: Protein Antigen Responders

• IgG1 and IgG3 predominantly mediate responses to protein antigens and are the primary antibodies produced against viral and bacterial protein structures 4, 5
• These subclasses have major ability to bind to Fc gamma receptors on immune cells, facilitating antibody-dependent cellular cytotoxicity and phagocytosis 6
• IgG1 and IgG3 autoantibodies predominate in non-organ-specific autoimmune conditions such as rheumatoid arthritis and systemic lupus erythematosus 7
• Low IgG1 levels are sometimes associated with low IgG3 levels 2

IgG2: Polysaccharide Antigen Specialist

• IgG2 mediates the response to polysaccharide antigens, particularly bacterial capsular carbohydrates from encapsulated organisms like Haemophilus influenzae and Streptococcus pneumoniae 4, 6
• Carbohydrate antigens preferentially elicit IgG2 antibodies, making this subclass critical for defense against encapsulated bacteria 5
• Impaired polysaccharide responses are observed commonly among young patients with IgG2 subclass deficiency 2
• Low IgG2 levels are sometimes associated with low IgG4 levels and/or low IgA levels 2

IgG4: The Enigmatic Subclass

• The biological role of IgG4 remains unclear, with ongoing debate about whether these antibodies function as protective or sensitizing antibodies 6
• IgG4 antibodies are regularly encountered in organ-specific autoimmune diseases, suggesting continuous stimulation by target organs 7
• IgG4 activates complement using an alternative route, distinct from other subclasses 6
• IgG4 deficiency is distinct from other antibody deficiencies and requires specific clinical context for interpretation 8

Clinical Implications of Subclass Biology

Infection Susceptibility Patterns

• An inability to produce antibody of the optimally protective isotype can result in selective immunodeficiency, particularly for responses to bacterial carbohydrate antigens that are normally of IgG2 isotype 4
• Recurrent respiratory tract viral and encapsulated bacterial infections are the most common clinical associations with IgG subclass deficiency 2
• Failure to produce appropriate specific antibody responses may result in recurrent upper and/or lower respiratory tract infections 4

Age-Related Considerations

• Normal ranges for IgG subclasses vary significantly with age, and approximately 2.5% of healthy individuals naturally have levels below 2 standard deviations of the mean for at least one subclass 1, 8
• The frequency and severity of infections might wane over time, even when the immunologic abnormality persists, or infections could persist while the subclass abnormality resolves 2

Associated Conditions

• IgG subclass deficiencies are often associated with IgA deficiency, absence of immune response following vaccination, allergic or autoimmune diseases, and diseases of the central nervous system 6
• Rare patients can present early with IgG subclass deficiency and evolve into more severe phenotypes such as Common Variable Immunodeficiency (CVID) later in life 2, 1

Critical Diagnostic Pitfalls

• Normal total IgG does not exclude clinically significant IgG subclass deficiency, and conversely, isolated low subclass levels may not be clinically significant 1, 8
• IgG subclass deficiency may be secondary to medications including antiepileptic drugs, gold, penicillamine, hydroxychloroquine, and NSAIDs 1, 3
• Measurement of IgG subclasses should only be performed when clinically indicated in patients with recurrent respiratory infections despite normal total immunoglobulin levels 1
• Abnormal subclass levels should be confirmed with repeat testing at least one month apart before making clinical decisions 8