IgG Subclasses: Structure, Function, and Their Roles in Health

Immunoglobulin G (IgG) is the most abundant antibody in human circulation, playing a vital role in immune defense. It is subdivided into four subclasses—IgG1, IgG2, IgG3, and IgG4—each with unique structural and functional properties that influence immune responses. These differences impact how the body responds to infections, autoimmune diseases, allergies, and therapeutic interventions.

Structure And Classification

IgG antibodies share a fundamental Y-shaped structure composed of two heavy and two light chains, linked by disulfide bonds. Despite this common framework, the four IgG subclasses exhibit distinct structural variations that affect stability, flexibility, and biological interactions. These differences arise primarily from variations in the hinge region, a segment between the Fab (antigen-binding) and Fc (effector function) domains. The hinge region dictates antigen binding, immune receptor interactions, and complement engagement, making it a defining feature of subclass functionality.

IgG3 has the longest hinge region, with up to 62 amino acids, enhancing flexibility and antigen-binding but making it more susceptible to proteolytic degradation, reducing its half-life to about 7 days—significantly shorter than the 21-day half-life of IgG1, IgG2, and IgG4. In contrast, IgG2 has a rigid hinge with additional disulfide bonds, limiting immune interactions but increasing structural stability. IgG4, while structurally similar to IgG1, uniquely undergoes Fab-arm exchange, where half-molecules swap between antibodies, forming bispecific antibodies that bind two different antigens.

The Fc region of each subclass also varies in affinity for Fc gamma receptors (FcγRs) and complement proteins, affecting immune interactions. IgG1 and IgG3 strongly bind FcγRI, FcγRIIa, and FcγRIII, facilitating antibody-dependent cellular cytotoxicity (ADCC) and phagocytosis. IgG2, with its rigid hinge, interacts weakly with FcγRs, limiting immune engagement. IgG4, despite structural similarity to IgG1, has reduced FcγR affinity and does not effectively activate complement, contributing to its immunomodulatory role.

Distinguishing Features Of Each Subclass

Each IgG subclass has distinct structural and biochemical properties that influence its behavior. These differences, stemming from variations in the hinge region, Fc domain interactions, and molecular flexibility, affect stability and function.

IgG1

IgG1 is the most abundant subclass in human serum, comprising 60-70% of total IgG. Its moderately flexible hinge region allows a balance between stability and antigen-binding. IgG1 interacts efficiently with FcγRs and complement proteins, forming stable immune complexes.

With a half-life of about 21 days, IgG1 remains in circulation longer, making it ideal for monoclonal antibody therapies, particularly in oncology and autoimmune diseases. Many therapeutic antibodies, such as rituximab and trastuzumab, are engineered as IgG1 due to their potent immune effector functions.

IgG2

IgG2 accounts for 20-30% of total IgG and has a rigid hinge with additional disulfide bonds, reducing flexibility but increasing stability. This structure influences its functional role, particularly in recognizing carbohydrate antigens on bacterial polysaccharide capsules, making it crucial in responses to encapsulated bacteria like Streptococcus pneumoniae and Haemophilus influenzae.

Unlike IgG1, IgG2 has lower affinity for FcγRs and weak complement activation, reducing its ability to mediate ADCC. While less common in monoclonal antibody therapies, it is sometimes preferred for targeting non-protein antigens or minimizing immune activation.

IgG3

IgG3 has an extended hinge region, providing exceptional flexibility and enhanced antigen-binding. However, this structure also makes it more susceptible to proteolytic cleavage, limiting its half-life to about 7 days.

Its Fc region strongly binds FcγRs, particularly FcγRI and FcγRIII, enhancing immune cell interactions. IgG3 is the most potent activator of complement among the IgG subclasses, making it highly effective in immune complex formation and complement-dependent cytotoxicity.

Despite its strong effector functions, IgG3’s short half-life limits therapeutic applications. Some engineered monoclonal antibodies aim to extend its stability while preserving its functional advantages.

IgG4

IgG4 is the least abundant subclass, comprising less than 5% of total IgG. It has a hinge region similar in length to IgG2 but with distinct functional properties, including Fab-arm exchange, which results in bispecific antibodies binding two different antigens.

IgG4 has low FcγR affinity and does not effectively activate complement, reducing immune effector functions. Instead, it plays a role in immunomodulation, particularly in chronic antigen exposure conditions. It is often observed in tolerance-inducing immune responses, such as allergen immunotherapy.

Due to its unique properties, IgG4 is used in therapeutic antibodies where reduced immune activation is desired. Pembrolizumab and nivolumab, both IgG4-based monoclonal antibodies, block immune checkpoints without triggering strong immune effector functions, making IgG4 valuable in immunotherapy.

Role In Infectious Disease Defense

The IgG subclasses contribute differently to immune defense against bacterial, viral, fungal, and parasitic infections. Their structural differences dictate how they interact with pathogens, influencing pathogen neutralization, opsonization, and complement activation.

IgG1 and IgG3, with strong FcγR and complement protein affinity, are highly effective in neutralizing viral particles and bacterial toxins. IgG1 dominates responses against protein-based antigens like viral envelope proteins and bacterial exotoxins, while IgG3 excels in forming immune complexes that enhance phagocytosis. This makes them particularly valuable in defending against pathogens like HIV, which requires strong antibody-mediated neutralization.

IgG2 specializes in targeting polysaccharide antigens, such as those on encapsulated bacteria like Streptococcus pneumoniae and Neisseria meningitidis. Its rigid hinge limits Fc receptor interactions but enhances stability, supporting prolonged immune surveillance. Individuals with IgG2 deficiencies are more susceptible to recurrent infections with encapsulated bacteria.

IgG4, in contrast, does not efficiently activate complement or bind Fc receptors, making it less effective in direct pathogen elimination. However, its Fab-arm exchange may contribute to immune regulation in chronic infections. Elevated IgG4 levels have been observed in helminth infections, where immune modulation prevents excessive inflammation and tissue damage.

Role In Autoimmune And Allergic Conditions

IgG subclasses influence autoimmune and allergic conditions through their structural and functional properties. IgG1 and IgG3, known for strong effector functions, are frequently implicated in autoimmune diseases where antibody-mediated tissue damage occurs. They are commonly associated with systemic lupus erythematosus (SLE) and rheumatoid arthritis, where immune complexes contribute to inflammation and tissue injury.

In contrast, IgG4 is linked to regulatory immune responses. Unlike other subclasses, IgG4 does not effectively activate complement or engage FcγRs, making it less inflammatory. This is evident in IgG4-related disease (IgG4-RD), a fibroinflammatory condition characterized by tissue infiltration of IgG4-expressing plasma cells. In allergic conditions, IgG4 is associated with immune tolerance, as allergen-specific immunotherapy often increases IgG4 levels, suggesting a role in dampening allergic responses by competing with IgE for antigen binding.

Clinical Assessment And Testing

IgG subclass evaluation involves immunological assays that measure serum concentrations, aiding in diagnosing immune deficiencies, assessing vaccine responses, and identifying links to chronic infections or autoimmune diseases. Since total IgG levels may appear normal despite subclass imbalances, subclass-specific testing provides a clearer picture of immune function.

Laboratories commonly use nephelometry or enzyme-linked immunosorbent assays (ELISA) to quantify IgG subclasses. Reference ranges vary by age, as IgG2 and IgG4 levels increase later in childhood. Physicians often pair subclass assessments with vaccine response tests, such as pneumococcal polysaccharide immunization, to determine clinical significance.

Subclass Deficiencies

IgG subclass deficiencies can lead to increased infection susceptibility, particularly in childhood. IgG2 deficiency, the most common, often manifests as recurrent respiratory infections due to its role in targeting encapsulated bacteria. Children with low IgG2 levels frequently experience sinusitis, otitis media, and pneumonia.

IgG3 deficiency, though less common, is associated with poor viral clearance, particularly in respiratory infections. IgG4 deficiency is often inconsequential, but its absence has been linked to increased allergic disease risk. Treatment strategies depend on severity, with immunoglobulin replacement therapy considered for recurrent, severe infections.

Therapeutic Relevance

IgG subclasses influence therapeutic antibody development. IgG1 is widely used in monoclonal antibody therapies due to its strong effector functions, making it ideal for cancer immunotherapy and autoimmune disease treatments. Many FDA-approved therapeutic antibodies, such as trastuzumab and adalimumab, belong to the IgG1 subclass.

IgG4-based therapeutics, such as pembrolizumab and nivolumab, are designed for immune checkpoint inhibition, benefiting from IgG4’s reduced immune activation properties. Research into IgG3 engineering aims to enhance its half-life while preserving its potent immune functions, potentially improving vaccines against challenging viral infections. IgG4’s role in immune tolerance is also being explored for allergen-specific immunotherapy.