Immunoglobulin G, or IgG, is the most abundant class of antibody in human blood, accounting for approximately 75% of all circulating antibodies. This protein is a primary component of the adaptive immune system, providing long-term protection and immunological memory against pathogens encountered previously. B cells produce IgG molecules that patrol the body, neutralizing toxins and marking invaders for destruction. While often discussed as a single entity, IgG exists as four distinct subtypes, each with a specialized structure and a unique role in the body’s defense strategy.
The Identity and Abundance of IgG Subtypes
The four human IgG subtypes are designated IgG1, IgG2, IgG3, and IgG4, and they are named in descending order of their concentration in healthy human serum. IgG1 is the most prevalent, typically making up between 60% and 70% of the total IgG pool, making it the workhorse of the antibody-mediated immune response. The second most common subtype, IgG2, accounts for approximately 20% to 30% of the total. IgG3 and IgG4 are present in much smaller amounts, each comprising only about 4% to 8% of the total IgG. This difference in baseline abundance hints at their distinct functions. The relative proportions of these four subtypes are maintained in a healthy state, but they can shift significantly during an active infection or an immune disorder.
Structural Differences and Half-Lives
Though the four subtypes share a largely identical overall Y-shaped structure, subtle but meaningful variations in their heavy chains dictate their functional diversity. The most significant structural difference lies in the flexible hinge region that connects the antibody’s antigen-binding arms (Fab) to its constant tail (Fc). The hinge region of IgG3 is notably longer and contains more disulfide bonds than the others. The structural variations in the constant Fc region also determine how the antibodies interact with immune cells and other proteins, such as those of the complement system. These molecular differences directly influence the half-life of each subtype in the bloodstream. IgG1, IgG2, and IgG4 all share a relatively long half-life of around 21 days, regulated by a receptor that recycles the antibodies back into circulation. Due to its extended hinge region, IgG3 has a much shorter half-life of only about seven days.
Specialized Immune Actions of Each Subtype
IgG1: Protein Antigens and Opsonization
IgG1 is the primary responder to protein antigens, making it highly effective against most viruses, toxins, and many soluble proteins. It excels at opsonization, the process of coating a pathogen to flag it for ingestion by phagocytic immune cells.
IgG2: Polysaccharide Antigens
IgG2 is uniquely adapted to target polysaccharide, or sugar-based, antigens, such as the thick capsules found on certain encapsulated bacteria like Streptococcus pneumoniae. An immune response to these carbohydrate structures largely relies on IgG2, making it a powerful defense against these particular bacterial infections.
IgG3: Complement Activation
IgG3 is the most potent activator of the classical complement cascade, a powerful chain reaction of proteins that can directly puncture the membrane of a pathogen. This subtype is produced early in an immune response, particularly against viral infections. Its strong complement-fixing ability allows for rapid clearance, and its short half-life suggests a role for immediate, high-impact action.
IgG4: Immune Modulation
The least abundant subtype, IgG4, plays a unique role in modulating, rather than driving, inflammation. It is often associated with chronic exposure to an antigen and promotes immune tolerance. IgG4 is known for its ability to undergo Fab-arm exchange, swapping half-molecules with another IgG4 antibody. This unique molecular flexibility prevents the formation of large, inflammatory immune complexes and is a key factor in blocking allergic responses by competing with IgE.
Diagnosing and Managing Subtype Deficiencies
A deficiency in one or more IgG subtypes occurs when the level of a specific subtype falls below the normal range for a person’s age, even if the total IgG level remains within normal limits. This condition often results in a pattern of recurrent bacterial infections, particularly affecting the respiratory tract, such as chronic sinusitis, otitis media, and pneumonia. The specific type of infection often correlates with the deficient subtype; for instance, a lack of IgG2 can lead to susceptibility to encapsulated bacteria.
Diagnosis begins with a blood test to measure the serum concentration of all four IgG subclasses. However, a low level alone is not sufficient for a diagnosis, as a significant portion of healthy individuals may have low levels of one subtype, most often IgG4. A clinically relevant deficiency must be confirmed by demonstrating a poor or absent functional antibody response to specific vaccines, such as the pneumococcal polysaccharide vaccine.
Management is tailored to the severity and frequency of the patient’s infections. For mild cases, treatment may involve using prophylactic antibiotics to prevent recurring infections. In more severe, persistent cases where patients fail to respond to antibiotics and show evidence of functional deficiency, Immunoglobulin Replacement Therapy may be necessary. This treatment, administered intravenously (IVIg) or subcutaneously (SCIg), involves providing purified IgG from healthy donors to restore the body’s protective antibody levels.