Immunoglobulin G (IgG) is the most abundant type of antibody found in human serum, making up about 75% of all antibodies in the blood. It is a major component of the body’s long-term defense against pathogens, responsible for neutralizing toxins and coating invaders for destruction by immune cells. IgG consists of four distinct variations, known as subclasses, which allow the immune system to tackle a diverse range of threats. These structural variations determine the specific functions each subclass performs in providing immunity.
Structure and Relative Abundance
Every IgG molecule shares a fundamental Y-shaped structure composed of two identical heavy chains and two identical light chains linked by disulfide bonds. The four subclasses (IgG1, IgG2, IgG3, and IgG4) are defined by subtle differences in the constant region protein sequences of the heavy chains. The most noticeable structural variation occurs in the hinge region, the flexible area connecting the two antigen-binding arms to the tail section. This tail section is responsible for interacting with immune cells and activating the complement system.
The length and rigidity of the hinge region vary significantly across the subclasses, directly influencing their biological activities. For instance, IgG3 possesses an elongated hinge region, making it the most flexible, while IgG2 has a shorter, more rigid hinge stabilized by extra disulfide bonds. These structural differences result in unique functional profiles and serum concentrations:
- IgG1 is the most common, accounting for approximately 60–70% of total serum IgG.
- IgG2 accounts for 20–30% of the total.
- IgG3 accounts for 5–8% of the total.
- IgG4 is the lowest level, typically 1–4% of the total.
Specific Biological Functions of Each Subclass
IgG1
IgG1 is the primary responder against protein antigens, including those from viruses and bacterial toxins like tetanus and diphtheria. As the most abundant subclass, it is highly effective at opsonization, a process where antibodies coat a pathogen for engulfment and destruction by phagocytic cells. IgG1 possesses a high affinity for receptors on phagocytes. It is also capable of activating the complement cascade, a system of plasma proteins that enhances the destruction of microbes.
IgG2
The main function of IgG2 is to provide protection against encapsulated bacteria, such as Streptococcus pneumoniae and Haemophilus influenzae, whose surfaces are covered in complex sugar molecules known as polysaccharide antigens. This subclass is the prevalent immune response against these carbohydrate-based structures. The ability to generate effective IgG2 antibodies against polysaccharides develops more slowly in children, which is why young children are often more susceptible to infections from encapsulated bacteria.
IgG3
IgG3 has the greatest capacity to activate the complement system among all the subclasses, making it highly effective at triggering the body’s inflammatory response. This subclass primarily targets protein antigens and is often one of the first IgG antibodies produced during a viral infection. However, IgG3 also has the shortest half-life in the bloodstream, lasting only about seven days, in contrast to the approximately 21-day half-life of the other three subclasses.
IgG4
IgG4 is typically the least abundant subclass and often serves a regulatory function within the immune system. It is commonly associated with allergic responses and developing immune tolerance, particularly during long-term or repeated exposure to an antigen. This subclass functions mainly by blocking the action of IgE antibodies, which are the main mediators of allergic reactions. IgG4 is also noted for its ability to exchange half-molecules with other IgG4 antibodies, resulting in a molecule with two different antigen-binding sites.
Clinical Significance of Abnormal Levels
Abnormal levels of IgG subclasses can point to a specific gap in the body’s immune defenses, known as Selective IgG Subclass Deficiency (IgGSD). Individuals with IgGSD often experience recurrent or chronic infections, especially those affecting the respiratory tract, such as pneumonia, sinusitis, and otitis media. The specific subclass deficiency often dictates the type of infection a person is most susceptible to, though total IgG levels may remain normal.
A deficiency in IgG2, often combined with an IgG4 deficiency, is the most common subclass abnormality associated with recurrent infections, particularly those caused by encapsulated bacteria. A lack of IgG1 is rare as an isolated finding and usually results in a low total IgG level, indicating a more general immune deficiency. Low IgG subclass levels are also observed in association with other health issues, including Celiac disease, IgA deficiency, and certain autoimmune disorders.
Diagnostic Testing and Treatment Approaches
Measuring IgG subclasses is a specialized diagnostic step, performed when a patient presents with recurrent, severe, or persistent infections. Initial testing involves measuring the concentration of each subclass in the serum, using techniques like nephelometry or specialized immunoassays. Because IgG subclass levels can fluctuate and are often low in healthy children, a single low result is not sufficient for a diagnosis.
A more definitive diagnosis of clinically significant deficiency requires functional testing, which assesses the patient’s ability to produce specific antibodies after vaccination with protein and polysaccharide vaccines. Treatment for diagnosed deficiencies ranges from supportive care to intensive replacement therapy. For milder cases, treatment may involve using prophylactic antibiotics to prevent recurrent bacterial infections.
For patients with severe recurrent infections and a confirmed inability to produce functional antibodies, Immunoglobulin Replacement Therapy (IRT) may be indicated. This therapy involves administering concentrated antibodies, typically intravenously (IVIG) or subcutaneously (SCIG), to supply the missing immune protection. The need for IRT depends on the severity of symptoms and the failure of conservative management, as many children with low subclass levels will naturally outgrow the deficiency over time.