Immunoglobulin G (IgG) is the most abundant antibody type found in the bloodstream and tissues. The measurement of IgG subclasses 1 through 4 is a specialized blood test performed when a person experiences recurrent, severe, or unusual infections. This testing helps clinicians pinpoint specific defects in the immune system’s ability to produce fully functional antibodies, often even when the total amount of IgG appears normal.
The Structure and General Role of Immunoglobulin G
IgG is the predominant antibody class in human serum, accounting for approximately 75% of all circulating antibodies. It provides long-term protection against invading microorganisms after infection or vaccination. IgG also crosses the placenta from mother to fetus, granting the newborn passive immunity during its first few months of life.
The IgG molecule is composed of two identical heavy chains and two identical light chains, forming a monomeric structure. It includes a fragment antigen-binding (Fab) region that attaches to the pathogen and a fragment crystallizable (Fc) region that interacts with immune cells. Subtle differences in the Fc region’s hinge area lead to the creation of four distinct subclasses: IgG1, IgG2, IgG3, and IgG4. These subclasses neutralize bacterial toxins, coat pathogens for consumption by immune cells, and initiate the complement system, which destroys foreign cells.
Specific Functions of IgG Subclasses 1, 2, 3, and 4
IgG1
IgG1 is the most prevalent subclass, making up 60% to 70% of total IgG in the blood. This subclass is the main responder to protein antigens, including bacterial toxins (like diphtheria and tetanus) and proteins from many viruses. Because of its high concentration, a significant deficiency in IgG1 often results in a measurable reduction of the total IgG level.
IgG2
IgG2 represents 20% to 30% of total IgG. Its primary specialization is defending against pathogens coated in polysaccharide capsules, such as Streptococcus pneumoniae and Haemophilus influenzae. This subclass is especially important in the immune response to these encapsulated bacteria, and a deficiency here is commonly associated with recurrent sinopulmonary infections.
IgG3
IgG3 is present at lower levels, between 5% and 8% of total IgG, but it is the most potent activator of the complement system. These antibodies are highly effective against protein antigens and are produced early in the immune response to certain infections. IgG3 has a relatively short half-life in the bloodstream compared to the other subclasses.
IgG4
IgG4 is the least abundant subclass, accounting for only 1% to 3% of total IgG. Its role is regulatory, as it does not efficiently activate the complement cascade. IgG4 may act as a blocking antibody, often seen in chronic exposures to antigens involved in allergic responses. Elevated IgG4 is a marker for IgG4-Related Disease, an inflammatory condition that can affect multiple organs.
Clinical Conditions Diagnosed by Subclass Testing
The primary reason for ordering an IgG subclass test is to investigate Primary Antibody Deficiencies (PIDs) in patients with frequent or persistent infections. The test is particularly relevant when the total IgG level is within the normal range, as a deficiency in one subclass can be masked by the abundance of others. The results help differentiate various forms of immune compromise.
A common finding is Selective IgG Subclass Deficiency, defined as low levels of one or two subclasses while total IgG remains normal. Deficiencies in IgG2 and/or IgG3 are the most frequently observed, leading to increased susceptibility to encapsulated bacterial and respiratory infections.
Subclass testing also aids in diagnosing Specific Antibody Deficiency (SAD), where patients fail to produce protective antibodies after vaccination despite normal subclass levels. Furthermore, the test supports the diagnosis of Common Variable Immunodeficiency (CVID), a broader and more severe antibody deficiency where low subclass levels may precede or accompany low total IgG and IgA.
Interpreting Abnormal IgG Subclass Levels
Low levels in one or more subclasses indicate a deficiency, but clinical significance must be evaluated alongside the patient’s symptoms and infection history. Since IgG subclass levels vary and change over time, low results are confirmed with repeat testing. A low result, particularly in IgG2, prompts a physician to order a vaccine challenge test to confirm a functional defect—assessing if the patient can mount a protective antibody response.
Management for confirmed deficiencies involves prophylactic antibiotics or, in severe cases with poor vaccine response, immunoglobulin replacement therapy. High levels of a subclass can also be informative; elevated IgG4 is a diagnostic marker for IgG4-Related Disease, an autoimmune-like condition characterized by organ inflammation. Interpretation requires a specialist who considers the specific pattern of reduction, the patient’s age, and their clinical history.