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IgG subclass deficiency

Patients with persistently low levels of one or two IgG subclasses and a normal total IgG level have a selective IgG subclass deficiency.


Most antibodies (also known as immunoglobulins) in the blood and the fluid that surround the tissues and cells of the body are of the IgG class. This class of antibodies is composed of four different subclasses: IgG1, IgG2, IgG3, and IgG4. Each subclass is present in different concentrations in the blood and those concentrations vary with age. The IgG in the bloodstream is 60-70% IgG1, 20-30% IgG2, 5-8% IgG3, and 1-3% IgG4. IgG1 and IgG3 reach normal adult levels by 5-7 years of age, while IgG2 and IgG4 levels rise more slowly, reaching adult levels at about ten years of age.

Each subclass serves predominantly (but not exclusively) a slightly different function in protecting the body against infection. For example, IgG1 and IgG3 subclasses protect against toxins from bacteria such as diphtheria and tetanus, and against viral infections. In contrast, IgG2 predominantly protects against the polysaccharide (complex sugar) capsule of certain disease-causing bacteria such as Streptococcus pneumoniae and Haemophilus influenzae.

Individuals with IgG subclass deficiency are defined as having recurrent infections, persistently low levels of one or more IgG subclasses, and normal concentrations of total IgG, IgM, and IgA. IgG2 or IgG3 deficiencies are the most common IgG subclass deficiencies. Since IgG1 comprises 60% of the total IgG level, having a deficiency of IgG1 usually drops the total IgG level below the normal range, resulting in hypogammaglobulinemia. 

Because IgG4 does not reach adult levels until the age of 10 years, a diagnosis of IgG4 deficiency should not be made in young children. In addition, it may also be undetectable in the serum of many healthy adult individuals, and therefore low IgG4 alone is insufficient evidence of an antibody deficiency disorder.

All individuals with IgG subclass deficiency require additional diagnostic evaluation. This evaluation must include the demonstration of a poor antibody response to vaccine challenge and careful documentation of recurrent infection. If both are present, the individual can be diagnosed with a clinically significant IgG subclass deficiency necessitating specific treatment.

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Clinical presentation

Most individuals with IgG subclass deficiency are completely asymptomatic. They may present, however, to a healthcare provider with recurrent ear and/or sinus infections; bronchitis and pneumonia may also have occurred. These infections are commonly caused by encapsulated bacteria such as Streptococcus pneumoniae and Haemophilus influenzae, infections common in other people with antibody deficiencies. These types of infections are seen most commonly among those with IgG2 deficiency, with or without IgG4 deficiency. 

Infections occurring in those with selective IgG subclass deficiency may not be as severe as infections in individuals with more significant antibody deficiencies, such as agammaglobulinemia or common variable immune deficiency (CVID). Individuals with IgG subclass deficiencies may have other types of invasive infections, such as episodes of bacterial meningitis or infections of the bloodstream (sepsis), but these are extraordinarily rare. Frequent viral infections have been associated with IgG3 subclass deficiencies.

As in people with selective IgA deficiency, allergic diseases, and autoimmune diseases are more common in those with IgG subclass deficiency. 

Important to note

IgG subclass deficiencies are clinically relevant only when the levels are absent or very low and when they are detected in people with recurrent upper and/or lower respiratory infections. 

In individuals without frequent or severe infections, low levels of IgG subclasses may be a clinically irrelevant finding. In the absence of infections, mild or moderately decreased subclass concentrations should not lead to unnecessary long-term use of immunoglobulin (Ig) replacement therapy. A subclass deficiency needs to be considered and looked for only under special circumstances discussed here.

Diagnosing IgG subclass deficiency

Measurement of IgG subclass levels is not universally recommended as part of the evaluation of antibody-mediated immunity in individuals with recurrent or severe infections. Assessing IgG subclasses adds cost and may not add clinical value when total immunoglobulins and specific antibodies are measured. Most clinical immunologists do not obtain or measure IgG subclasses.

When IgG subclasses are measured, all four should be measured at the same time. An abnormal level should be confirmed at least one month after the first measurement. It is important to consider that IgG subclasses vary over time and among different laboratories. In addition, normal range values are usually defined as those values found in 95% of healthy individuals of that person’s age. This means that 2.5% of healthy individuals will be considered deficient, and 2.5% of normal individuals will have values above that range.

Measurement of IgG subclasses can be recommended in the presence of known associated disorders, particularly if recurrent infections are also present. These circumstances include individuals with:


No clear-cut pattern of inheritance has been observed in the IgG subclass deficiencies. Both males and females may be affected. Occasionally, two individuals with IgG subclass deficiency may be found in the same family. In some families, IgG subclass deficiencies have been found in some family members, while other family members may have selective IgA deficiency or CVID. A partial gene deletion has been found in a few individuals with IgG subclass deficiency. Rarely, individuals with a complete absence of IgG2 due to deletion of the gene coding for its production have been described.

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Treatment includes the appropriate use of antibiotics to treat and prevent infections. The type and severity of infection usually determine the type of antibiotic used and the length of treatment. Additional immunization with pneumococcal vaccines may also be used to enhance immunity. It is important to encourage patients to continue normal activities of daily living, such as school or work.

A trial (6 months) of immunoglobulin (Ig) replacement therapy may be considered in patients with recurrent infections affecting quality of life who have failed antibiotic therapy. At a minimum, before approving Ig therapy, most insurers will require documentation demonstrating a failure of such conservative treatment, in addition to persistently low IgG subclass levels and deficient antibody responses to vaccines. Children diagnosed with IgG subclass deficiency should be reevaluated with increasing age, as many appear to outgrow their deficiencies.


The natural history of individuals with a clinically significant IgG subclass deficiency is not completely understood, but the outlook is generally good. Many children appear to outgrow their deficiency as they get older. For those with a persistent deficiency and impaired antibody responses, the use of prophylactic antibiotics and, in certain circumstances, the use of Ig replacement therapy may prevent serious infections and complications, such as impaired lung function, hearing loss, or injury to other organ systems.

Recent studies have shown that many children with a subclass deficiency in early childhood (younger than 5 years of age) develop normal subclass levels and the ability to make antibodies to polysaccharide vaccines as they get older. IgG subclass deficiencies, however, may persist in some children and adults. In some instances, a selective IgG subclass deficiency may evolve into a more serious antibody deficiency, such as common variable immune deficiency (CVID). At this time, it is not possible to determine which individuals will have the transient type of subclass deficiency and which individuals may later evolve into a more significant immunodeficiency. For these reasons, regular reevaluation of immunoglobulin levels and function, as well as IgG subclass levels, is necessary. 

This page contains general medical and/or legal information that cannot be applied safely to any individual case. Medical and/or legal knowledge and practice can change rapidly. Therefore, this page should not be used as a substitute for professional medical and/or legal advice.

Adapted from the IDF Patient & Family Handbook for Primary Immunodeficiency Diseases, Sixth Edition 
Copyright ©2019 by Immune Deficiency Foundation, USA