Immunoglobulin G4 deficiency is a primary immunodeficiency characterized by abnormally low concentrations of the IgG4 subclass of antibodies in the blood. This condition is part of a larger group of disorders known as IgG subclass deficiencies. The resulting defect in the adaptive immune system compromises the body’s defenses, leading to increased susceptibility to various infections. While the total level of Immunoglobulin G may remain within the normal range, the selective decrease in IgG4 impairs certain immune functions.
The Normal Function of Immunoglobulin G4
Immunoglobulin G (IgG) is the most abundant type of antibody in human blood and is divided into four distinct subclasses, including IgG4. This subclass is typically the least prevalent, accounting for less than 5% of the total circulating IgG antibodies. IgG4 is structurally unique because it can undergo “Fab-arm exchange,” swapping half-molecules with another IgG4 antibody.
This feature results in a functionally monovalent antibody that binds to only one antigen at a time instead of cross-linking two. This limits its ability to form large immune complexes or strongly activate the complement system. Consequently, IgG4 is often described as having anti-inflammatory or immunomodulatory properties.
The function of IgG4 is associated with chronic exposure to antigens, such as those in allergic conditions or parasitic infections. IgG4 acts as a “blocking antibody,” competing with IgE antibodies for binding to the allergen. By binding the allergen without triggering the full inflammatory cascade, IgG4 helps dampen severe allergic reactions and promotes immune tolerance.
Clinical Presentation of IgG4 Deficiency
The absence of the IgG4 subclass compromises the immune system’s ability to neutralize certain pathogens, primarily manifesting as recurrent infections. Patients frequently experience infections of the upper and lower respiratory tracts, including chronic sinusitis, otitis media, and bronchitis that persist despite standard antibiotic courses.
A serious manifestation is an increased risk of developing pneumonia, particularly infections caused by encapsulated bacteria like Streptococcus pneumoniae and Haemophilus influenzae. Repeated respiratory infections can lead to structural damage in the lungs, known as bronchiectasis. Bronchiectasis involves the permanent widening and scarring of the airways, creating pockets where mucus and bacteria accumulate, perpetuating the infection cycle.
While primary symptoms are infectious, IgG4 deficiency is also observed in patients with certain non-infectious conditions. Low IgG4 levels are associated with increased severity of inflammatory bowel disease (IBD), suggesting a role in gut immune regulation. Patients may also have a higher prevalence of allergic diseases or autoimmune phenomena.
Diagnosis and Therapeutic Management
Diagnosis begins by identifying a clinical pattern of recurrent infections, particularly those affecting the sinuses and lungs, unexplained by other causes. A definitive diagnosis requires a blood test to quantify the levels of the four IgG subclasses. The test must show a persistently low or absent concentration of the IgG4 subclass, regardless of whether total IgG levels are normal.
For adults, an IgG4 concentration below an established laboratory threshold, often less than 6 mg/dL, confirms the deficiency. Diagnosis in children younger than 10 years old is often deferred because IgG4 levels naturally increase slowly throughout childhood. Physicians must also rule out secondary causes of low IgG4, such as certain medications or underlying systemic diseases.
The therapeutic management focuses on two main strategies: preventing infections and replacing missing antibodies. Prophylactic antibiotics are often prescribed to prevent bacterial infections, especially for patients with frequent respiratory symptoms or documented bronchiectasis. These antibiotics are typically low-dose and taken long-term to reduce the bacterial load in the airways.
For patients who continue to experience severe or frequent infections, Immunoglobulin Replacement Therapy (IRT) may be recommended. This treatment involves infusing concentrated antibodies, derived from healthy donors, either intravenously (IVIG) or subcutaneously (SCIG). The goal of IRT is to restore protective antibody levels, reducing the frequency and severity of infections and minimizing further organ damage.