The immune system produces immunoglobulins, or antibodies, to recognize and neutralize foreign substances. Immunoglobulin G (IgG) is the most abundant antibody class in the blood, divided into four subclasses: IgG1, IgG2, IgG3, and IgG4. An IgG4 test specifically measures the concentration of the IgG subclass 4 in the serum. This measurement provides information about a specific component of the adaptive immune response, and results are interpreted based on the context in which the test was ordered.
Biological Role of Immunoglobulin G4
The IgG4 subclass has a distinctive structure and function, setting it apart from other IgG subclasses. Unlike IgG1, which activates inflammatory pathways, IgG4 is considered anti-inflammatory. This property results from “Fab-arm exchange,” where IgG4 molecules swap half-molecules in the bloodstream. This exchange creates a “bispecific” and “functionally monovalent” antibody, which prevents the formation of large, damaging immune complexes.
Because it cannot efficiently cross-link antigens or activate the complement cascade, IgG4 acts as a blocking antibody. High levels of IgG4 are often seen during long-term, chronic antigen exposure, such as successful desensitization therapy for allergies or in response to helminth (parasitic worm) infections. In these scenarios, IgG4 dampens the immune response, preventing excessive inflammation and promoting immunological tolerance.
Diagnosis of IgG4-Related Disease
The primary medically accepted application of the serum IgG4 test is diagnosing IgG4-Related Disease (IgG4-RD). IgG4-RD is a chronic, systemic fibro-inflammatory condition that can affect nearly any organ system, often mimicking malignant tumors. Common organs involved include the pancreas, salivary and lacrimal glands, bile ducts, kidneys, and retroperitoneum, leading to conditions like autoimmune pancreatitis. Diagnosis relies on clinical, radiological, and pathological findings, with serum IgG4 level serving as a biomarker.
A concentration greater than 135 mg/dL is often used as a diagnostic cut-off. However, this level alone is insufficient, as only about 70% of patients with IgG4-RD have elevated serum levels, and other inflammatory conditions can cause mild increases. For a definitive diagnosis, elevated serum IgG4 must be paired with histopathological evidence from a biopsy of the affected organ. The tissue must show a dense lymphoplasmacytic infiltrate rich in IgG4-positive plasma cells, often requiring that over 40% of IgG-positive plasma cells belong to the IgG4 subclass. Further features include storiform fibrosis and obliterative phlebitis. A markedly elevated serum IgG4 level, defined as more than twice the upper limit of normal (e.g., >270-280 mg/dL), is highly specific for IgG4-RD but still requires histological confirmation. Monitoring serum IgG4 levels is also used after diagnosis to track disease activity and predict the risk of relapse.
Testing for Food Sensitivities
The most common public use of the IgG4 test is its promotion for diagnosing food sensitivities or intolerances. This application is based on the theory that high levels of food-specific IgG4 antibodies indicate an adverse reaction, suggesting dietary elimination. Commercial laboratories often market these tests, screening for reactions to dozens of food items. However, major allergy and immunology organizations, such as the American Academy of Allergy, Asthma & Immunology (AAAAI), do not support using food-specific IgG4 testing for diagnosing sensitivities.
The presence of IgG4 antibodies to a food is recognized as a normal physiological response to dietary exposure and a marker of immunological tolerance. The immune system generates these antibodies upon repeated consumption, indicating the body has learned to tolerate the antigen without an inflammatory attack. True food allergies are mediated by Immunoglobulin E (IgE), which triggers the immediate release of histamine. Since the IgG4 response is non-inflammatory, it cannot provoke a hypersensitivity reaction. Therefore, a positive IgG4 test for a food usually means the individual consumes that food frequently, not that it is causing pathology. Adopting a restrictive diet based on a positive IgG4 panel can lead to unnecessary nutritional limitations. Professional medical bodies actively recommend against using this test as a guide for dietary elimination due to a lack of controlled studies proving symptom improvement after removing IgG4-positive foods.
Interpreting Test Results
Interpreting an IgG4 test requires careful consideration of the context in which it was ordered. The normal range for serum IgG4 concentration typically falls between 6 and 121 mg/dL, though this varies between laboratories. A result within this range is considered normal.
If the test was ordered due to suspicion of systemic disease, an elevated serum IgG4 level exceeding the 135 mg/dL cut-off raises suspicion for IgG4-Related Disease (IgG4-RD). Results of 270 mg/dL or higher are highly suggestive of IgG4-RD. However, elevated IgG4 must be interpreted alongside clinical signs, and the patient requires evaluation by a specialist for a necessary tissue biopsy. A mild increase can be a non-specific finding in various chronic inflammatory conditions.
In the context of food sensitivity testing, an elevated result for a specific food should not be interpreted as a mandate for dietary restriction. A high food-specific IgG4 level confirms frequent exposure and reflects a state of tolerance. Self-diagnosing a food intolerance based on this test and initiating an elimination diet is not supported by scientific evidence. Individuals with persistent symptoms should consult a physician or allergist for proper diagnostic work-up, such as IgE testing or a supervised oral food challenge.