Antibodies are protective proteins produced by the immune system that recognize and help remove foreign substances. Immunoglobulin G (IgG) is the most abundant antibody, and IgG4 is one of its four subclasses. While IgG4 is a normal immune system component, elevated levels can signal an underlying medical condition. High IgG4 levels are not a diagnosis but an indicator requiring further investigation to identify the specific cause.
Understanding IgG4 and Its Normal Functions
IgG4 is the least abundant of the four IgG subclasses in healthy individuals, typically making up 1-5% of total IgG. It is considered unique due to its distinct structural and functional properties. Unlike other antibodies that aggressively activate immune responses, IgG4 generally plays a more subtle, anti-inflammatory role, contributing to immune tolerance. This function is particularly relevant in chronic antigen exposure, such as allergen immunotherapy, where IgG4 acts as a “blocking” antibody to reduce allergic reactions.
The normal range for IgG4 levels in the blood varies slightly between laboratories but is generally 3 to 201 mg/dL. Levels exceeding this range are considered elevated, prompting further clinical evaluation.
IgG4-Related Disease
IgG4-Related Disease (IgG4-RD) is a distinct, chronic, immune-mediated condition characterized by elevated serum IgG4 and specific microscopic findings in affected tissues. This disease can affect multiple organs, leading to inflammation, swelling, and often fibrosis (scar tissue formation). Its systemic nature means it manifests in various ways depending on the organs involved.
Commonly affected organs include the pancreas (causing autoimmune pancreatitis), salivary glands, lacrimal glands, kidneys, lungs, and aorta. Patients may experience painless swelling or organ dysfunction, sometimes mimicking serious conditions like cancer. Although elevated IgG4 levels are a feature, a comprehensive diagnostic approach involving clinical, imaging, and pathological assessments is necessary to confirm an IgG4-RD diagnosis.
Other Conditions Linked to High IgG4 Levels
While IgG4-RD is the primary condition associated with high IgG4 levels, these elevations can also occur in other medical conditions. In these instances, elevated IgG4 is often a non-specific finding, playing a secondary role in diagnosis compared to other markers.
Some chronic allergic conditions, especially those with prolonged allergen exposure, can lead to increased IgG4 levels. These elevations may reflect the body’s attempt to develop immune tolerance. Certain parasitic infections, such as filariasis and schistosomiasis, induce a strong IgG4 antibody response. Elevated IgG4 levels can also be observed in a subset of patients with other autoimmune diseases, though it is not a diagnostic criterion. Additionally, some cancers, including certain lymphomas or solid tumors, can be associated with elevated IgG4 levels, though the exact mechanism is not fully understood.
How Doctors Investigate High IgG4 Levels
When a patient presents with elevated IgG4 levels, doctors follow a systematic process to identify the underlying cause. This begins with a thorough clinical evaluation, including patient history and physical examination. This initial assessment guides subsequent diagnostic steps.
Further investigation often involves blood tests beyond IgG4 levels, including markers of inflammation or organ function. Imaging studies (CT, MRI, PET scans) are frequently used to pinpoint organ involvement or abnormalities. For a definitive diagnosis, especially for IgG4-RD, a tissue biopsy is crucial. Pathologists examine the tissue for specific microscopic features, such as dense immune cell infiltration, a unique fibrosis pattern, and increased IgG4-positive plasma cells, often alongside an elevated IgG4 to total IgG ratio. Ruling out other conditions with similar symptoms or findings is a significant part of the diagnostic process, ensuring accurate diagnosis and appropriate treatment.