Immunoglobulin G4 (IgG4): Meaning, Blood Test, Normal Range & IgG4-Related Disease

Immunoglobulin G4 (IgG4): Clinical Significance, Blood Test Interpretation, and IgG4-Related Disease

The immune system is a highly coordinated defense network designed to identify and neutralize harmful substances. One of its most important components is antibodies, also known as immunoglobulins. These proteins circulate in the bloodstream and tissues, constantly scanning for foreign antigens.

While antibodies are commonly discussed in relation to infections and vaccinations, not all immunoglobulins behave in the same way. Each class has a specialized function. Among them, Immunoglobulin G4 (IgG4) stands out due to its unusual biological behavior and its association with a distinct systemic disease.

Once regarded as a minor antibody with limited importance, IgG4 has gained significant attention over the past two decades. Researchers discovered that abnormal IgG4 activity is linked to a chronic inflammatory condition now recognized as IgG4-Related Disease (IgG4-RD), a disorder capable of affecting multiple organs.

What Is Immunoglobulin G4 (IgG4)?

Immunoglobulin G4 is one of the four subclasses of Immunoglobulin G (IgG), the most abundant antibody class in human blood. IgG antibodies are essential for long-term immune protection and memory.

Understanding Antibodies

Antibodies are produced by B lymphocytes and plasma cells. Their primary function is to bind antigens such as bacteria, viruses, and toxins and either neutralize them or signal other immune cells to eliminate the threat.

There are five major immunoglobulin classes: IgG, IgA, IgM, IgE, and IgD. Among these, IgG accounts for approximately 70–75% of total circulating antibodies and is subdivided into four subclasses: IgG1, IgG2, IgG3, and IgG4.

IgG4 is the least abundant subclass, usually representing less than 5% of total IgG. Unlike other subclasses, IgG4 typically plays a regulatory role rather than an inflammatory one.

IgG Subclasses and Their Differences

Although IgG subclasses appear structurally similar, they differ in immune function and inflammatory potential.

Subclass	Relative Amount	Main Role	Inflammation
IgG1	Highest	Defense against viruses and bacteria	High
IgG2	Moderate	Response to bacterial polysaccharides	Moderate
IgG3	Low	Strong complement activation	Very High
IgG4	Lowest	Immune tolerance and regulation	Minimal

IgG4 differs from the other subclasses because it does not efficiently activate the complement system, which is responsible for inflammation and tissue damage.

Biological Role of IgG4

IgG4 functions primarily as an immune-modulating antibody rather than an aggressive defender.

Fab-Arm Exchange: IgG4 molecules can exchange half of their structure with other IgG4 antibodies, creating bispecific antibodies. This unique feature reduces immune complex formation and suppresses inflammation.

Allergen Tolerance: In chronic allergen exposure, IgG4 can block IgE-mediated allergic reactions. This mechanism explains why individuals undergoing allergen immunotherapy often show rising IgG4 levels.

IgG4 Blood Test: What Does It Measure?

The IgG4 blood test measures the concentration of IgG4 antibodies in serum. It is not part of routine blood testing and is ordered only when specific immune-mediated conditions are suspected.

The test involves a standard blood draw and does not usually require fasting. Results should always be interpreted in clinical context.

Normal Range of IgG4

Reference ranges vary among laboratories, but commonly accepted adult values fall between:

• Approximately 4–86 mg/dL
• Some laboratories use an upper cutoff of 135 mg/dL

Age, gender, laboratory technique, and clinical condition can influence results.

High IgG4 Levels: What Do They Indicate?

Elevated IgG4 levels are not diagnostic by themselves. They serve as a marker that must be correlated with symptoms, imaging, and tissue findings.

IgG4-Related Disease

IgG4-related disease is a chronic immune-mediated condition characterized by organ enlargement, inflammation, and progressive fibrosis. Elevated IgG4 is common but not universal in affected patients.

Other Conditions Associated With High IgG4

• Allergic diseases
• Parasitic infections
• Autoimmune blistering disorders
• Certain malignancies
• Systemic inflammatory diseases

Low IgG4 Levels

Low IgG4 levels may occur in isolation or alongside other immunoglobulin deficiencies. While some individuals remain asymptomatic, others may experience recurrent respiratory infections.

IgG4-Related Disease (IgG4-RD)

IgG4-RD is a systemic fibroinflammatory disorder characterized by tumor-like lesions, dense immune cell infiltration, and progressive scarring of affected organs.

Commonly affected organs include the pancreas, salivary glands, lymph nodes, kidneys, retroperitoneum, thyroid, lungs, and major blood vessels.

Diagnosis of IgG4-Related Disease

Diagnosis requires a combination of:

• Serum IgG4 testing
• Imaging studies (CT, MRI, PET)
• Histopathological confirmation via biopsy

Biopsy findings such as storiform fibrosis and IgG4-positive plasma cell infiltration are considered diagnostic hallmarks.

Treatment Approaches

Corticosteroids are the first-line treatment and often result in rapid clinical improvement. For relapsing or steroid-resistant cases, biologic therapies such as rituximab are highly effective.

Conclusion

Immunoglobulin G4 represents one of the most intriguing discoveries in modern immunology. While it normally promotes immune tolerance, dysregulated IgG4 activity can lead to a complex multi-organ disease.

Early recognition, appropriate testing, and specialist management are essential to prevent irreversible organ damage. IgG4 testing should always be interpreted by experienced clinicians within a broader diagnostic framework.

⚠️ Medical Disclaimer: This content is provided for educational and informational purposes only. It is not a substitute for professional medical advice, diagnosis, or treatment. Immunological tests such as IgG4 require expert interpretation. Always consult a qualified healthcare provider, immunologist, or rheumatologist for personalized medical guidance.