What is IgG4?
IgG4 (Immunoglobulin G4) is the least abundant subclass of IgG antibodies in human serum, representing a unique immunoglobulin with distinct structural properties including the ability to undergo "half-antibody exchange" in vivo, resulting in functionally monovalent antibodies that are relatively weak activators of immune effector responses. 1, 2
Biological Characteristics
IgG4 comprises only a small fraction of total IgG in healthy individuals, with approximately 2.5% of healthy people naturally having IgG subclass levels below 2 standard deviations of the mean for at least one subclass. 3
IgG4 production is driven primarily by Th2 cytokines that also mediate allergic responses and IgE production, and elevated IgG4 can occur in response to various stimuli including allergens, parasites, autoimmune reactions, and malignancy. 1, 2
The unique phenomenon of half-antibody exchange allows IgG4 molecules to recombine in vivo, creating antibodies composed of two different binding specificities, which fundamentally distinguishes it from other IgG subclasses. 1
Clinical Significance
IgG4-Related Disease (IgG4-RD)
IgG4-RD is a systemic fibro-inflammatory disorder first recognized as a unified entity in 2001, characterized by lymphoplasmacytic infiltration of tissues leading to fibrosis and obliterative phlebitis. 4, 5, 2
The disease can affect virtually any organ system, with common presentations including autoimmune pancreatitis (the most frequent manifestation), salivary and lacrimal gland enlargement, orbital disease, retroperitoneal fibrosis, and tubulointerstitial nephritis. 6, 4, 7
Diagnostic Interpretation
Elevated serum IgG4 levels are found in 50-80% of patients with IgG4-RD, but elevated IgG4 alone cannot definitively diagnose the disease. 6, 8
Serum IgG4 >4× upper limit of normal is highly specific for IgG4-related sclerosing cholangitis, though tissue diagnosis remains essential. 6, 8
An IgG4/IgG1 ratio >0.24 improves specificity for distinguishing IgG4-related sclerosing cholangitis from primary sclerosing cholangitis. 6, 3, 8
Important Caveats
Elevated serum IgG4 occurs in 9-15% of patients with primary sclerosing cholangitis and only 1% of patients with primary biliary cholangitis, highlighting the need for clinical context. 3, 8
IgG4 percentage should always be interpreted in clinical context, not as an isolated laboratory value, and abnormal levels require confirmation with repeat testing at least one month apart before making clinical decisions. 3
Histopathological Criteria
Key tissue findings include >10 IgG4-positive plasma cells per high-power field and an IgG4+/IgG+ plasma cell ratio >40%. 6, 8
Additional histological features include storiform fibrosis and obliterative phlebitis, though these are not seen in bone marrow and lymph nodes, making these sites suboptimal for diagnosis. 7
Pathogenic Role
A key unanswered question is whether IgG4 is directly pathogenic in IgG4-related disease, given that it is a relatively weak activator of effector cells compared to other IgG subclasses. 1
The disease responds characteristically to glucocorticoid therapy, with prompt clinical and radiographic improvement, unlike primary sclerosing cholangitis which typically does not respond to steroids. 6