Immunoglobulins, commonly known as antibodies, are Y-shaped proteins the immune system uses to identify and neutralize foreign objects like bacteria and viruses. These proteins are grouped into five main classes, with Immunoglobulin G (IgG) being the most abundant and divided into four subclasses: IgG1, IgG2, IgG3, and IgG4. While all subclasses protect the body, high levels of IgG4 are an unexpected finding. This elevation often indicates a chronic, immune-mediated disorder that affects multiple organs.
The Normal Function of IgG4
IgG4 is the least common of the four IgG subclasses in human serum, typically accounting for less than six percent of the total IgG pool. This antibody possesses unique structural characteristics, most notably its ability to undergo “Fab arm exchange” in the bloodstream. This exchange occurs when an IgG4 molecule swaps half of its structure with a half-molecule from a different IgG4 antibody. The resulting antibody is bi-specific, meaning it can bind to two different antigens simultaneously.
This unique structure makes the IgG4 molecule functionally monovalent, preventing it from effectively cross-linking antigens to form large, inflammatory immune complexes. Since it cannot efficiently activate the complement system, IgG4 is generally considered a non-inflammatory or “blocking” antibody. This anti-inflammatory role is beneficial in chronic exposure to allergens or parasites, as IgG4 can bind to the foreign substance without triggering a damaging immune response.
IgG4-Related Disease (IgG4-RD)
The most significant cause of pathologically high IgG4 concentrations is Immunoglobulin G4-Related Disease (IgG4-RD). This is a chronic, systemic fibroinflammatory condition characterized by a distinctive constellation of clinical and pathological features that can mimic various cancers. IgG4-RD can affect nearly any organ, often causing painless swelling or the formation of tumor-like masses called pseudotumors.
The histopathological hallmark of IgG4-RD is a dense infiltration of the affected tissue by lymphocytes and IgG4-positive plasma cells. This infiltrate is accompanied by a pattern of tissue scarring called storiform fibrosis, which resembles the spokes of a wagon wheel. Another characteristic feature is obliterative phlebitis, which involves the inflammation and subsequent destruction of veins.
IgG4-RD is a multi-organ disease, and its manifestations depend on the parts of the body involved. Common sites include:
- The pancreas, leading to autoimmune pancreatitis.
- The salivary and lacrimal glands, causing Mikulicz’s disease.
- The bile ducts, resulting in sclerosing cholangitis.
- The kidneys and lungs.
- The retroperitoneum and aorta.
Inflammation and fibrosis in these areas can lead to organ failure if left untreated.
An elevated serum IgG4 level is a common finding, but it is not universally present and is insufficient for diagnosis alone. Confirmation requires the combination of characteristic clinical presentation and specific histological findings. The disease is known for its tendency to relapse and remit, often requiring long-term management to prevent irreversible organ damage.
Underlying Immune Mechanisms Driving IgG4 Elevation
The high production of IgG4 antibodies in IgG4-RD is driven by a specific dysregulation of the adaptive immune system. This process centers on the hyperactivity of certain T-helper cell subsets, particularly T-helper type 2 (Th2) cells and regulatory T cells (Tregs). These cells release signaling molecules, or cytokines, that instruct B cells to switch their antibody production to the IgG4 isotype.
Th2 cells produce cytokines such as Interleukin-4 (IL-4) and Interleukin-13 (IL-13), which promote B-cell differentiation toward IgG4. Regulatory T cells also secrete high levels of Interleukin-10 (IL-10). This IL-10 acts as a potent signal that drives B cells into becoming IgG4-producing plasma cells.
This cytokine environment also contributes directly to the tissue damage seen in the disease. Transforming Growth Factor-beta (TGF-beta), released by Tregs and other cells, is a major pro-fibrotic factor. TGF-beta stimulates fibroblasts to produce excess collagen, which causes the characteristic dense scarring, or storiform fibrosis, in the affected organs.
The elevated IgG4 is a consequence of this skewed T-cell response, not merely a marker of the disease. The plasma cell infiltration and the TGF-beta-driven scarring work together to create the mass-forming lesions and tissue destruction that define IgG4-RD. This interplay between specific T-cell subsets and their cytokine output drives the systemic nature and pathological features of the condition.
Non-RD Conditions Associated with Elevated IgG4
Although IgG4-RD is the most common cause of significant IgG4 elevation, other conditions can also lead to increased serum levels. These alternative causes are important to consider, as they sometimes mimic the clinical or laboratory findings of IgG4-RD. Elevated IgG4 is often observed in chronic allergic diseases, reflecting its normal “blocking” function.
Increased IgG4 levels are frequently seen in patients with severe atopic dermatitis, chronic asthma, and allergic rhinitis, especially those undergoing allergen-specific immunotherapy. Parasitic infections, such as chronic infestations like filariasis, also stimulate a robust immune response that includes a marked increase in IgG4 production. This response is thought to be an attempt by the immune system to dampen the chronic inflammation caused by the parasite.
Some autoimmune conditions, certain cancers, and plasma cell disorders can also be associated with elevated IgG4. Examples include primary sclerosing cholangitis and multicentric Castleman disease. In these situations, the elevation is typically less pronounced, and the overall clinical and pathological picture differs significantly from the fibroinflammatory pattern of IgG4-RD.