Immunoglobulin G4 (IgG4) is the least abundant of the four Immunoglobulin G subclasses found in human serum. This antibody accounts for less than five percent of the total IgG antibodies in the body. Its primary function is thought to be regulatory, playing a role in immune tolerance and neutralizing toxins.
IgG4 is unique because it can exchange half-molecules with other IgG4 antibodies, preventing it from activating the immune system’s inflammatory cascade. This characteristic gives it an immune-inhibitory role, particularly in allergic responses, where it may help prevent severe anaphylactic reactions. Measuring IgG4 concentration is often part of a larger panel of tests when a systemic inflammatory disorder is suspected.
IgG4 Elevation Not Due to Systemic Disease
An elevated serum IgG4 level does not automatically indicate a chronic, systemic disease. The antibody concentration can temporarily spike or be mildly elevated in response to common, non-life-threatening conditions. Mild elevations, defined as less than two times the upper limit of normal, are often seen in chronic allergic states.
These reactive elevations frequently occur in patients with severe asthma, atopic dermatitis, or other chronic inflammatory conditions where the immune system is persistently stimulated. Certain parasitic infections can also trigger a polyclonal increase in IgG4 production. Some individuals without apparent disease may also have a slightly elevated IgG4 level, as this finding is not specific to a single condition.
Other serious conditions, such as primary sclerosing cholangitis or certain malignancies like pancreatic cancer, may also present with high serum IgG4 levels. Due to this lack of specificity, a high IgG4 number serves as a flag that warrants further investigation rather than being a standalone diagnosis for IgG4-Related Disease. A definitive diagnosis requires a broader clinical and pathological picture.
Defining IgG4-Related Disease
When persistently elevated IgG4 levels occur alongside specific organ damage, the condition is recognized as Immunoglobulin G4-Related Disease (IgG4-RD). This is a chronic, immune-mediated, fibroinflammatory disorder that can affect almost any organ system in the body. The disease is characterized by a distinctive pathological process that drives systemic symptoms.
Affected tissues show a dense infiltration of immune cells, specifically lymphocytes and plasma cells, with a disproportionate number expressing IgG4. This infiltration leads to the hallmark feature: the formation of scar tissue, known as storiform fibrosis. This fibrosis often displays a characteristic whorled pattern under a microscope.
Ongoing inflammation and scarring lead to the formation of tumor-like masses and organ enlargement, often causing the condition to be mistaken for cancer. A third pathological feature is obliterative phlebitis, which is the inflammation and blockage of small veins within the affected tissue. This combination of dense infiltration, scarring, and blocked vessels is what unifies the diverse organ manifestations of this disorder.
IgG4-RD primarily affects middle-aged and older individuals, with a slight predominance in males. Untreated, the progressive fibrosis can lead to irreversible organ damage and failure, emphasizing the need for early recognition. It is understood to be a systemic process where the immune system mistakenly targets the body’s own tissues, causing chronic inflammation and scarring.
Organ Manifestations of IgG4-Related Disease
The impact of IgG4-RD depends heavily on which organs are involved, with symptoms ranging from discomfort to life-threatening complications. One of the most common manifestations is Type 1 Autoimmune Pancreatitis (AIP), which causes the pancreas to become enlarged and firm, often appearing “sausage-like” on imaging.
Pancreatic involvement may be painless, but it can cause abdominal pain or jaundice if the enlarged gland compresses the common bile duct. Chronic inflammation and fibrosis eventually destroy the organ’s ability to produce digestive enzymes, leading to exocrine insufficiency marked by weight loss and steatorrhea. It can also impair insulin production, resulting in endocrine insufficiency that manifests as new-onset diabetes.
In the biliary system, IgG4-related cholangitis (IgG4-SC) causes the bile ducts to thicken and narrow due to inflammation and scarring. The resulting strictures cause bile flow obstruction and painful jaundice. This condition is difficult to distinguish from primary sclerosing cholangitis or bile duct cancer, and chronic obstruction can eventually lead to liver damage if left untreated.
The disease frequently involves the head and neck, affecting the salivary and lacrimal glands. This manifestation, sometimes called Mikulicz syndrome, results in painless, bilateral swelling of the glands on the face or below the chin. While the glands are enlarged, their function is often only mildly impaired, and symptoms of dry eyes or mouth are not prominent.
Retroperitoneal Fibrosis (RPF) is another significant manifestation, where a mass of fibrous tissue forms in the retroperitoneum, the area at the back of the abdomen behind the lining of the abdominal cavity. This mass can compress vital structures, most notably the ureters, which carry urine from the kidneys to the bladder. Ureter compression obstructs urine flow, leading to hydronephrosis, a dangerous swelling of the kidneys.
Steps for Diagnosis and Treatment
Diagnosing IgG4-RD requires a multi-pronged approach, as an elevated IgG4 blood level alone is not definitive, and many patients have normal serum levels. The process begins with a medical evaluation combining clinical symptoms, such as unexplained organ masses or painless swelling, with advanced imaging studies. CT or MRI scans can reveal characteristic findings, such as diffuse enlargement of the pancreas or fibrotic masses in the retroperitoneum.
The most reliable confirmation is a tissue biopsy from the affected organ, allowing doctors to look for characteristic microscopic features. A pathologist examines the tissue for dense lymphoplasmacytic infiltration, storiform fibrosis, and an increased ratio of IgG4-positive plasma cells. This histopathological evidence is crucial to distinguish IgG4-RD from conditions it mimics, such as infection, malignancy, or other autoimmune diseases.
Once confirmed, the primary treatment is typically systemic glucocorticoids, or steroids. High-dose glucocorticoids rapidly induce remission by reducing systemic inflammation, often leading to a quick improvement in symptoms and a reduction in organ mass size.
Following the initial induction phase, the steroid dose is gradually tapered to a lower maintenance dose to prevent relapse. For patients who cannot tolerate long-term steroids or whose disease relapses, second-line therapies are employed. These treatments often involve B-cell depletion agents, such as the monoclonal antibody rituximab, which targets the B-cells responsible for producing pathogenic antibodies.