IgG Subclasses

Immunoglobulin G comprises four subclasses (IgG1, IgG2, IgG3, IgG4), with distinct structure, function and distribution. IgG1 makes up 60 to 70% of total IgG and responds to protein antigens. IgG2 (20 to 30%) responds to polysaccharide antigens of encapsulated bacteria.

IgG3 (5 to 8%) fixes complement efficiently, and IgG4 (1 to 4%) is a non-complement-fixing subclass linked to chronic antigen exposure. Serum levels are measured by nephelometry, turbidimetry or ELISA with age specific reference ranges. Testing is requested in recurrent sinopulmonary infections despite normal total IgG, and for diagnosis of IgG4-related disease.

IgG subclass deficiency (IgG1 to IgG3) is controversial as a cause of disease: low subclasses occur in up to 10% of healthy people, and clinical significance needs recurrent infection plus impaired vaccine response.

IgG4-related disease is a fibro inflammatory condition affecting the pancreas (autoimmune pancreatitis type 1), biliary tree, salivary and lacrimal glands, retroperitoneum, aorta, kidney and orbit, with serum IgG4 raised in 60 to 70%. Its incidence is about 1 in 100 000 a year, with a male predominance in middle to older age.

Indications. Recurrent or severe sinopulmonary infections (otitis media, sinusitis, pneumonia, bronchiectasis) with normal total immunoglobulins. Suspected IgG4-related disease (pancreatic mass or enlargement, bile duct strictures, enlarged salivary or lacrimal glands, retroperitoneal fibrosis, orbital pseudotumour, aortitis).

Suspected selective IgA deficiency with infections, ataxia telangiectasia, hyper-IgM syndromes. Evaluation of poor antibody response to polysaccharide vaccine.

Specimen. Serum 1 mL, no fasting. Stable for several days at 2 to 8 °C. Interpreted with age specific ranges, since values change with age.

Adult reference ranges (typical, assay dependent).

• IgG1: 3.8 to 9.3 g/L.
• IgG2: 2.4 to 7.0 g/L.
• IgG3: 0.22 to 1.76 g/L.
• IgG4: 0.04 to 1.4 g/L (adult upper limit 1.4 g/L, or 140 mg/dL).
• Total IgG: 7 to 16 g/L.
• Values are lower in children, with adult levels reached by adolescence (IgG2 and IgG4 are slower to mature, 8 to 10 years).

IgG subclass deficiency.

• Defined as a level under the 5th percentile (under 2 SD) for age on at least two occasions, in a patient with recurrent infections and impaired specific antibody responses.
• IgG2 deficiency: recurrent pneumococcal and Haemophilus infections, often with IgA deficiency, and poor response to polysaccharide vaccines.
• IgG3 deficiency: recurrent sinopulmonary infections and, in adults, linked to asthma.
• IgG1 deficiency usually lowers total IgG.
• Normal total IgG with a low subclass in an asymptomatic person: no treatment.
• Management requires proof of functional antibody deficiency (poor titres after pneumococcal polysaccharide and tetanus vaccines), prophylactic antibiotics, and immunoglobulin replacement in selected severe cases.

IgG4-related disease.

• Serum IgG4 over 1.35 g/L (135 mg/dL) has sensitivity 70 to 90% and specificity 60 to 90%. Levels over 2 times the upper limit (over 2.8 g/L) have higher specificity (over 95%) and in many studies positive predictive value of 80%.
• An IgG4 to total IgG ratio over 8 to 10% and IgG4 plasma cells to IgG plasma cells ratio over 40% in tissue (with over 10 to 50 IgG4-positive plasma cells in each high power field, storiform fibrosis and obliterative phlebitis) is diagnostic.
• Serum IgG4 can be normal in 20 to 30% of confirmed cases (especially single organ disease) and raised in other conditions.
• Other raised IgG4 conditions: pancreatic cancer (10%), cholangiocarcinoma, Castleman disease, eosinophilic granulomatosis with polyangiitis and granulomatosis with polyangiitis, Sjögren syndrome, atopic disease, parasitic infection, lymphoma and pemphigus.
• Serum IgG4 is a monitoring tool: levels fall with steroids and rebound before relapse, though the correlation is imperfect. Plasmablast count and IgE help with activity.

Critical values and findings needing immediate action.

• Raised IgG4 with obstructive jaundice and a pancreatic mass: IgG4-related disease versus pancreatic cancer, urgent imaging, endoscopic ultrasound with biopsy and CA 19-9, avoiding unnecessary surgery.
• Raised IgG4 with renal impairment: IgG4-related kidney disease, urinalysis, complement and renal biopsy, with urgent steroid treatment.
• Recurrent pneumonia with bronchiectasis and low subclass: evaluation for antibody deficiency, spirometry and CT, and prophylaxis.
• Severe infection in a patient with IgG2 deficiency: urgent antibiotic therapy and immunology referral.

Interferences and pitfalls.

• Reference ranges vary with age, assay and laboratory. Age specific ranges are required for children.
• Subclass deficiencies are common in healthy people, and low levels with no infection or poor vaccine response have no clinical meaning.
• IgG4 can be raised in unrelated conditions and normal in true disease, so diagnosis rests on histology and clinical features.
• High IgG4 concentrations can give falsely low results on some nephelometric assays because of antigen excess (the prozone effect), and dilution is requested if IgG4-related disease is strongly suspected.
• Immunosuppressants, steroids and rituximab lower levels and can normalise IgG4.
• Total IgG should be measured with subclasses, and IgA and IgM added.
• Vaccine response testing (tetanus, Haemophilus influenzae type b, pneumococcal polysaccharide) is the functional test.
• Immunoglobulin replacement raises IgG1 mostly, and subclasses are not monitored on therapy.

Special groups.

• Children: immunoglobulin maturation delays and transient hypogammaglobulinaemia of infancy occur, and IgG2 deficiency is more common under 5 years.
• Pregnancy: IgG falls slightly, and maternal IgG crosses the placenta.
• Older adults: IgG4-related disease peaks in the sixth and seventh decade.
• Regions: chronic infection and malnutrition lower immunoglobulin levels, and access to functional antibody testing is limited.

Follow up tests. Total IgG, IgA, IgM and IgE, vaccine antibody titres (pneumococcal, tetanus), lymphocyte subsets, complement, CT of chest and sinuses, spirometry, pancreatic MRI or CT, MRCP, endoscopic ultrasound with biopsy, tissue histology with IgG4 immunostaining, CA 19-9, and PET-CT to assess extent of disease.