Primary Immunodeficiency (PI) Subclass

What is PI?

IgG immunoglobulins are composed of four sub types named IgG1, IgG2, IgG3 and IgG4. Each subclass is present in the serum in different concentrations, varies with age, and has different roles for immune response. Abnormal levels of one or more subclasses may be associated with certain conditions: antibody deficiencies, cellular immunodeficiency’s, and innate immune disorders.

Because they are prevalent in varying serum concentrations, a deficiency may be masked when only measuring total IgG. Many patients with PI are undiagnosed, underdiagnosed, or misdiagnosed. Compared to 2013 in 2018 there has been a 57% increase the number of patients followed and identified with a PI defect in the United States.1

For this reason, the measurement of IgG subclass concentrations is important in the assessment of the immune system. Early diagnosis results in decreased morbidity and mortality and in lower costs, estimated to be annual savings to the health care system for each diagnosed patient of $85,882.1

Symptoms of PI

One of the most common signs of primary immunodeficiency is having infections that are more frequent, longer lasting, or harder to treat than the infections of someone with a normal immune system. Also, PI patients may get infections that a person with a healthy immune system would not be likely to get (so called, “opportunistic infections”).

Clinical signs and symptoms differ depending on the type of primary immunodeficiency disorder and can vary from person to person.

Signs and symptoms of primary immunodeficiency can include2:

  • Frequent and recurrent pneumonia, bronchitis, sinus infections, ear infections, meningitis, or skin infections
  • Inflammation and infection of internal organs
  • Blood disorders, such as low platelet counts or anemia
  • Digestive problems, such as cramping, loss of appetite, nausea, and diarrhea
  • Delayed growth and development
  • Autoimmune disorders, such as lupus, rheumatoid arthritis, or type 1 diabetes

Available Testing

There are four IgG subtypes, however, IgG1 and IgG2 comprise 85% of the total concentration. IgG1 and IgG3 fix complement best; IgG3 is hyperaggregable and effects serum viscosity disproportionately.

The four subclasses of IgG differ in the constant regions of their heavy chains. A patient may have a normal total IgG yet still have a significant decrease in one subclass. IgG1 deficiencies are associated with EBV infections, IgG2 with sinorespiratory infections and infections with encapsulated bacteria, IgG3 with sinusitis and otitis media, and IgG4 with allergies, ataxia telangiectasia, and sinorespiratory infections. See tables in individual subclass listings.

IgG antibody responses to certain antigens may occur to a greater extent in one type of IgG subclass over another. Therefore, some patients with normal total IgG levels may have problems with pyogenic infections because they do not produce IgG2 or combinations of IgG2, IgG3, and/or IgG4. Some clinically significant IgG subclass deficiencies occur in patients who have IgA deficiency.

Panel for PID patient screening and studying patients with recurrent bacterial infections or allergy:

IgG Subclass Panel component

Tests may be ordered individually for focused evaluation or confirmation of previous results:

Panel for monitoring the treatment of patients with intravenous IgG infusions

For patients who exhibit primary immunodeficiency with recurrent infections (The panel has established “treatment-relevant” concentration cut-point levels)

Test to aid in the diagnosis of “IgG4-releated disease (IgG4-RD)”

  1. Modell V, Orange JS, Quinn J, Modell F. Global report on primary immunodeficiencies: 2018 update from the Jeffrey Modell Centers Network on disease classification, regional trends, treatment modalities, and physician reported outcomes. Immunologic Research. 2018;66(3):367-380. doi:10.1007/s12026-018-8996-5
  2. Primary immunodeficiency - Symptoms and causes - Mayo Clinic. Accessed August 25, 2020.