The main immunoglobulin (Ig) in human blood is IgG. This is the second most abundant circulating protein and contains long-term protective antibodies against many infectious agents. IgG is a combination of four slightly different types of IgG called IgG subclasses: IgG1, IgG2, IgG3 and IgG4. When one or more of these subclasses is persistently low and total IgG is normal, a subclass deficiency is present. Although this deficiency may occasionally explain a patient’s problems with infections, IgG subclass deficiency is a controversial diagnosis and experts disagree about the importance of this finding as a cause of repeated infections.
A common misdiagnosis:
The misdiagnosis of IgG subclass deficiency as a cause of presumed immunodeficiency is common, often leading to unnecessary long-term use of Ig replacement therapy. A subclass deficiency needs to be considered and looked for only under special circumstances discussed in this chapter.
Different functions of IgG subclasses:
While all the IgG subclasses contain antibodies to components of many disease-causing bacteria and viruses, each subclass serves a slightly different function in protecting the body against infection. For example, IgG1 and IgG3 subclasses are rich in antibodies against proteins such as the toxins produced by the diphtheria and tetanus bacteria, as well as antibodies against viral proteins. In contrast, IgG2 antibodies are predominantly against the polysaccharide (complex sugar) coating (capsule) of certain disease-producing bacteria (such as, Streptococcus pneumoniaeand Haemophilus influenzae).
More details on IgG subclass deficiencies:
The normal IgG breakdown in the bloodstream is:
- 60-70% IgG1,
- 20-30% IgG2,
- 5-8% IgG3
- 1-3% IgG4
IgG subclass deficiencies affect only IgG subclasses (usually IgG2 or IgG3), with normal total IgG and IgM immunoglobulins and other components of the immune system being at normal levels. These deficiencies can affect only one subclass or involve an association of two subclasses, such as IgG2 and IgG4.
IgG2 or IgG3 deficiencies are the most common IgG subclass deficiencies. Since IgG1 comprises 60% of the total IgG level, deficiency of IgG1 usually drops the total IgG level below the normal range, resulting in hypogammaglobulinemia.
IgG subclass levels are age-dependent:
The amount of the different IgG subclasses present in the bloodstream varies with age. For example, IgG1 and IgG3 reach normal adult levels by 5-7 years of age while IgG2 and IgG4 levels rise more slowly, reaching adult levels at about 10 years of age. In young children, the ability to make IgG2 antibodies to the polysaccharide coatings of bacteria develops more slowly than the ability to make antibodies to proteins.
Sources:
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- People with persistently low levels of one or two IgG subclasses and a normal total IgG level have a selective IgG subclass deficiency.
- People with IgG subclass deficiency require more extensive diagnostic evaluation including the demonstration of a poor antibody response to vaccine challenge before one is diagnosed with a clinically significant IgG subclass deficiency necessitating specific treatment that may include Ig replacement therapy.
- IgG subclass deficiencies may be associated with other immunoglobulin abnormalities. One common pattern is IgG2 and IgG4 subclass deficiency associated with IgA deficiency.
- IgG subclass deficiencies are also an integral component of other well-known primary immunodeficiency diseases, such as Wiskott-Aldrich Syndrome and Ataxia-Telangiectasia.
- IgG subclass deficiencies are sometimes associated with poor or partial responses to pneumococcal polysaccharides, specifically IgG2 deficiency with or without IgG4 deficiency.
IgG1 deficiency:
Selective IgG1 deficiency is very rare, as it is usually associated with deficiency of either IgG3, or other immunoglobulin classes, such as in common variable immunodeficiency. Isolated IgG1 deficiency has been reported in chronic fatigue syndrome. As IgG1 is the most abundant IgG subclass, its deficiency often results in hypogammaglobulinemia.
IgG1 and IgG3 deficiency:
People with this combination are commonly present with infections of the lower airways, which can progress to chronic lung disease.
IgG2 and IgG4 deficiency:
Conversely, IgG2 and IgG4 deficiencies manifest in the form of otitis media and sinusitis. IgG2 deficiency is the most common type of IgG subclass deficiency, either as an isolated finding or together with IgG4 deficiency. People with this defect have recurrent infections with encapsulated bacteria such as Streptococcus pneumonia and/or Haemophilus influenza type B. IgG2 deficiency often results in infectious complications, such as bronchiectasis, bronchopneumonia, bronchitis, obstructive lung disease, and asthma. It has also been associated with ataxia telangiectasia and systemic lupus erythematosus (SLE). Children with SLE and IgG2 and IgG4 deficiency may present with cardiac tamponade, instead of the more common nephropathy and arthritis. The impact of decreased concentration of IgG4 cannot be easily assessed, since IgG4 may be present in low concentrations in healthy children. Nevertheless, it was shown that low concentrations of IgG4 are present in a large percentage of patients with recurrent respiratory tract infections.
Possible symptoms:
People with any form of IgG subclass deficiency occasionally suffer from recurrent respiratory infections similar to the ones seen in other antibody deficiency syndromes, chiefly infections with encapsulated bacteria such as Streptococcus pneumoniae and Haemophilus influenzae. An increased frequency of viral upper respiratory infections may not be an indication of antibody deficiency. Therefore, it is critical to distinguish between infections caused by respiratory viruses from those due to bacterial pathogens.
A few people with IgG subclass deficiency may appear very similar to patients with severe immunoglobulin deficiencies. Rarely, IgG subclass deficient patients may have recurrent episodes of bacterial meningitis or infections of the bloodstream (sepsis).
Diagnosis:
The finding of an IgG subclass deficiency should prompt reevaluation over a period of months before determining that the patient is truly immunodeficient. Subclass deficiencies need to be carefully interpreted taking into account the clinical status of the patient as well as the person’s ability to produce specific antibodies in response to vaccines.
Measurement of IgG subclasses can be recommended in the presence of known associated abnormalities, particularly if recurrent infections are also present.
These circumstances include:
- IgA deficient patients with recurrent infections to determine if there is an associated IgG2 and IgG4 subclass deficiency
- Wiskott-Aldrich and Ataxia-Telangiectasia patients at the onset of recurrent infections
- Specific Antibody Deficiency patients with normal total immunoglobulins
Possible treatment:
- Recurrent or chronic infections of the ears, sinuses and lungs need comprehensive treatment to prevent permanent damage that might result in hearing loss or chronic lung disease. It is also important to encourage patients to continue normal activities of daily living, such as school or work.
- The mainstay of treatment includes appropriate use of antibiotics to treat and prevent infections. The type and severity of infection usually determines the type of antibiotic used and the length of treatment.
- Ig therapy is an option for selected symptomatic patients that have persistent IgG subclass deficiencies, documented poor responses to polysaccharide vaccines and who fail prophylactic antibiotic therapy. The decision to begin Ig replacement therapy needs to be carefully discussed with the healthcare provider
- People with frequent infections and persistent IgG subclass deficiencies with normal anti-polysaccharide antibodies should also be treated using adequate prevention, vaccine and antibiotic therapy, perhaps even considering the use of Ig replacement if other treatment fails.
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