B cell and immunoglobulin immunodeficiencies are caused by inherited defects in either B cells or antibody production. These primary immunodeficiency syndromes have a prevalence of 1:500 to 1:500000 persons in the Western world, with B cell immunodeficiencies accounting for half of cases. Individuals tend to develop recurrent infections.
This article will discuss the unique features and management of B cell and immunoglobulin immunodeficiencies.
X-linked agammaglobulinaemia (or Bruton agammaglobulinaemia) is inherited in an X-linked recessive pattern. It is distinguished from other B-cell immunodeficiency disorders by a lack of mature B cells in circulation.
Mutations in the Bruton tyrosine kinase gene on the X chromosome cause this disorder. This gene is vital to B cell development, and mutations cause a decrease of mature B cells and lack of antibody production.
Most cases present in infancy with recurrent infections caused by staphylococcus, streptococcus, Haemophilus, and Giardia. These infections can include ear infections, respiratory tract infections, sinus infections, and diarrhoea. Examination reveals smaller than normal secondary lymphoid organs due to a lack of B cell development.
X-linked agammaglobulinaemia is identified by the lack of B cells in circulation and a reduction in immunoglobulins of all classes.
Patients with X-linked agammaglobulinaemia require lifelong intravenous immunoglobulin replacement to prevent infection. Live-attenuated vaccines should be avoided due to the risk of infection.
Common variable immunodeficiency is caused by a defect in B cell activity, resulting in low levels of immunoglobulins in the blood. This disorder presents in early adulthood rather than in childhood.
CVID is associated with impaired immunoglobulin production by plasma cells. In some cases, a genetic basis has been identified, and certain genes involved in B cell development and class switching are thought to be affected.
CVID usually presents in early adulthood with recurrent infections.
Common Variable Immunodeficiency (CVID) is characterized by a reduction of all immunoglobulin classes, and is associated with an increased incidence of autoimmune disease and malignancy.
Patients with CVID present with a normal B cell and plasma count, but reduced levels of all immunoglobulin classes.
Due to the infectious complications as well as the autoimmune and malignant complications of the condition, CVID patients require a multidisciplinary approach and intravenous IgG infusions. They must also avoid live attenuated vaccines in order to minimize risk of infection.
Hyper-IgM Syndrome is an immunodeficiency characterized by high levels of IgM antibodies and low levels of other antibody classes (IgG, IgA, etc.).
This syndrome occurs due to a defect in B cell class switching, and can be caused by deficiencies in factors such as CD40, CD40L, activation-induced cytidine deaminase and uracil-DNA glycosylase. Mutations in these genes are x-linked for CD40L, and mostly autosomal recessive for the rest.
Opportunistic infections within the first two years of life are common in patients with Hyper-IgM Syndrome, including cryptococcus, toxoplasmosis, JC virus, pneumocystis, histoplasma, and cryptosporidium infection and its associated complications in the biliary system. Other notable features include liver disease, mucosal diseases, and an increased incidence of malignancies.
Typical laboratory findings in Hyper-IgM Syndrome include increased levels of IgM, a normal amount of B cells, and reduced levels of IgG, IgA, and IgE molecules. Flow cytometry can be used to identify the lack of cell surface markers that may cause the syndrome.
Patients with Hyper-IgM Syndrome should receive IVIG replacement, trimethoprim/sulfamethoxazole antibiotics to prevent Pneumocystis jirovecii infection, and should take precautions to avoid exposure to cryptosporidium. The definitive treatment is a hematopoietic stem cell transplant.
IgA Deficiency is a selective immunoglobulin deficiency characterized by a reduction of IgA immunoglobulins in a child greater than four years of age. As IgA is a secreted immunoglobulin, the reduction can result in gastrointestinal and respiratory infections. It is the most common selective immunoglobulin deficiency.
The exact cause of IgA deficiency is under investigation, but it is thought to be due to an inability of B cells to differentiate into IgA-producing plasma cells.
Two-thirds of affected patients are asymptomatic.
Common features of IgA deficiency include recurrent respiratory and gastrointestinal infections, other gastrointestinal illnesses (e.g. diarrhoea) and sinus infections. There is a high incidence of allergy and autoimmune diseases in children with IgA deficiency and a particularly high incidence of coeliac disease.
Rarely, IgA deficiency may cause anaphylactic reactions to blood transfusions from blood that contains IgA molecules.
For a diagnosis of IgA deficiency, serum IgA levels must be less than 7 mg/dL. Importantly, levels of other immunoglobulins, as well as B and T cell counts, should be normal.
Treatment should be aimed at the specific complications of the disease (i.e. the specific infections and associated autoimmune conditions). Patients with significant recurrent upper respiratory tract infections may benefit from a 6-month course of prophylactic antibiotics. At present no suitable IgA replacement therapy exists.
The disease can range from mild to severe, and outcomes are difficult to predict.
Normally, a physiological nadir in immunoglobulins occurs between 3 and 6 months of age when the maternal antibodies begin to disappear, and an infant begins producing their own antibodies.
Transient hypogammaglobulinaemia of infancy occurs when infants are found to have reduced levels of immunoglobulins (mainly IgG) than what would be expected for an infant at greater than 6 months of age.
The cause is unknown. However, several proposed mechanisms include suppressive maternal antibodies persisting in the infant circulation, abnormal B cells or T-cells failing to stimulate antibody production, and abnormal cytokine production.
Transient hypogammaglobulinaemia of infancy may present upper and lower respiratory tract infections, ear and sinus infections, allergies, asthma, eczema, gastrointestinal difficulties, thrush, swollen glands, and evidence of infections in various organs systems such as those mentioned above.
By definition, transient hypogammaglobulinaemia of infancy requires IgG levels less than 2 standard deviations below the mean in the population. This typically equated to less than 400 mg/dL. IgM and IgA levels may also be reduced.
Imaging may show signs of infection in the respiratory tract, sinuses, or other organ systems depending on the specific presentation.
A normal response to vaccines can be expected in children with transient hypogammaglobulinaemia of infancy.
Patients can usually be monitored with IgG levels taken every 4 to 6 months. Reducing infective exposures and postponing live attenuated vaccines until IgG levels normalise is usually enough to safely manage the condition.
In rare cases where children are failing to thrive due to recurrent infections, intravenous immunoglobulins may be administered. Most children will attain normal IgG levels by five years of age.
Table 1. Common features and management of primary B cell immunodeficiency syndromes
Clinical featuresManagementTransient hypogammaglobulinaemia of infancyUpper and lower respiratory tract infections, ear and sinus infections, allergies, asthma, eczema, gastrointestinal difficulties, thrush, swollen glands, and evidence of infections in various organs systemsMonitor with IgG levels taken every 4 to 6 months; reducing infective exposures and postponing live attenuated vaccines until IgG levels normalise; intravenous immunoglobulins in rare casesIgA deficiencyRecurrent respiratory and gastrointestinal infections, other gastrointestinal illnesses (e.g. diarrhoea) and sinus infections; high incidence of allergy and autoimmune diseases; anaphylactic reactions to blood transfusionsTreat complications; prophylactic antibiotics in some cases; no IgA replacement therapy available
B cell and immunoglobulin immunodeficiency syndromes are characterised by a disorder affecting either B cell function or the production of one or more immunoglobulin subtypes. Common findings in these immunodeficiency syndromes include recurrent infections and infections from opportunistic organisms. Table 1 lists some of the primary B cell immunodeficiency syndromes and the corresponding clinical management.
Transient hypogammaglobulinaemia of infancy
X-linked agammaglobulinaemia
Common variable immunodeficiency (CVID)
Hyper-IgM syndrome
IgA deficiency
Table 2. Laboratory findings in primary B cell immunodeficiency syndromes
B cellsIgMIgGIgAIgE
Transient hypogammaglobulinaemia of infancy
Normal
Low
Normal/low
Normal/low
Normal/low
X-linked agammaglobulinaemia
Low
Low
Low
Low
Low
Common variable immunodeficiency (CVID)
Normal
Low
Low
Low
Low
Hyper-IgM syndrome
Normal
High
Low
Low
Low
IgA deficiency
Normal
Normal
Normal
Low
Normal
Common variable immunodeficiency is believed to originate from a problem with B cell development, leading to a decrease in immunoglobulin production. It tends to present in early adulthood, unlike other B-cell/immunoglobulin immunodeficiencies that appear in childhood or infancy.
Hyper-IgM syndrome is caused by an issue with B-cell class switching, which causes high IgM levels and low levels of other immunoglobulins. IgA deficiency is brought on by reduced production of IgA molecules and is associated with recurrent infections, allergies, and autoimmune diseases.
Transient hypogammaglobulinaemia of infancy is characterised by a short-term low IgG level in infancy which usually rectifies itself as time passes.
