B Cell and Immunoglobulin Immunodeficiencies

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Introduction

B cell and immunoglobulin immunodeficiencies occur due to inherited defects in either B cells or in antibody production.

The prevalence of primary immunodeficiency syndromes is between 1:500 and 1:500000 persons in the general population of the Western world, and B cell immunodeficiencies account for half of these cases.1 In general, these syndromes are characterised by recurrent infections.

This article will discuss the unique features and management of the different classes of B cells and immunoglobulin immunodeficiencies.

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X-linked agammaglobulinaemia

X-linked agammaglobulinaemia (or Bruton agammaglobulinaemia) is inherited most often in an x-linked recessive pattern. It can be distinguished from other B-cell immunodeficiency disorders by a lack of mature B cells in circulation.

Aetiology

Mutations in the Bruton tyrosine kinase gene on the X chromosome are responsible for causing the disorder. This gene is crucial in B cell development, and mutations in the gene result in a lack of mature B cells in circulation and a lack of antibody production.2,3

Clinical features

Most cases present in infancy after maternal IgG begins to disappear and recurrent infections develop in the first few years of life. These infections are most often caused by staphylococcus, streptococcus, Haemophilus, and Giardia and can include ear infections, respiratory tract infections, sinus infections, and diarrhoea3.

A notable feature on examination of patients with x-linked agammaglobulinaemia is smaller than normal secondary lymphoid organs (e.g. tonsils and lymph nodes) resulting from a lack of B cell development.2

Laboratory features

X-linked agammaglobulinaemia is characterised by a lack of B cells in circulation, leading in turn to a reduction in the number of immunoglobulins of every class in circulation.2,3

Management

Patients with X-linked agammaglobulinaemia require lifelong intravenous immunoglobulin replacement. This is successful in preventing infection in most cases. Live-attenuated vaccines must be avoided in these patients because of the risk of infection.3


Common variable immunodeficiency

Common variable immunodeficiency (CVID) results from a defect in B cell activity. While the number of B cells is preserved, antibody production is impaired, and there are low levels of immunoglobulins in the blood. Unlike other B cell immunodeficiencies, CVID often presents in early adulthood rather than in childhood.4

Aetiology

CVID results from impaired immunoglobulin production by plasma cells. The exact is unknown, however, in 10% of cases a genetic basis has been established, and several genes involved in B cell development and class switching are theorised to be affected.4

Clinical features

CVID presents in early adulthood with recurrent infections. These are most often sinusitis, respiratory tract infections, gastrointestinal infections causing diarrhoea, and infections caused by opportunistic organisms. CVID is also associated with an increased incidence of autoimmune disease and malignancy.5

Laboratory features

In CVID, a normal B cell and plasma count is observed. However, a reduced level of all immunoglobulin classes is seen.5

Management

CVID patients require a multidisciplinary approach to manage both the infectious complications as well as the autoimmune and malignant complications of the disease. They will require intravenous IgG infusions and must avoid live attenuated vaccines for risk of infection.5


Hyper-IgM syndrome

Hyper-IgM syndrome is an immunodeficiency that, as its name implies, is characterised by high levels of IgM antibodies. A defect in antibody class switching results in high levels of IgM antibodies and low levels of other antibody classes (IgG, IgA, etc.).

Aetiology

Hyper-IgM syndrome occurs because of a defect in B cell class switching. Normally, the interaction between activated T-cells and B cells will stimulate B cells to proliferate and switch from producing IgM to producing other immunoglobulins including IgG and IgA antibodies.

Deficiencies in such factors as CD40, CD40L, activation-induced cytidine deaminase and uracil-DNA glycosylase can all cause hyper IgM syndrome. Inheritance patterns of mutations in these genes is x-linked for CD40L, and mostly autosomal recessive for the rest.4

Clinical features

Opportunistic infections within the first two years of life (e.g. cryptococcus, toxoplasmosis, JC virus, pneumocystis, Histoplasma) are common in hyper-IgM syndrome. In particular, cryptosporidium infection and its associated complications in the biliary system are often seen.4,6

Other notable features common in patients with hyper IgM syndrome are liver disease resulting from cytomegalovirus and hepatitis, mucosal diseases, and a higher incidence of malignancies.4

Many patients with hyper-IgM syndrome will die in childhood or will develop malignancy and chronic complications in adulthood.6

Laboratory features

The typical laboratory findings in hyper-IgM syndrome include increased blood levels of IgM, a normal amount of B cells, and reduced IgG, IgA, and IgE molecules.

Flow cytometry can be performed to identify the lack of cell surface markers that may cause hyper IgM syndrome (e.g. lack of CD40L on T cells).6

Management

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.6


IgA deficiency

IgA deficiency occurs when there is a reduction in IgA immunoglobulins in a child greater than four years of age. As IgA is a secreted immunoglobulin, the reduction of IgA can result in gastrointestinal and respiratory infections. IgA deficiency is the most common selective immunoglobulin deficiency.

Aetiology

The exact cause of IgA deficiency is under investigation. It is thought that an inability of B cells to differentiate into IgA-producing plasma cells may cause the disease.4

Clinical features

Two-thirds of affected patients will be 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.4,7

Rarely, IgA deficiency may cause anaphylactic reactions to blood transfusions from blood that contains IgA molecules.7

Laboratory features

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.4

Management

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.7


Transient hypogammaglobulinaemia of infancy

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.

Aetiology

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.8

Clinical features

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.8

Laboratory features

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.8

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.

Management

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.8


Summary tables

Table 1. Common features and management of primary B cell immunodeficiency syndromes

  Clinical features Management
Transient hypogammaglobulinaemia of infancy
  • Age: 3-6 years old
  • Respiratory, Gl, and sinus infections
  • Atopy
  • Check IgG levels every 4 months
  • Avoid infectious exposures
  • Postpone live vaccines
X-linked agammaglobulinaemia
  • Age: first few years
  • Staphylococcus, Streptococcus,
  • Haemophilus and Giardia infections
  • Smaller secondary lymphoid organs
  • Lifelong IVIG
  • Avoid live vaccines
Common variable immunodeficiency (CVID)
  • Age: early adulthood
  • Opportunistic respiratory, GI and sinus infections
  • Autoimmune disease
  • IVIG
  • Avoid live vaccines
  • Autoimmune disease management
Hyper-IgM syndrome
  • Age: first 2 years of life
  • Opportunistic infections (esp. cryptosporidium)
  • Hepatic disease and malignancy
  • IVIG
  • Antibiotic prophylaxis
  • Definitive treatment: stem cell transplant
IgA deficiency
  • Age: >4 years
  • Anaphylaxis to blood products
  • Respiratory, GI and sinus infections
  • Autoimmune disease
  • Treatment specific to presenting infections or autoimmune disease

Table 2. Laboratory findings in primary B cell immunodeficiency syndromes

  B cells IgM IgG IgA IgE

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


Key points

  • B cell and immunoglobulin immunodeficiency syndromes are characterised by a disorder in either B cell function or the production of one or more immunoglobulin subtypes.
  • A common finding in all these immunodeficiency syndromes is recurrent infections and infections by opportunistic organisms.
  • X-linked agammaglobulinaemia is caused by a defect in the Bruton tyrosine kinase gene that results in low levels of circulating B cells and immunoglobulin proteins.
  • Common variable immunodeficiency is thought to result from an issue in B cell development, which causes a reduction in immunoglobulin production.
  • Common variable immunodeficiency presents in early adulthood, unlike most other B-cell/immunoglobulin immunodeficiencies which present in infancy or childhood.
  • Hyper-IgM syndrome is caused by a defect in B-cell class switching leading to high IgM levels and low levels of other immunoglobulins.
  • IgA deficiency results from the reduced production of IgA molecules and leads to recurrent infections and a tendency towards allergy and autoimmune disease.
  • Transient hypogammaglobulinaemia of infancy occurs due to a transient low IgG level in infancy and often self-resolves with time.

Reviewer

Dr Anda Dumitrescu

Clinical Lecturer

Department of Paediatrics

University College Cork/Cork University Hospital


Editor

Dr Chris Jefferies


References

  1. Knott L, Cox J. Immunodeficiency: Primary and Secondary. Last edited 2015. Available from: [LINK]
  2. National Institute of Allergy and Infectious Disease. X-linked agammaglobulinaemia (XLA). Last updated 2019. Available from: [LINK]
  3. American Academy of Allergy Asthma and Immunology. X-linked agammaglobulinaemia. 2022. Available from: [LINK]
  4. Smith T, Cunningham-Rundles C. Primary B-cell immunodeficiencies. Hum Immunol. 2019 Jun;80(6):351-362. Available from: [LINK]
  5. Knott L, Cox J. Common variable immunodeficiency. Last edited 2015. Available from: [LINK]
  6. Fernandez J. Hyper-IgM syndrome. Last reviewed 2021. Available from: [LINK]
  7. Immune Deficiency Foundation. Selective IgA Deficiency. 2013. Available from: [LINK]
  8. Immune Deficiency Foundation. Transient hypogammaglobulinaemia of infancy. 2013. Available from: [LINK]

 

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