Selective IgA Deficiency

Selective immunoglobulin A (IgA) deficiency is the most common type of primary immunodeficiency. The condition is a hypogammaglobulinemia characterized by a lack or reduced levels of IgA. This antibody mainly resides in the mucous membranes of the mouth, airways, and digestive tract. The exact cause is unknown. The disease is usually asymptomatic, although some patients can present with recurrent respiratory and gastrointestinal infections as well as autoimmune and malignant disorders. Diagnosis is made with a measure of exceptionally low IgA levels in the serum in the presence of normal IgG and IgM levels.

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Epidemiology and Pathophysiology

Epidemiology

  • 1 in 1001,000 people have selective IgA deficiency worldwide
  • More common in Caucasians
  • More common in males than females
  • More common in patients with autoimmune diseases such as celiac disease and diabetes mellitus type 1

Etiology

  • Exact cause is unknown.
  • Most cases are sporadic, but inherited types have been linked to chromosomes 6 and 17 with an autosomal dominant and recessive inheritance pattern.
  • IgA deficiency is also seen in ataxia-telangiectasia, along with cerebellar degeneration, movement and coordination issues, and increased risk for some cancers.
  • Some cases of IgA deficiency have been traced back to inducing agents:
    • Drugs:
      • Antirheumatic medications (e.g., sulfasalazine, D penicillamine, cyclosporine)
      • Anticonvulsant medications (e.g., phenytoin, valproic acid)
      • Thyroxine
      • Captopril
      • Levamisole
    • Infections (cause transient IgA deficiency):
      • Cytomegalovirus
      • Rubella
      • Toxoplasmosis
      • Epstein-Barr virus

Pathophysiology

  • Associated with an intrinsic B-cell lymphocyte defect, T-cell abnormalities, and impairment of cytokine networks 
  • B cells cannot fully mature into IgA-secreting plasma cells.
  • Defects have been reported in the following cytokines: IL‐4, IL‐6, IL‐7, IL‐10, and IL‐21
  • The inherited inability to produce immunoglobulin A (IgA) occurs mainly in the mucosal surfaces of the respiratory and gastrointestinal (GI) tracts, leading to frequent bacterial infections in these organ systems.
  • Associated with autoimmune diseases in 5%30% of cases
Dimeric structure of IgA antibody

The dimeric structure of the IgA antibody

Image by Lecturio.

Clinical Presentation

Approximately 90% of cases are asymptomatic.

Symptomatic patients may present a mixture of the following symptoms:

  • Recurrent pulmonary infections: 
    • The first presentation in 40%90% of symptomatic patients
    • Usually caused by extracellular encapsulated bacteria (e.g., Haemophilus influenzae, Streptococcus pneumoniae)
  • Gastrointestinal conditions:
    • Less common than pulmonary infections as IgM can more effectively compensate for the absence of IgA in the GI tract
    • Giardiasis (increased susceptibility due to a defective GI mucosal barrier)
    • Crohn’s disease
    • Nodular lymphoid hyperplasia (NLH)
    • Ulcerative colitis 
  • Allergies: 
    • Due to compensatory elevated IgE levels
    • Conjunctivitis
    • Rhinitis
    • Urticaria
    • Eczema
    • Food allergy
  • Autoimmune diseases:
    • Celiac disease
    • Systemic lupus erythematosus
    • Rheumatoid arthritis
    • Thyroiditis
    • Diabetes mellitus type 1
    • Graves’ disease
    • Autoimmune hemolytic anemia
  • Higher incidence of malignancies:
    • Gastric adenocarcinoma
    • B-cell lymphoma
    • Colorectal cancer
    • Ovarian cancer
    • Melanoma

Diagnosis and Management

Diagnosis

  • Confirmed by laboratory measurement of IgA < 7 mg/dL with normal serum IgG and IgM (measured at least twice) in a patient > 4 years of age
  • Secondary causes of hypogammaglobulinemia must be excluded, with a normal IgG antibody response to all vaccinations, and exclusion of a T-cell defect.

Management

  • Symptomatic therapy:
    • Anti-inflammatory medications and antihistamines for allergy-based symptoms
    • Prophylactic antibiotics and/or targeted at recurrent infections  
  • Administration of pneumococcal vaccine
  • Immunoglobulin (IVIG) replacement therapy is not recommended due to the risk of anaphylactic reactions!

Differential Diagnosis

The following conditions are other congenital B-cell immunodeficiencies that serve as differential diagnoses for selective IgA deficiency.

  • X-linked agammaglobulinemia: also known as Bruton’s agammaglobulinemia. A recessive genetic disorder characterized by the improper development of B cells from immature to mature cells. This results in a complete or near-complete lack of all antibodies. More common in males than females, X-linked agammaglobulinemia presents as recurrent bacterial infections after the first few months of life. 
  • Common variable immunodeficiency (CVID): a type of primary immunodeficiency characterized by reduced serum levels of immunoglobulins IgG, IgA, and IgM.  The underlying causes are unknown. Patients with this condition are prone to infections in the GI tract and the upper and lower respiratory tracts and have a higher risk of developing autoimmune, granulomatous, and neoplastic diseases.
  • Ataxia-telangiectasia: a rare, autosomal recessive disorder characterized by the association of severe combined immunodeficiency, tumor development, and neurological abnormalities. Presents as gait ataxia, apraxia, abnormal movements, telangiectasia, recurrent pulmonary infections, and a higher risk of lymphoma, leukemia, and gastric carcinoma.
  • Severe combined immunodeficiency (SCID): the most severe form of primary immunodeficiency. Severe combined immunodeficiency is a genetic disorder that involves defective antibody response due to either direct involvement with B lymphocytes or through improper B-lymphocyte activation due to non-functional T-helper cells. Presents as severe and recurrent opportunistic infections and is diagnosed through quantitative polymerase chain reaction (PCR) testing and flow cytometry.
  • Hyper IgM syndrome: a disorder caused by an X-linked mutation in the CD40 ligand gene that results in abnormal signaling between B and T lymphocytes. Presentation is mild and often only presents in later life as opportunistic infections and immune dysregulation of IgE eosinophils, B cells, NK cells, and CD8+ T cell proliferation and activation.

References

  1. Le, T., & Bhushan, V. (2020). First Aid for the USMLE Step 1 (30th anniversary edition) (P. 116). New York: McGraw-Hill Medical.
  2. Kumar, V., Abbas, A. K., Aster, J. C., & Robbins, S. L. (2013). Robbins basic pathology (P. 141). Philadelphia, PA: Elsevier/Saunders.
  3. Genetic and Rare Diseases Information Center. Selective IgA deficiency. National Center for Advancing Translational Sciences; rarediseases.info.nih. Retrieved August 18, 2020, from https://rarediseases.info.nih.gov/diseases/10197/selective-iga-deficiency
  4. Mayo Clinic (2020). Selective IgA deficiency. https://www.mayoclinic.org/diseases-conditions/selective-iga-deficiency/diagnosis-treatment/drc-20450490

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