Humoral Immunodeficiency

Aka: Humoral Immunodeficiency, Humoral Immunity Disorder, Humoral Immune Defect, Humoral Disorder, B-Cell Disorder, Immunoglobulin Disorder, Immunoglobulin Deficiency, Antibody Disorder, Agammaglobulinemia, Hypogammaglobulinemia, X-Linked Agammaglobulinemia, XLA, Bruton's Agammaglobulinemia, Common Variable Immunodeficiency, CVID, Transient Hypogammaglobulinemia of Infancy, Hyper Immunoglobulin E, Hyper-IgE Syndrome, Job Syndrome, Hyper Immunoglobulin M, HIGM, Hyper-IgM Syndrome

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II. Epidemiology

  1. Antibody or humoral or B-Cell Disorders account for Immunodeficiency in 78% of U.S. cases and 55% in Europe

III. Physiology

  1. See Humoral Immunity (Immunoglobulin)

IV. Pathophysiology

  1. Humoral Immunodeficiency presents after 3 months of age (when maternal antibodies are no longer present)
  2. B Cell deficiency or maturation defect results in Antibody deficiency
  3. Results in recurrent respiratory (ears, sinus, lungs) infections with encapsulated organisms
    1. Streptococcus Pneumoniae
    2. HaemophilusInfluenzae

V. Causes: No B-Cells: Agammaglobulinemia

  1. X-Linked Agammaglobulinemia or XLA (84% of Agammaglobulinemia cases in Europe)
    1. Bruton Tyrosine Kinase defect (Btk gene) results in defective B-Cell maturation
    2. Absent peripheral B-Cells results in very low serum IgG, IgA and IgM
    3. Infants may have no Tonsils or Lymph Nodes on exam
    4. Severe respiratory infections with Encapsulated Bacteria (e.g. pneumococcus, H. Influenzae)
    5. Chronic Diarrhea (echoviruses and coxsackie virus), recurrent varicella

VI. Causes: Decreased B Cells or Antibody (Hypogammaglobulinemia)

  1. IgG Subclass Deficiency of IgG2, IgG3, IgG4 (26% of U.S. cases)
  2. IgA Deficiency (30% of U.S. cases and most common B-Cell Disorder overall in U.S.)
    1. Low levels or absent IgA
    2. Prone to respiratory or gastrointestinal infections
    3. May be associated with IgG2 or IgG4 deficiency
  3. Common Variable Immunodeficiency or CVID (15% in U.S. and 46% in Europe of cases)
    1. Bimodal onset in preschool and in young adults
    2. Two Immunoglobulin subtypes are low (typically including Low total IgG, as well as IgM and IgA)
    3. B-Cells may be decreased in number and have defective function (T Cells may also be defective)
    4. Similar to X-Linked Agammaglobulinemia, but more mild
    5. Ear, sinus and lung infections occur as with other Antibody Disorders (e.g. pneumococcus, H. Influenzae)
    6. CVID also present with malabsorption from Infectious Diarrhea
      1. Examples: C. difficile, Giardia, Salmonella, Campylobacter, Yersinia
  4. Transient Hypogammaglobulinemia of Infancy (3% of U.S. cases)
    1. Increased mild Bacterial respiratory infections
    2. Normal nadir that corrects by age 2-4 years

VII. Causes: Increased Immunoglobulin (Hypergammaglobulinemia)

  1. Hyper-Immunoglobulin E (IgE) Syndrome (Job Syndrome)
    1. Significantly increased IgE levels
    2. Skin disorders (e.g. Eczema) and infections
    3. Recurrent lung infections (staphylococcal empyema)
  2. Hyper-Immunoglobulin M or Hyper-IgM Syndrome (HIGM)
    1. CD40 Ligand deficiency (most common cause, X-Linked)
    2. T-Lymphocytes are unable to trigger B-Cells to switch Immunoglobulin production of IgM to IgG, IgA and IgE
    3. IgM levels increase, but other Antibody levels are deficient
    4. Results in recurrent and severe infections (including opportunistic infections)
    5. Results in increased malignancy risk

VIII. Resources

  1. National Primary Immunodeficiency Resource Center
    1. http://npi.jmfworld.org
  2. Immune Deficiency Foundation
    1. http://www.primaryimmune.org

IX. References

  1. Mahmoudi (2014) Immunology Made Ridiculously Simple, MedMaster, Miami, FL
  2. Cooper (2003) Am Fam Physician 68:2001-11 [PubMed]
  3. Reust (2013) Am Fam Physician 87(11): 773-8 [PubMed]
  4. Rosen (1995) N Engl J Med 333(7):431-440 [PubMed]

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