Common Variable Immunodeficiency
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- Common variable immunodeficiency is the most common clinically important primary immunodeficiency syndrome, characterized by
- Low IgG, IgA, and/or IgM
- Recurrent infections
- A wide spectrum of immunologic abnormalities, including autoimmune disease, inflammatory conditions, and the development of lymphomas
- Other terminology for this disease include the following:
- Acquired hypogammaglobulinemia
- Adult-onset hypogammaglobulinemia
- Common variable hypogammaglobulinemia
- Diagnosis of exclusion, requiring low IgG and variable reduction in IgA and/or IgM, impaired specific antibody responses
- Prevalence is estimated to be 1 in 25,000 to 1 in 66,000 in the general population.
- Can present at any age
- Most diagnosed between 20 and 40 years old
- Diagnosis is usually made several years after the onset of recurrent infections (pneumonia, sinusitis, otitis).
- A subgroup of children has been described in which the onset of disease was most often <5 years of age. This group was characterized by a relapsing and remitting course in which autoimmune disease predominated.
- About 20–25% of patients with common variable immunodeficiency have 1 or more autoimmune conditions at time of diagnosis.
- Affects males and females equally
- Complex genetics, likely multifactorial
- Rare recessive mutations described in
- T-cell inducible costimulatory (ICOS) in one kindred, <1% of patients
- CD19 in a few unrelated families
- B-cell activating factor (BAFF)
- CD20 and CD81
- Transmembrane activator and calcium-modulating cyclophilin ligand interactor (TACI, TNFRSF13B) in 8% of patients, associated with autoimmunity and lymphoid hyperplasia; heterozygous mutation more common than homozygous; significance not clear due to similar mutation found in healthy family members
- IgA deficiency more likely in offspring of parents with common variable immunodeficiency
- Incidence of IgA deficiency, autoimmune disease, and malignancies is increased in family members of patients with common variable immunodeficiency.
- Main characteristic is hypogammaglobulinemia.
- Impaired immunoglobulin and specific antibody production despite normal B cell numbers
- Often increased proportion of immature B cells
- Deficiency of class-switched memory B cells associated with more complex disease (autoimmunity, granulomatous disease, hypersplenism, and lymphoid hyperplasia)
- Functional defects of both B and T lymphocytes are described.
- The primary immunologic defect(s) leading to this syndrome is unknown.
- Multiple defects have been associated with common variable immunodeficiency, including the following:
- Lack of somatic mutation within variable region genes
- Lack of memory B cells
- Impaired maturation, IL-12 secretion, and upregulation of costimulatory molecules by antigen-presenting cells may impair T cells, which are important for providing help to B cells for antibody production.
- Toll-like receptor 9 (TLR9) response and expression by B cells may also be impaired. TLR signaling pathways are being investigated for their potential role in pathogenesis of common variable immunodeficiency.
- Some genetic defects have been described but do not account for the majority of cases.