Common Variable Immunodeficiency

Basics

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
Diagnosis of exclusion, requiring low IgG and variable reduction in IgA and/or IgM, impaired specific antibody responses

Prevalence has been estimated at between 1:100,000 and 1:10,000 of the population.
Prevalence can vary across different populations.
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 one or more autoimmune conditions at time of diagnosis.
Affects males and females equally

Complex genetics
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.

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