Excerpt from Common Variable Immunodeficiency

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Background

Common variable immunodeficiency (CVID) is a disorder that involves the following: (1) low levels of most or all of the immunoglobulin (Ig) classes, (2) a lack of B lymphocytes or plasma cells that are capable of producing antibodies, and (3) frequent bacterial infections.

CVID is a common immune disorder and is, in fact, the most prevalent primary immunodeficiency. However, it is diverse, both in its clinical presentation and in the types of deficiency. Although decreased serum levels of immunoglobulin G (IgG) and immunoglobulin A (IgA) are characteristic, approximately 50% of patients with the deficiency also have diminished serum immunoglobulin M (IgM) levels and T-lymphocyte dysfunction. About 20% of those with CVID develop an autoimmune disease.¹

The eMedicine Pediatrics article, Common Variable Immunodeficiency, may be of interest.

Pathophysiology

In patients with CVID, numerous immune-system abnormalities are reported, the most common of which is defective antibody formation. Consequently, both humoral and cell-mediated lymphocytic responses are affected.

Changes in the humoral response

The basic pathophysiologic process in CVID is a simple failure in the differentiation of B lymphocytes. However, evidence shows that this defect in the pathway is not common among patients. One study showed that, when B lymphocytes were stimulated with pokeweed mitogen in vitro, plasma cells failed to differentiate, even in the presence of normal T cells. This finding suggests a defect in B-cell expression in surface molecules.

Such cellular deficits have been traced to the second messenger and translocation pathways of B cells. These deficits include problems with protein kinase C activation and tyrosine phosphorylation. Findings from other studies suggest the complete absence of IgG and IgA production, an increased rate of spontaneous apoptosis, impaired DNA repair, and the presence somatic mutations affecting B-cell regulation.

Changes in the cell-mediated response

A number of factors and cofactors stimulate Ig secretion from B cells harvested from patients with CVID. These factors include B-cell mitogens, soluble T-cell factors, specific B-cell differentiation factors, the Epstein-Barr virus, interleukin 2 (IL-2), interleukin 4 (IL-4), and interleukin 10 (IL-10). Perhaps the most potent stimulant is the CD40 ligand, which is expressed by activated CD4⁺ cells. In fact, in 40% of patients with CVID, the CD40 ligand is expressed in low levels on activated T cells. In these patients, decreased IL-2 production after T-cell receptor stimulation is also present.

A common defect is the response to antigens by CD4⁺ T lymphocytes. After immunization, some patients with CVID have decreased numbers of circulating responsive CD4⁺ T cells. Other patients have an increased number of CD4⁺ T cells, but they also have an increased rate of apoptosis of these cells. Signal transduction appears to be the primary defect in these T cells.

Of all patients with CVID, 25-30% often have increased numbers of CD8⁺ T cells and a reduced CD4/CD8 ratio (<1). The cause is an increase in cyclic adenosine monophosphate levels and the increased activation of protein kinase A. On physical examination, patients with this subtype often have splenomegaly and bronchiectasis. In addition, 60% of patients with CVID have a diminished response to T-cell receptor stimulation and expression of receptors for IL-2, IL-4, interleukin 5 (IL-5), and interferon gamma. However, the T-cell receptors show no evidence of abnormality; in fact, genetic findings indicate normal heterogeneity of the genetic rearrangements. Therefore, most patients with CVID can be said to have antibody deficiency secondary to T-cell signaling abnormalities, as well as defective interactions between T and B lymphocytes.

Both the transient and permanent recovery of Ig production has been reported in both patients with HIV and in patients with hepatitis C infection. This finding may indicate that CVID is associated with potentially reversible defects in humoral and/or cellular immunoregulatory factors.

TACI (transmembrane activator and calcium-modulator and cyclophilin ligand interactor) mediates isotype switching in B cells. One series found that 4 of 19 unrelated individuals with CVID and 1 of 16 individuals with IgA deficiency had a missense mutation in 1 allele of TNFRSF13B (encoding TACI).² TTACI mutations can result in CVID and IgA deficiency. Four genes have been documented to be mutated in CVID patients: ICOS, TNFRSF13B (encoding TACI), TNFRSF13C (encoding BAFF-R) and CD19.³ Heterozygous mutations in TNFRSF13B are also associated with CVID, whereas the other 3 genes are recessive.

Autosomal dominant CVID has been linked to chromosome 4q.⁴ One study supports the existence of a disease-causing gene for autosomal dominant CVID/IgA deficiency on chromosome 4q. Other possible loci for dominant CVID genes are on chromosomes 5p and 16q.

Frequency

United States

The prevalence of CVID is approximately 1 case per 50,000 population.

International

The international prevalence is similar to that in the United States.

Mortality/Morbidity

• A 20-year survival rate is 64% for male patients and 67% for female patients.
• In general, the expected survival rate for male and female patients is 92% and 94%, respectively.
• Death may result from various causes (see Complications).

Race

CVID does not show a predilection for any specific race.

Sex

CVID equally affects males and females.

Age

CVID can occur in infants, young children, adolescents, or even those aged 20-40 years or older.

• CVID can become evident at any time from infancy to after the fourth decade of life.
• Peaks of onset occur in children aged 1-5 years and in persons aged 16-20 years.
• More than two thirds of patients are aged 21 years or older when CVID is diagnosed.

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