Immunodeficiency, Common Variable, 1

A number sign (#) is used with this entry because this form of common variable immunodeficiency (CVID), referred to here as CVID1, is caused by homozygous mutation in the ICOS gene (604558) on chromosome 2q33.

Common variable immunodeficiency (CVID) is a clinically and genetically heterogeneous group of disorders characterized by antibody deficiency, hypogammaglobulinemia, recurrent bacterial infections, and an inability to mount an antibody response to antigen. The defect results from a failure of B-cell differentiation and impaired secretion of immunoglobulins; the numbers of circulating B cells are usually in the normal range, but can be low. Most individuals with CVID have onset of infections after age 10 years. CVID represents the most common form of primary immunodeficiency disorders and is the most common form of primary antibody deficiency. Approximately 10 to 20% of patients with a diagnosis of CVID have a family history of the disorder (reviews by Chapel et al., 2008, Conley et al., 2009, and Yong et al., 2009).

Genetic Heterogeneity of Common Variable Immunodeficiency

Common variable immunodeficiency is a genetically heterogeneous disorder. See also CVID2 (240500), caused by mutation in the TACI gene (TNFRSF13B; 604907); CVID3 (613493), caused by mutation in the CD19 gene (107265); CVID4 (613494), caused by mutation in the BAFFR gene (TNFRSF13C; 606269); CVID5 (613495), caused by mutation in the CD20 gene (112210); CVID6 (613496), caused by mutation in the CD81 gene (186845); CVID7 (614699), caused by mutation in the CD21 gene (CR2; 120650); CVID8 (614700), caused by mutation in the LRBA gene (606453); CVID10 (615577), caused by mutation in the NFKB2 gene (164012); CVID11 (615767), caused by mutation in the IL21 gene (605384); CVID12 (616576), caused by mutation in the NFKB1 gene (164011); CVID13 (616873), caused by mutation in the IKZF1 gene (603023); and CVID14 (617765), caused by mutation in the IRF2BP2 gene (615332).

The disorder formerly designated CVID9 has been found to be a form of autoimmune lymphoproliferative disorder; see ALPS3 (615559).

In a comprehensive review of common variable immunodeficiency, Hammarstrom and Smith (1999) stated that patients have a marked reduction in serum levels of both IgG and IgA, and in half of the patients, IgM is also reduced. Patients usually present with clinical symptoms due to hypogammaglobulinemia, such as frequent bacterial respiratory and gastrointestinal tract infections. In addition to the B-cell defect, some patients may have variable degrees of T-cell dysfunction. The onset of infection can occur at any age, but there are 2 main peaks in the first and third decades (Hermaszewski and Webster, 1993), and the disorder is equally distributed between the 2 sexes.

Cunningham-Rundles and Bodian (1999) described the clinical and immunologic status of 248 consecutively referred patients ranging in age from 3 to 79 years with a clinical diagnosis of CVID. The median age at the time of onset of symptoms and diagnosis was in the third decade for both males and females, although males showed an earlier age of both. In addition to reduced serum immunoglobulins, 40% of patients had subnormal lymphocyte proliferation responses to mitogens, indicating T-cell abnormalities. Associated conditions included autoimmune diseases and lymphoma. Survival 20 years after the diagnosis of CVID was 64% for males and 67% for females. Parameters associated with mortality in the 20-year period were lower levels of serum IgG, poorer T-cell responses to phytohemagglutinin, and particularly, a lower percentage of peripheral B cells.

Chapel et al. (2008) followed 334 European patients diagnosed with CVID for more than 5 years (average length of follow-up, 25.6 years) and defined 5 distinct clinical phenotypes: no complications, autoimmunity, polyclonal lymphocytic infiltration, enteropathy, and lymphoid malignancy. The authors found that 83% of patients had only 1 of these phenotypes; 12.6% had criteria for 2 phenotypes. Analysis by clinical phenotypes showed that the highest mortality rates were associated with enteropathy or polyclonal lymphocytic infiltration (relative risks of 4.0 and 3.0, respectively; p less than 0.001 for both). The only clinical predictor was polyclonal lymphocytic infiltration, which was associated with a 5-fold increased risk of lymphoid malignancy. There was widespread variation in the levels of serum immunoglobulin isotypes as well as in the percentages and absolute numbers of B cells, confirming the heterogeneity of these conditions. Higher serum IgM and lower circulating CD8 T-cell (see 186910) levels were found to be predictive markers for polyclonal lymphocytic infiltration and autoimmunity, respectively.

In a review of the clinical features of CVID, Yong et al. (2009) stated that the majority of patients are prone to recurrent respiratory and gastrointestinal infections. A subset of patients may develop other complications, including lymphoid proliferation, splenomegaly, granulomatous inflammation, autoimmune disorders, and malignancy. In addition to hypogammaglobulinemia and an inability to mount an antibody response to stimulation, some patients may have additional immunologic abnormalities of monocyte-derived cells and/or T cells. Relatives of patients with CVID have an increased frequency of selective IgA deficiency (see, e.g., IGAD1, 137100).

Common Variable Immunodeficiency 1

Grimbacher et al. (2003) reported 4 patients between the ages of 19 and 28 years from 2 unrelated families with recurrent bacterial infections of the respiratory and digestive tracts characteristic of humoral immunodeficiency and consistent with a clinical diagnosis of CVID. They lacked other complicating features such as splenomegaly, autoimmune phenomena, or sarcoid-like granulomas, and did not present with clinical signs of overt T-cell immunodeficiency. One of the patients was female, suggesting autosomal recessive inheritance. Laboratory studies showed low peripheral blood B-cell counts ranging from 0.7 to 1.3% in 1 family and 2.8 to 3.3% in the other. Although there were no gross abnormalities in T-cell substrate development, there was a severe disturbance of T-cell-dependent B-cell maturation occurring in secondary lymphoid tissue. No ICOS-specific signal was detected on activated T cells, whereas normal amounts of ICOS were expressed in the activated T cells of the other CVID patients and in those of controls. Patient monocytes expressed normal amounts of ICOS ligand (ICOSLG; 605717). Nearly all B cells of ICOS-deficient individuals exhibited a naive IgD+/IgM+ phenotype. Correspondingly, the numbers of IgM memory and switched memory B cells were substantially reduced. CD80 (112203) expression was reduced on resting B cells of ICOS-deficient individuals, whereas equivalent CD86 (601020) expression was observed on both patient and control B cells. However, ICOSLG expression on the patients' B cells was elevated, an observation consistent with the notion that interaction of ICOS with its ligand downregulates the ligand (Witsch et al., 2002). Data on these 4 affected individuals revealed a profound disturbance of the memory B-cell compartment and decreased Ig production.

Salzer et al. (2004) reported 5 patients from 2 additional CVID families with ICOS deficiency. The age at onset ranged from 18 months to 15 years, which was slightly earlier than that reported by Grimbacher et al. (2003). Infections included recurrent bronchitis, sinusitis, and pneumonia, as well as diarrhea. Additional variable features in some patients included splenomegaly, lymphadenopathy, herpes simplex eruptions, and chronic autoimmune neutropenia due to IgG anti-neutrophil antibodies. All patients had decreased switched memory B cells and decreased levels of serum IgG and IgA; IgM was low-normal or low. The T-cell compartment appeared normal. Treatment with intravenous Ig resulted in resolution in some cases.

In a comprehensive review of common variable immunodeficiency, Hammarstrom and Smith (1999) estimated that the disorder affects approximately 1 in 10,000 to 100,000 individuals.

Kirkpatrick and Schimke (1967) focused on low IgM as a 'marker' in familial hypogammaglobulinemia.

In patients with low serum gammaglobulin, Cooper et al. (1971) found normal numbers of B lymphocytes bearing membrane-bound immunoglobulins; germinal centers were normally formed in antigen-stimulated lymph nodes. They postulated that although the B lymphocytes in such patients have surface recognition antigens, they lack the mechanism for plasma cell differentiation.

Farrington et al. (1994) found that 23 of 31 patients (74%) with CVID also had a T-cell defect, whereas the remaining 8 patients did not. Patients with T-cell dysfunction could be further subdivided into those with a broader defect (n = 11) resulting in depressed expression of gp39 (CD40LG; 300386) and variable lymphokine deficiency; others had a more selective defect of either CD40 ligand expression (n = 2) or deficiency of 1 particular lymphokine (n = 10). Thus, CVID may arise from a number of different molecular aberrations. Inefficient signaling via CD40 may be responsible, in part, for failure of B-cell differentiation in some patients with CVID.

In a study of 8 patients, including 6 with CVID and 2 with slightly less severe hypogammaglobulinemia and recurrent infections, Levy et al. (1998) found that 2 CVID patients had a dramatic reduction in somatic hypermutation in the variable (V) region of Ig genes. Between 40 and 75% of IgG transcripts were totally devoid of somatic mutation in the circulating memory B-cell compartment. Since functional assays of the T-cell compartment were normal, the findings pointed to an intrinsic B-cell defect in the process of antibody affinity maturation in CVID.

Holm et al. (2003) found that T cells from CVID patients activated by anti-CD3 (see 186740) and anti-CD28 (186760) secreted less IL10 (124092) than healthy controls, regardless of proportions of T-cell subsets. Furthermore, sensitivity to cAMP-dependent inhibition of protein kinase A type I (see 188830)-mediated T-cell activation was greater in CVID patients. Holm et al. (2003) proposed that impaired IL10 secretion by CVID patient T cells may be a link between T-cell deficiency and impaired B-cell function in CVID.

Using flow cytometry to assess the immunologic profiles of 32 patients with CVID, Cunningham-Rundles et al. (2006) found that, in addition to reduced levels of CD27 (TNFRSF7; 186711)-positive memory B cells, CVID patients had unrelated, pronounced TLR9 (605474) defects. CpG oligonucleotides did not activate CVID B cells, even when costimulated by B-cell receptor, and they did not stimulate surface or intracytoplasmic expression of TLR9 or production of IL6 (147620) or IL10. In addition, CVID plasmacytoid dendritic cells, which expressed normal amounts of intracytoplasmic TLR9, produced only low amounts of IFNA (147660). No TLR9 mutations or polymorphisms were detected. Cunningham-Rundles et al. (2006) concluded that CVID patients have broad TLR9 activation defects that result in impaired CpG-initiated innate immunity.

By flow cytometric analysis, Bossaller et al. (2006) found that ICOS-deficient patients, but not other CVID patients, had a severe reduction of CXCR5 (BLR1; 601613)-positive/CD4 (186940)-positive T cells and nearly complete absence of CD57 (see 151290)-positive/CXCR5-positive/CD4-positive T cells. Immunohistochemical analysis demonstrated disturbed germinal center formation in the lymph node of an ICOS-deficient patient. T-cell stimulation with anti-CD3 and anti-ICOS induced CXCR5 expression in normal individuals, but did so only poorly in ICOS-deficient patients. CD40L (300386)-deficient patients also had abrogated germinal center formation and a severe reduction of CXCR5-positive T cells.

In ICOS-deficient individuals with CVID1, Grimbacher et al. (2003) identified a partial deletion of ICOS mRNA with fully absent protein. The 443-nucleotide deletion of mRNA was due to a deletion of 1,815 basepairs of the ICOS gene, comprising partial deletion of intron 1, a complete deletion of exon 2, intron 2, and exon 3, and a partial deletion of intron 3 (604558.0001). The DNA region deleted in the patients is normally flanked by and partially involves two 150-bp stretches of highly homologous DNA sequences, including a 13-bp (TCTTGTCAGAGTA) repeat. Grimbacher et al. (2003) proposed that the original deletion event occurred during meiotic recombination through homologous unequal recombination, eliminating 1 of the two 13-bp repeats and the entire intervening sequence. This deletion was found in all 4 affected patients from 2 families who were thought to be unrelated; however, identical SNPs were seen in the sequenced region, suggesting a common founder for all 4 patients. This deletion was not found in 100 healthy control alleles.

In 5 affected individuals from 2 families with CVID due to ICOS deficiency, Salzer et al. (2004) identified the same homozygous deletion in the ICOS gene that was found by Grimbacher et al. (2003). All 4 families were from the same region along the Danube River in Austria and Germany, and haplotype analysis indicated a founder effect.

Wollheim (1961) described 2 females with 'acquired' hypogammaglobulinemia who came from different parts of Sweden but were remotely related. He suggested that a recessive genetic factor may be involved in 'acquired' hypogammaglobulinemia.

Kamin et al. (1968) found that phytohemagglutinin-induced incorporation of labeled precursors into DNA and RNA by lymphocytes was significantly diminished in cells of adults with so-called 'acquired' agammaglobulinemia. The difference was independent of the characteristics of the culture-medium, indicating a cellular abnormality.

McAdam et al. (2001) found that Icos-deficient mice had similar basal levels of IgM, slightly elevated IgG3, and reduced IgG1, IgG2a, and IgE compared to wildtype mice. Immunized knockout and wildtype mice, except in the presence of the highly inflammatory complete Freund adjuvant, also had similar levels of IgM-specific antibody but reduced IgG1- and IgG2a-specific antibody and reduced germinal center formation. Class switching from IgM to IgG was restored in Icos -/- mice by stimulation of CD40 (109535).

Bossaller et al. (2006) showed that Icos-deficient mice had reduced numbers of Cxcr5-positive/Cd4-positive T cells in blood, spleen, and lymph node. Immunohistologic analysis demonstrated a lack of full germinal centers and a reduction of Cd4-positive T cells in B-cell follicles of Icos-deficient mice.