Pathogenesis of common variable immunodeficiency

INTRODUCTION — Common variable immunodeficiency (CVID) is a heterogeneous immune disorder characterized by recurrent sinopulmonary infections, autoimmune disorders, granulomatous disease, and an enhanced risk of malignancy [1-7].

Definition — CVID is defined by the following:

●Markedly reduced serum concentrations of immunoglobulin (Ig)G, in combination with low levels of IgA and/or IgM

●Poor or absent antibody response to infection or immunization, or both

●An absence of any other defined immunodeficiency state

The pathogenesis of CVID will be reviewed here. The clinical manifestations, diagnosis, and management of CVID are discussed separately. Special issues in children are also reviewed separately. (See "Clinical manifestations, epidemiology, and diagnosis of common variable immunodeficiency in adults" and "Treatment and prognosis of common variable immunodeficiency" and "Common variable immunodeficiency in children".)

OVERVIEW — Although CVID has been recognized since the 1950s, its pathophysiology remains incompletely understood despite dramatic advances in the molecular elucidation of many other primary immunodeficiency diseases [1,7]. The clinical heterogeneity of CVID suggests that multiple immunoregulatory and genetic defects can result in the final common pathway of hypogammaglobulinemia [2-5].

The hallmark immune defect in CVID is defective B cell differentiation into plasma cells, with impaired secretion of immunoglobulin. However, CVID is associated with a high incidence of inflammatory, autoimmune, and malignant conditions, whereas these disorders are not observed in X-linked agammaglobulinemia, a disease that specifically affects early B cell development [2,6]. This suggests that CVID represents a more global form of immune dysfunction.

The Immune Deficiency Foundation (IDF) has a Consulting Immunologist Program (CIP) to connect health care providers who have questions about patients with known or suspected immunodeficiency with clinicians experienced in diagnosing and managing these disorders. The Jeffrey Modell Foundation contains an international directory of expert immunologists.

B CELL ABNORMALITIES — The overall B cell number is normal in the majority of patients, although many have reduced percentages of isotype-switched memory B cells (and lack plasma cells) capable of producing antigen-specific IgG and IgM, immunoglobulin isotypes that are critical for recall (or secondary) antibody responses [8,9]. Examination of the B cell receptor (BCR) by high resolution sequencing shows a number of abnormalities that appear to have occurred in the bone marrow. These include aberrant gene rearrangement, decreased V gene replacements, which normally occur to counteract autoimmunity, decreased diversity of the naive B cell repertoire, impaired somatic hypermutation, and abnormal expansion of unmutated B cell clones [10,11]. In the bone marrow, about one-third of CVID patients appear to have a partial block at the pre-B1 to pre-B2 transition during central B cell development [12], perhaps due to altered (pre)-BCR signaling. (See "Normal B and T lymphocyte development".)

Toll-like receptor signaling — B cell maturation is defective in patients with CVID, and the function of toll-like receptor (TLR) 7 and 9 on both B cells and dendritic cells is impaired [13,14]. Normally, B cell responses may be initiated by binding of viral RNA to TLR7 or bacterial DNA to TLR9, both of which lead to B cell activation, cytokine secretion, proliferation, and survival [15]. The loss of these stimuli may contribute to the B cell defects observed. The relevance of impaired TLR9 dysfunction in CVID was demonstrated in a study showing that stimulation with microbial extracts from Streptococcus pneumoniae and Haemophilus influenzae resulted in impaired activation and proliferation of B cells [16]. However, the mechanism(s) by which TLR function is impaired is not defined. (See "Toll-like receptors: Roles in disease and therapy".)

Memory B cells and other subsets — Memory B cells in humans can be identified on flow cytometry by the presence of CD27, a member of the tumor necrosis factor (TNF) receptor gene family (which is also found on a subset of T lymphocytes) [17]. Memory B cells can also be subdivided into those cells that have not yet undergone isotype-switching and produce predominantly IgM (CD27+IgM+IgD+) and those that have isotype-switched (CD27+IgM-IgD-) and can synthesize IgG, IgE, or IgA [8,18]. Determining the number of isotype-switched memory B cells is not a standard component for the diagnosis of CVID. However, it is of interest because it provides information about the immaturity of the B cell, relates to the numbers of plasma cells in the bone marrow [12], and provides some information about selected clinical outcomes. Studies have attempted to identify and classify CVID patients based on numbers of isotype-switched memory B cells and other B cell populations:

●One study proposed that <0.4 percent switched CD27+IgM-IgD- memory B cells based on total blood lymphocytes (compared with healthy donors at 1.6±0.6 percent) could be used to classify patients with CVID [8,9]. These patients had a higher prevalence of splenomegaly and autoimmune cytopenias.

●Another study classified CVID patients into three groups based on different subpopulations of memory B cells and found that certain disorders that are seen in patients with CVID (eg, splenomegaly, lymphoid proliferation, and granulomatous disease) were more prevalent in patients with the lowest numbers of memory B cells [19].

●Subsequently, a study of 105 patients with CVID found that a level of <0.55 percent switched memory B cells, based on total blood lymphocytes, was an independent risk factor for autoimmune disease, granuloma formation, and splenomegaly [20]. In addition, female patients were found to have significantly higher levels of memory B cells.

●Lower levels of circulating IgM memory B cells and poor antipneumococcal polysaccharide IgM responses were associated with recurrent bacterial pneumonia and the development of bronchiectasis in patients with CVID [15]. In contrast, CVID patients with no chronic pulmonary disease had relatively normal measurements of these two parameters.

●However, another study followed 33 CVID patients from 3 to 19 years after diagnosis and found that the percentage of switched memory B cells changed in some patients over time. Therefore, classification of patients based solely on switched memory B cells may not be ideal [16].

●An investigational approach involves the identification of antibody-secreting memory B cells using an enzyme-linked immunosorbent spot (ELISpot) assay and combining this information with that obtained from flow cytometry [17]. However, this test is technically challenging to perform.

●In addition to the above, about 10 percent of patients have an increased percentage of circulating transitional B cells [8] often associated with low total B cell counts and autoimmunity.

●The expansion of activated CD21^low B cells [21,22] has been observed in a number of patients, predominantly those with autoimmunity, lymphoproliferation, splenomegaly, and evidence of chronic immune activation [8,23].

OTHER CELLULAR ABNORMALITIES — Other cellular abnormalities in CVID include the following:

●Decreased T lymphocyte proliferation to mitogens and antigens, previously demonstrated in up to 40 percent of patients in some groups [24]. Phytohemagglutinin, pokeweed, and concanavalin A are used to measure mitogen response. Candida albicans and tetanus toxoid were used to measure antigen response. (See "Laboratory evaluation of the immune system".)

●Low CD4/CD8 T cell ratio due to a decrease in CD4+ cells or an increase in the absolute number of CD8+ cells in some. Those with the most reduced numbers (<200 x 10⁶ cells/L) and low numbers or percentage of naive T cells may have opportunistic infections and a higher prevalence of splenomegaly, granulomatous disease, gastrointestinal disease, and lymphoma. The term "late-onset combined immunodeficiency" has been proposed for this subset [25-27].

●In patients with increased numbers of CD8+ cells, chronic infection with cytomegalovirus was previously proposed to play a role in the pathogenesis of inflammatory disease, such as granulomatous disorders and enteropathy [28].

●Reduced numbers of T regulatory cells in a subset of patients [29,30].

●Reduced thymic output. Reduced numbers of T cell receptor excision circles (TRECs) suggesting thymic dysregulation [31]. One study found that low TREC levels, kappa-deleting recombination excision circle (KREC) levels, or both correlated with severity of illness and overall survival. However, these findings should be replicated in larger groups of patients [32].

●Deficiency of antigen-primed T cells.

●Reduced T cell production or expression of interleukin (IL)-2 and other cytokines.

●Defective T cell receptor signal transduction [33].

●Reduced capacity of dendritic cells to secrete IL-12 [34] but increased serum IL-12 in some [35].

●Loss of plasma cells in tissue, such as the gastrointestinal tract and bone marrow [12].

●Increased serum levels of soluble CD26 and CD30 in patients with CVID compared with controls [36]. While serum levels of CD26 were not associated with any clinical phenotypes, serum levels of CD30 were associated with splenomegaly and malignancy.

●Evidence of T cell exhaustion [37,38].

●CD8 T cells exhibit high levels of activation with markers including CD29, CD38, CD95, CD45RO and human leukocyte antigen (HLA)-DR and low expression of CD27, CD62L, and CD45RA [37].

●Individuals with low natural killer (NK) cell numbers may have a more severe phenotype. One study looked at the association between numbers of NK cells and specific complications in nearly 500 patients with CVID [39]. Those with low NK cell numbers (<50 × 10⁶ cells/L) had more noninfectious complications, especially granulomatous disorders, as well as more invasive bacterial infections and pneumonia.

BONE MARROW ENVIRONMENT — Some patients with CVID treated with hematopoietic stem cell transplantation have demonstrated incomplete B cell regeneration, suggesting that the bone marrow compartment of these individuals could not support normal B cell development [40]. To evaluate this further, bone marrow derived precursors from 15 patients with CVID were studied in vitro to assess differentiation into immature B cells, as compared to normal donor cells [41]. A subset were able to develop normally when removed from the patient, indicating that one or more factors in the bone marrow environment were abnormal. Another subset developed partially, suggesting a mixed picture of intrinsic B cell defects and other factors.

OTHER FINDINGS — Additional in vitro abnormalities have been reported, although these have not been as well-characterized as those discussed above. These include:

●Accelerated peripheral B cell apoptosis [42]

●Increased serum tumor necrosis factor (TNF)-alpha and soluble TNF receptors, also noted, homocysteine as an indicator of oxidative stress [43,44]  

●Defective T cell activation from impairment of TNF-RII co-signaling [45]

●Increased levels of CD30, which is expressed on activated T cells, although the clinical implication of this is unclear [36,46]

Serum levels of transmembrane activator and calcium-modulator and cyclophilin ligand (CAML) interactor (TACI), its ligand a proliferation-inducing ligand (APRIL), and B cell-activating factor of the tumor necrosis factor family (BAFF), can be markedly elevated in patients with CVID, although the biologic significance of these findings is unclear [47]. Elevations in these proteins are also found in several rheumatologic disorders and also hematologic malignancies [48-50].

PHENOTYPIC APPROACH TO CATEGORIZING PATIENTS — A phenotypic approach to categorizing CVID has been proposed based upon the type of complications the patient develops. This arose from an analysis of the European Common Variable Immunodeficiency Disorders registry (composed of patients from multiple centers in Europe and the United Kingdom), in which over 300 patients with CVID were followed for an average of 26 years [2]. Five phenotypic categories were proposed:

●Patients with no complications

●Patients with autoimmune disease

●Patients with lymphocytic organ infiltration (ie, lymphocytic enteropathy, granulomas, unexplained hepatomegaly, persistent lymphadenopathy, splenomegaly, and/or lymphoid interstitial pneumonitis)

●Patients with predominant enteropathy

●Patients with lymphoid malignancy

Over 80 percent of patients had just one of these phenotypes. The best and worst prognoses were seen in patients with no complications and those with malignancy, respectively. Patients with lymphocytic organ infiltration and/or higher levels of serum IgM were at the highest risk (fivefold) of eventually developing lymphoid malignancies [2]. In a cohort of 473 patients with CVID followed over four decades, noninfectious complications were observed in 68 percent [6]. The risk of death was 11 times higher for patients with noninfectious complications (hazard ratio = 10.95). (See "Treatment and prognosis of common variable immunodeficiency", section on 'Prognosis'.)

GENETICS — Approximately 90 percent of patients with CVID have no history of affected family members, while 10 percent of patients may have at least one family member with either CVID, selective immunoglobulin A deficiency (sIgAD), IgG subclass deficiency, specific antibody deficiency, and relative hypogammaglobulinemia (ie, less than 2 standard deviations below normal levels) and a familial pattern of inheritance (both autosomal dominant and autosomal recessive) [51,52]. Possible susceptibility loci have been identified in major histocompatability complex (MHC) genes [51,53,54]. The relationship between CVID and IgA deficiency has suggests that, in some families, the two disorders may represent the variable expression of a common defect. (See "Selective IgA deficiency: Clinical manifestations, pathophysiology, and diagnosis".)

Indications for genetic testing — Genetic testing is not required for diagnosis of CVID. However, it may be useful in understanding the genetics for inheritance and family planning purposes and may be helpful in a few cases where specific therapies can be useful, such as in patients with mutations in LPS-responsive and beige-like anchor (LRBA) or cytotoxic T lymphocyte antigen 4 (CTLR4), who may benefit from treatment with abatacept (a CTLA4-Ig chimeric molecule) and/or sirolimus [55].

Defects in specific molecules — A single gene defect can be identified in one-quarter to one-half of patients with CVID, depending upon the rigor of the diagnostic measures applied to the CVID diagnosis, the ethnicity of the population studied, and methods of analysis. These defects may be either recessive in inheritance or autosomal dominant with variable penetrance (table 1). If testing is performed by methods that include the complete range of mutations reported, generally 20 to 30 percent of patients will have identifiable mutations when the diagnosis of CVID is rigorously made.

Some of the identified mutations affect the normal processes of B cell maturation and differentiation into memory B cells [56-60]. The first mutations described were rare and mostly found in families with consanguineous inheritance [61-63]. However, subsequent studies have identified an increasing number of autosomal dominant gene defects, each of which has variable penetrance, in up to 30 percent of patients [7,61,64-67].

●In the largest study to date, 571 patients with CVID were studied with whole-exome sequencing. The patients were recruited from the United States (n = 235), Iran (208), and Sweden (128), and mutations were identified in 31, 54, and 36 percent, respectively [67]. The Iranian population had a high rate of consanguinity, and biallelic mutations were significantly more prevalent. Clinical patterns of illnesses did not correlate with specific gene defects. For the American and Swedish cohorts, CVID subjects with noninfectious complications, lymphoid infiltrations, or inflammatory or autoimmune disorders were somewhat more likely to have an identifiable mutation, but no specific defects were found in a significant proportion of this subgroup. In addition to the genes already known to cause CVID (table 1), mutations associated with other known disorders, including WHIM, ICF (Immunodeficiency, Centromeric instability, and Facial anomalies) and Kabuki syndromes, were detected, indicating that other inborn errors of immunity can resemble CVID.

●Mutations in the gene transmembrane activator and calcium-modulator and cyclophilin ligand interactor (TACI) are found in 8 to 10 percent of CVID patients (table 1) [68-70]. TACI is expressed on B cells and activated CD4+ T cells, and it mediates isotype-switching through its ligand, a proliferation-inducing ligand (APRIL) [56]. However, mutations in the TACI gene appear to induce susceptibility to CVID rather than directly causing the disorder, as the same mutations can be found in healthy controls and unaffected family members of patients with CVID [57-59,70]. The gene for TACI, tumor necrosis factor receptor superfamily 13B (TNFRSF13B), is on chromosome 17p. The function of TACI in normal humoral immune responses is discussed separately. (See "The adaptive humoral immune response", section on 'TACI, BAFF, and APRIL'.)

●In a subset of CVID patients with early-onset, inflammatory, or autoimmune complications, one study revealed 17 probable disease-causing mutations in 15 of 50 patients (30 percent) [60]. Patients selected for this analysis included: (1) patients who presented before the age of 10 years with disorders such as autoimmune cytopenias and organ-specific autoimmune disorders and (2) older patients with these issues or combinations of interstitial lung disease, lymphoid hyperplasia, inflammatory bowel disease, nodular regenerative hyperplasia of the liver, and/or granulomatous infiltrations. The mutations detected in these subjects were rare or private (ie, not detected in other patients or controls) and in addition to TACI, included monoallelic mutations in nuclear factor (NF)-kappa-B1 (NFKB1), signal transducer and activator of transcription 3 (STAT3), cytotoxic T-lymphocyte antigen 4 (CTLA4), the catalytic subunit of phosphatidylinositol 3-kinase delta (PIK3CD), and the gene encoding IKAROS (IKZF1). While in many cases these occurred in families with no apparent immune defects in other members, some of these mutations were still autosomal dominantly inherited but with quite variable penetrance. In addition, biallelic mutations in the gene for protein lipopolysaccharide (LPS)-responsive vesicle trafficking, beach- and anchor-containing (LRBA), and syntax binding protein 2 (STXBP2) were also found [60].

●NFKB1 mutations have been studied in affected families and are inherited as an autosomal dominant trait [71]. These are now found in approximately 8 percent of all patients.

●Other heterozygous mutations that have been found in CVID patients show variable penetrance immunologically and clinically [65,71].

SUMMARY — Common variable immunodeficiency (CVID) is a heterogeneous disorder characterized by markedly reduced serum levels of immunoglobulin (Ig)G and low IgA or IgM, with impaired antibody responses, despite the presence of B cells. (See 'Introduction' above.)

●The disorder is characterized by defective B cell differentiation with impaired secretion of immunoglobulin. However, CVID is associated with a high incidence of inflammatory, autoimmune, and malignant conditions, features of more fundamental immune dysregulation. (See 'Overview' above.)

●Overall B cell numbers are normal in approximately 90 percent of subjects with CVID. Many patients have low percentages of isotype-switched memory B cells (and also plasma cells) capable of producing antigen-specific IgG and IgM, which are the immunoglobulin isotypes that are critical for recall (or secondary) antibody responses. (See 'B cell abnormalities' above.)

●T cell abnormalities include a low CD4/CD8 T cell ratio (present in a subset of patients) and impaired responses to mitogens and antigens. (See 'Other cellular abnormalities' above.)

●In about 20 to 30 percent of subjects, CVID appears to result from a specific mutation, which may be either recessive in inheritance or autosomal dominant with variable penetrance. Some of these mutations lead to defects in B cell signaling molecules, but additional genes affecting immune regulation may also result in the CVID phenotype (table 1). (See 'Genetics' above.)

ACKNOWLEDGMENTS — The UpToDate editorial staff acknowledges E Richard Stiehm, MD, who contributed as a Section Editor to an earlier version of this topic review.