Pediatric Common Variable Immunodeficiency

The common immunologic defect in patients with common variable immunodeficiency is defective antibody formation. As is expected in a heterogeneous group of diseases, many different immune system defects have been reported in this group of patients.

B-cell defect

The basic and common immunologic defect in common variable immunodeficiency is a failure of B-lymphocyte differentiation into plasma cells that produce the various immunoglobulin (Ig) isotypes. Earlier studies suggested a primary B-lymphocyte defect as a cause of common variable immunodeficiency in a small group of patients. B lymphocytes from these patients failed to differentiate into Ig-producing cells when stimulated with pokeweed mitogen (PWM) in vitro, even when cocultured with normal T cells; they were also L-selectin negative. These studies described failure of B-cell differentiation because of altered B-cell surface–molecule expression.

Primary B-cell dysfunction secondary to newly discovered genetic defects has been described in a small number of patients with common variable immunodeficiency (see Causes). These include CD19 deficiency and mutations in the genes that encode TACI (the transmembrane activator and calcium-modulating cyclophilin ligand interactor, TNFRSF13B), ICOS (the inducible costimulator of activated T cells), and BAFFR (the B-cell activating factor of the tumor necrosis factor [TNF] family receptor, TNFRSF13C). CD19 plays a crucial role in regulating B-cell responses to antigens and B-cell survival.

TACI is one of the TNF receptor superfamily members. TACI plays an indispensable role in isotype switching, terminal differentiation of B cells, and T-cell–independent antibody responses. TACI mutations that lead to immunodeficiency account for an estimated 10-15% of patients with common variable immunodeficiency. ICOS mutation is associated with absent ICOS expression on the surface of activated T cells and results in reduced class-switched memory B cells. The BAFFR defect is also associated with reduced class-switched and nonswitched memory B cells.

B cells develop in bone marrow from pluripotent hemopoietic stem cells through rearrangement of immunoglobulin heavy-chain and light-chain genes and initial positive and negative selection in the bone marrow. Mature B cells expressing both IgM and IgD leave bone marrow and enter secondary lymphoid organs. Within the secondary lymphoid follicles, affinity maturation and class switching take place through somatic hypermutation of the variable region genes and class-switch recombination. These B cells become either memory B cells or long-lived plasma cells that home back to the bone marrow and produce high-affinity antibodies.

Enumeration of the B-cell subsets in peripheral blood may be useful in classifying of common variable immunodeficiency. These subsets include class-switched memory B cells (CD27+IgD-IgM-), nonswitched memory B cells (CD27+IgD+IgM+), IgM memory B cells (CD27+IgM+IgD^dim), transitional B cells (CD38+++IgM+++), plasmablasts (CD38+++IgM-), mature B cells (CD19+CD21+), and CD21^lo B cells (CD19+CD21^lo). Expansion of CD21^lo B cells in the peripheral blood of patients with common variable immunodeficiency was reported; these were associated with deficiency in activating the calcium pathway.

Several groups have reported classification of common variable immunodeficiency based on B-cell subtype using flow-cytometry techniques. Paris ^[2] and Freiburg ^[3] classifications are based on the presence or absence of class-switched memory B cells. A EUROclass trial unified the 2 classifications and attempted to provide clinical links with B-cell subset phenotypes and clinical manifestations. ^[4] The data included 303 patients with common variable immunodeficiency and suggested that severe reduction in the number of class-switched memory B cells is associated with granulomatous disease, splenomegaly, and autoimmune cytopenias.

Mutations interfering with the regulation of the Ig gene expression, deficiency of memory B cells, and somatic hypermutation (SHM) abnormalities have been reported in patients with common variable immunodeficiency. Memory B cells develop in the germinal centers where SHMs are introduced, followed by antigen-mediated selection of cells with high affinity for the antigen. Low level of SHM, which correlated with increased frequency of severe respiratory tract infection, has been reported in patients with common variable immunodeficiency. B cells from these patients were unable to undergo isotype switching and were unable to upregulate activation markers on B cells when stimulated in vitro.

Other defects described in common variable immunodeficiency include the following:

• Lack of protein kinase C activation following stimulation with phorbol ester or anti-µ antibody

• Increased spontaneous apoptosis associated with increased expression of CD95 (APO-1/Fas)

• Impaired B-cell signal transduction cascade associated with abnormalities in protein tyrosine phosphorylation

• Chromosomal radiosensitivity, presumably due to impaired ability to repair DNA

• Loss of IgM memory B cells, correlating with clinical features of recurrent pneumonia caused by encapsulated microbes and bronchiectasis

• Impaired TLR9 signaling in B cells and plasmacytoid dendritic cells (PDCs), leading to lower expression of costimulatory molecules and reduced production of proinflammatory cytokines

• Impaired TLR 7/8 signaling in B cells

• Reduced or absent plasma cells in bone marrow was associated with increased complications and adverse clinical outcomes

T-cell defect

An overwhelming body of literature suggests that most patients with common variable immunodeficiency have intact B lymphocytes of immature phenotype. Common variable immunodeficiency B cells can secrete immunoglobulins (Ig), although often limited to IgM, if given the appropriate in vitro stimulation. Ig secretion has been induced from common variable immunodeficiency B cells using B-cell mitogens with soluble T-cell factors, monoclonal B-cell differentiation factors, Epstein-Barr virus (EBV), anti-CD40 plus interleukin (IL)-4 and IL-10. CD40 ligand (CD154) is expressed by activated CD4⁺ cells and is pivotal in inducing B-cell proliferation and differentiation.

Approximately 40% of patients with common variable immunodeficiency have low expression of CD40 ligand on activated T cells. At least 30% of patients with common variable immunodeficiency have lymphopenia due to the low number of CD4⁺ subsets. These patients also have decreased in vitro production of IL-2 when their peripheral blood mononuclear cells are stimulated in vitro. Decreased IL-2 production with stimuli via T-cell receptors is correlated with diminished CD40 ligand expression. Reduced expression of ICOS was reported in some families with autosomal recessive common variable immunodeficiency due to homozygous mutations in the ICOS gene. ICOS deficiency results in severe B-cell defect, which is caused by impaired T-cell help.

T cells in patients with common variable immunodeficiency have low frequency of antigen-specific precursor T cells following immunization with the neoantigens keyhole-limpet hemocyanin and dinitrophenol (DNP)-Ficoll. Many patients with common variable immunodeficiency have a defect in CD4⁺ T-cell priming to antigens, as measured by the number of circulating responsive CD4⁺ T cells following immunization. Many patients have a reduction in CD4⁺ CD45RA⁺ ("unprimed") T cells, suggesting activation of T cells.

Most patients with common variable immunodeficiency reportedly have increased production of interferon gamma by circulating CD8⁺ subsets, increased numbers of DR⁺/CD4⁺ T cells with up-regulated Fas expression, and an increased apoptosis. The abnormality appears to reside in CD4⁺ T cells and can be overcome by stimulating T cells with phorbol myristate acetate (PMA) and ionomycin, an alternative T-cell activation pathway. This is consistent with defective signal transduction in T cells.

Increased endogenous cyclic adenosine monophosphate (cAMP) levels in T cells from patients with common variable immunodeficiency are associated with increased activation of protein kinase A type I (PKAI) in T cells and with decreased proliferative response to anti-CD3. A selective antagonist of PKAI induces a significant increase in anti-CD3-stimulated proliferative responses, particularly in CD4⁺ lymphocytes. Approximately 25-30% of patients with common variable immunodeficiency have increased numbers of CD8⁺ lymphocytes, normal or decreased CD4⁺, and reduced CD4/CD8 ratios (< 1). This increase in CD8⁺ T cells has been observed most often in patients with splenomegaly and bronchiectasis. These cells coexpress human leukocyte antigen (HLA)-DR and IL-2 receptors, suggesting in vivo activation.

Approximately 60% of patients with common variable immunodeficiency have diminished proliferative responses to T-cell receptor stimuli and decreased induction of gene expression for IL-2, IL-4, IL-5, and interferon gamma. T-cell receptors of patients with common variable immunodeficiency have no evident abnormality; T-cell receptor gene analyses indicate normal heterogeneity of gene rearrangements. TNF production from T cells and monocytes is increased in a subgroup of patients with granulomatous diseases. Standard tests to assess T-cell function, including in vitro proliferation in response to mitogens, antigens, and allogeneic cells, are subnormal in as many as 50% of patients with common variable immunodeficiency with a small subgroup of patients having very low responses. These results support the hypothesis that most patients with common variable immunodeficiency have antibody deficiency secondary to abnormalities in T-cell signaling and defective T-cell and B-cell interactions.

The recovery of Ig production (mostly IgG and IgM) transiently or permanently following human immunodeficiency virus (HIV) or hepatitis C virus (HCV) infection has been reported in patients with common variable immunodeficiency. These cases indicate that common variable immunodeficiency is associated with potentially reversible defects in immunoregulatory factors and intact B-cell systems.

Other defects

A decrease in the number of peripheral blood dendritic cells (DCs) was noted in patients with common variable immunodeficiency. Low numbers of DCs correlated with a greater incidence of autoimmunity, splenomegaly, and granulomatous disease and a higher incidence of clinical complications. DCs play a role in B-cell growth and differentiation of plasma cells into immunoglobulin-secreting plasma cells. Others reported defective functions of DCs in patients with common variable immunodeficiency, inducing weak proliferation of allogeneic T cells and producing significantly low amounts of interleukin 12 upon CD40 signaling.

Increased functional capacity in both classic and alternative complement pathways in patients with common variable immunodeficiency was noted. Many patients with common variable immunodeficiency with increased levels of complement split products, presumably from complement activation, had autoimmune manifestations. Others reported a strong inverse correlation between mannose-binding lectin levels and the frequency of lower respiratory tract infection and bronchiectasis in patients with common variable immunodeficiency.

Other defects include the following:

• Reduction in regulatory T cells (T_regs) that is associated with autoimmune manifestation, granulomatous disease, and splenomegaly (Reduced T_regs correlated significantly with the expansion of CD21^low B cells.)

• Reduced expression of markers of T_regs, such as FoxP3, granzyme A, and pStat5 that correlated with the degree of T_regs dysfunction

• Reduced thymic and bone marrow output, reduced TREC(+) and KREC(+) lymphocytes

• Lymphopenia and poor lymphocyte proliferation

• Increased CD8+ cell numbers

• Lack of antigen-specific T cells

• Restricted T-cell receptor repertoire

• Oligoclonal expansion of CD8+ T cells

• Decreased CD4+ CD45RA+ T cells

• Decreased production of IL-2, IFN-gamma, IL-4, IL-5, IL-10, and IL-12

• Impaired T-cell activation

• Impaired intracellular tyrosine kinase expression

• Reduced Zap-70 mobilization

• Deficient CD28 co-signaling

• Accelerated T-cell death and increased expression of CD95

• Monocytoid and plasmacytoid dendritic cell defects

The prognosis for patients with common variable immunodeficiency is reasonably good if they do not have bronchiectasis and chronic lung damage, severe autoimmune disease, or malignancy.

Resnick et al summarized morbidity and mortality among 473 patients with common variable immunodeficiency at Mt. Sinai Hospital, NY over the past 4 decades. ^[5] Reduced survival was associated with age at diagnosis, lower baseline IgG, higher IgM, and fewer peripheral B cells. The risk of death was 11 times higher for patients with noninfectious complications. Mortality was associated with lymphoma, any form of hepatitis, functional or structural lung impairment, and GI disease, but not with bronchiectasis, autoimmunity, other cancers, or granulomatous disease.

Chapel et al reported European common variable immunodeficiency registry data that included 326 patients followed for at least 10 years since onset of symptoms. ^[6] The 75th percentile for survival was 25 years after diagnosis, and the 60th percentile for survival was 41 years after diagnosis. No associations between survival and sex or initial serum IgG, IgA, or IgM levels were noted. In the European registry, the highest mortality rates were in patients with the enteropathy phenotype or the polyclonal lymphocytic infiltrative phenotype. An association between increased mortality and lymphoid malignancy was also noted.

United States

Estimated incidence of common variable immunodeficiency is approximately 1 case per 30,000 population based on data over the last 2 decades.

International

European Society for Immunodificiencies (ESID) Registry reported 2880 in the internet-based database in 2011. Prevalence (per 100,000 inhabitants) varies greatly by countries (France 0.977. Spain .567, Netherlands 0.865, United Kingdom 0.604, Italy 0.719, Germany 0.524, Poland 0.073).

Demographics

Common variable immunodeficiency has been reported in many different races. Common variable immunodeficiency equally affects males and females. 

This is most frequently diagnosed in adults aged 20–40 years. However, about 28% of subjects are given a diagnosis before age of 21 years. Median age at characteristic symptom onset was 24 years for males and 27 years for females, but males were diagnosed with common variable immunodeficiency earlier at a median age of 30 years than females at a median age of 33.5 years. ^[5]