Clinical Information

Primary B-cell disorders and humoral immunodeficiencies are characterized by an insufficient number of B cells or the impaired functioning or differentiation of B cells. B-cell disorders account for approximately half to two-thirds of all genetic primary immunodeficiency disorders (PIDD). They may result in a decrease or dysfunction of one or more isotypes of immunoglobulin, leading to increased susceptibility to infection, particularly bacterial infections, such as sinopulmonary infections, gastrointestinal infections, otitis, skin infections, and conjunctivitis. In the absence of infection, patients may be asymptomatic and, thus, difficult to diagnose. In addition, primary B-cell disorders may result in lymphoproliferative disorders or be associated with autoimmune (AI) manifestations, including AI cytopenias, AI endocrine disorders, and AI enteropathy.

PIDD that are primarily antibody deficiencies fall into four main categories:

1. Agammaglobulinemias, which are characterized by severe reduction in all serum immunoglobulin isotypes with profoundly decreased or absent B cells

2. Common variable immunodeficiency (CVID)-like diseases that are characterized by severe reduction in at least two serum immunoglobulin isotypes with normal or low number of B cells

3. Hyper-IgM syndromes, which are characterized by severe reduction in serum IgG and IgA with normal or elevated IgM and normal numbers of B cells

4. A mixed group of isotype, light chain, or functional antibody deficiencies generally with normal numbers of B cells

In addition, there are several PIDD that also have an associated T-cell or other cellular immunodeficiency as well as B-cell defects.

Agammaglobulinemia typically presents in the first few years of life with recurrent bacterial infections, a severe life-threatening bacterial infection (ie, meningitis, sepsis), and decreased lymphoid tissue (ie, small adenoids, tonsils, and lymph nodes in X-linked agammaglobulinemia, due to Bruton tyrosine kinase [BTK] gene variants). Inheritance can be either X-linked (eg, due to variants in BTK), autosomal dominant (eg, TCF3, TOP2B), or autosomal recessive (eg, IGHM, CD79A, CD79B, IGLL1, BLNK, and PIK3R1).

Common variable immunodeficiency (CVID) is the most common adult humoral immunodeficiency disorder with an incidence of approximately 1:10,000 to 1:50,000. CVID may present with frequent and unusual infections during early childhood, adolescence, or adulthood. As per current diagnostic criteria, CVID is not considered in children younger than 4 years of age. In addition, a significant proportion of patients may have autoimmune or inflammatory manifestations, enlarged lymphoid tissues, granulomas, and an increased susceptibility to cancer. These patients typically have normal numbers of B cells (<5% of CVID patients have <1% B cells, which is due to early B-cell defects) but have impaired terminal differentiation, resulting in decreased levels of IgG and IgA, with or without a decrease in IgM. Over two-thirds of patients have quantitative defects in switched memory B cells. Some patients may also have quantitative and functional T-cell defects or natural killer (NK) cell deficiency. Patients with decreased naive T-cell numbers are considered to have late-onset combined immunodeficiency. Genetic variants have been identified in several genes, including ICOS, TNFRSF13B (TACI), CD19, TNFRSF13C (BAFFR), MS4A1 (CD20), CR2 (CD21), CD81, LRBA, NFKB2, and IKZF1 (IKAROS) in a subset of CVID patients. However, most of these patients have unknown genetic defects and may have oligogenic or polygenic causes of disease.

Hyper IgM syndrome is characterized by an inability to switch from the production of IgM-type antibodies to IgG, IgA, or IgE isotypes. The condition is most often caused by variants in CD40LG, but variants in other genes (eg, CD40, AICDA, PI3KCD, UNG) have also been reported to cause disease. Patients with CD40L and CD40 deficiency tend to present with severe opportunistic infections more reminiscent of a cellular immunodeficiency and, therefore, may also be considered as combined immunodeficiencies.

Selective antibody deficiencies may occur when a patient is either lacking a specific immunoglobulin isotype (eg, selective IgA deficiency or IgG deficiency) or a specific vaccine antibody response (impaired pneumococcal polysaccharide responsiveness). Selective deficiencies may be due to variants in genes encoding immunoglobulin heavy or light chains. Selective IgA deficiency (sIgAD) is the most common PIDD with an incidence of 1:200 to 1:1000, depending on the cohort studied. Most patients with sIgAD are asymptomatic though some may have frequent infections. There is also a higher incidence of celiac disease in this group. Most patients with selective antibody deficiencies are treated if they have frequent infections in addition to impaired vaccine antibody responses. Some patients with sIgAD may have autoantibodies to IgA.