Clinical Information

The adaptive immune response includes both cell-mediated (mediated by T cells and NK cells) and humoral immunity (mediated by B cells). After antigen recognition and maturation in secondary lymphoid organs, some antigen-specific B cells terminally differentiate into antibody-secreting plasma cells or become memory B cells. Memory B cells are of 3 subsets: marginal zone B cells (MZ or nonswitched memory), class-switched memory B cells, and IgM-only memory B cells. Decreased B-cell numbers, B-cell function, or both, result in immune deficiency states and increased susceptibility to infections. These decreases may be either primary (genetic) or secondary. Secondary causes include medications, malignancies, infections, and autoimmune disorders.

Common variable immunodeficiency (CVID), a disorder of B-cell function, is the most prevalent primary immunodeficiency with a prevalence of 1:25,000 to 1:50,000.(1) CVID has a bimodal presentation with a subset of patients presenting in early childhood and a second set presenting between 15 and 40 years of age, or occasionally even later. Four different genetic defects have been associated with CVID, including mutations in the ICOS, CD19, BAFF-R, and TACI genes. The first 3 genetic defects account for approximately 1% to 2%, and TACI mutations account for 8% to 15% of CVID cases.

CVID is characterized by hypogammaglobulinemia usually involving most or all of the Ig classes (IgG, IgA, IgM, and IgE), impaired functional antibody responses, and recurrent sinopulmonary infections.(1,2) B-cell numbers may be normal or decreased. A minority of CVID patients (5%-10%) have very low B-cell counts (<1% of peripheral blood leukocytes), while another subset (5%-10%) exhibit noncaseating, sarcoid-like granulomas in different organs and also tend to develop a progressive T-cell deficiency.(1) Of all patients with CVID, 25% to 30% have increased numbers of CD8 T cells and a reduced CD4:CD8 ratio (<1). Studies have shown the clinical relevance of classifying CVID patients by assessing B-cell subsets, since changes in different B-cell subsets are associated with particular clinical phenotypes or presentations.(3,4)

The B-cell phenotyping assay can be used in the diagnosis of hyper-IgM syndromes, which are characterized by increased or normal levels of IgM with low IgG and/or IgA.(5) Patients with hyper-IgM syndromes can have 1 of 5 known genetic defects—mutations in the CD40L, CD40, AID (activation-induced cytidine deaminase), UNG (uracil DNA glycosylase), and NEMO (NF-kappa B essential modulator) genes.(5) Mutations in CD40L and NEMO are inherited in an X-linked fashion, while mutations in the other 3 genes are inherited in an autosomal recessive fashion. Patients with hyper-IgM syndromes have a defect in isotype class-switching, which leads to a decrease in class-switched memory B cells, with or without an increase in nonswitched memory B cells and IgM-only memory B cells.

In addition to its utility in the diagnosis of the above-described primary immunodeficiencies, B-cell phenotyping may be used to assess reconstitution of B-cell subsets after hematopoietic stem cell or bone marrow transplant. This test is also used to monitor B-cell-depleting therapies, such as Rituxan (Rituximab) and Zevalin (Ibritumomab tiuxetan).