Which B-cell defects are found in common variable immunodeficiency (CVID)?

Updated: Oct 16, 2018
  • Author: C Lucy Park, MD; Chief Editor: Harumi Jyonouchi, MD  more...
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Answer

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+IgDdim), transitional B cells (CD38+++IgM+++), plasmablasts (CD38+++IgM-), mature B cells (CD19+CD21+), and CD21lo B cells (CD19+CD21lo). Expansion of CD21lo 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


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