CD19 deficiency is a very rare cause of CVID and, up to now, has only been described in four patients worldwide.17,18 The CD19 molecule is expressed solely on B cells and is therefore one of the most widely used surface markers to identify the B cell lineage in flow cytometry. CD19 forms a receptor complex with CD21 (CR2), CD81, and CD225 (Leu13), which is referred to as the CD19-complex. This signaling complex fine-tunes and amplifies B cell receptor (BCR) signals after antigen binding (See Figure 1C, below). CD19-deficient patients have decreased or even no expression of CD19 on the surface of their B cells and an impaired antigen-dependent Ca2+ signaling, resulting in diminished B cell responses upon BCR triggering. In these patients, the formation of memory B cells and CD5+ B cells is also reduced, consequently leading to hypogammaglobulinemia and absent vaccine responses in vivo.
My colleagues and I were able to identify two cases of homozygous BAFFR deficiency in one single kindred.19 BAFF-R is closely related to TACI and BCMA and interacts exclusively with BAFF. The BAFF-BAFFR interaction mediates signals important for B cell survival and regulates peripheral B cell homeostasis (See Figure 1D, below). BAFF-R deficiency presents with a distinct immunological phenotype which had been inferred by BAFF-R-deficient mouse models: peripheral B cell numbers are low, transitional B cell numbers are proportionally increased, and IgA production is intact.
Therapeutic Management of CVID
The primary objective of CVID therapy is reducing the frequency and duration of recurrent and chronic infections, especially sinusitis, bronchitis, otitis, pneumonia, and gastrointestinal infections and their sequelae. Immunoglobulin replacement therapy is the treatment of choice and forms the foundation of therapy.
The standard dosing recommendation for intravenous immunoglobulin (IVIG) is 400 mg per kilogram body weight every three to four weeks. Immunoglobulins may also be administered subcutaneously in weekly intervals. An IgG trough level (the IgG level before the next infusion) of at least 5 g/L should be attained. The individual patient’s clinical history and outcome will determine the amount of IVIG required; some patients (e.g., those with bronchiectasis, diarrhea, or IgG hypercatabolism) may require higher IVIG doses to reach the mandatory trough level. To maximize treatment success, the dose, frequency, way of administration, and product type should be adapted to each individual needs.
Antimicrobial therapy is the other main component of CVID therapy, because immunoglobulin replacement alone may not adequately prevent or treat local and/or persistent infections. Consider prolonged and intensified therapeutic regimens (e.g., intravenous antibiotics for patients with known bronchiectasis).
