The homeostasis of circulating B cell subsets in the peripheral blood of healthy adults is well regulated, but in disease it can be severely disturbed. Thus, a subgroup of patients with common variable immunodeficiency (CVID) presents with an extraordinary expansion of an unusual B cell population characterized by the low expression of CD21. CD21^lowB cells are polyclonal, unmutated IgM⁺IgD⁺B cells but carry a highly distinct gene expression profile which differs from conventional naïve B cells. Interestingly, while clearly not representing a memory population, they do share several features with the recently defined memory-like tissue, Fc receptor-like 4 positive B cell population in the tonsils of healthy donors. CD21^lowB cells show signs of previous activation and proliferation in vivo, while exhibiting defective calcium signaling and poor proliferation in response to B cell receptor stimulation. CD21^lowB cells express decreased amounts of homeostatic but increased levels of inflammatory chemokine receptors. This might explain their preferential homing to peripheral tissues like the bronchoalveolar space of CVID or the synovium of rheumatoid arthritis patients. Therefore, as a result of the close resemblance to the gene expression profile, phenotype, function and preferential tissue homing of murine B1 B cells, we suggest that CD21^lowB cells represent a human innate-like B cell population.

T cell–derived IFNγ and CD40L/IL-21R signals are crucial for the differentiation of human T-bet ^high CD21 ^low B cells.

Common variable immunodeficiency (CVID) describes a heterogeneous subset of hypogammaglobulinemias of unknown etiology. Typically, patients present with recurrent bacterial infections of the respiratory and gastrointestinal tract. A significant proportion of CVID patients develops additional autoimmune, inflammatory or lymphoproliferative complications. CVID is the most frequent symptomatic primary immunodeficiency encountered in adults. Informative monogenetic defects have been found in single patients and families but in most cases the pathogenesis is still elusive. Numerous immunological studies have demonstrated phenotypic and functional abnormalities of T cells, B cells and antigen-presenting cells. A hallmark is the impaired memory B-cell formation that has been taken advantage of for classifying CVID patients. Clinical multi-center studies have demonstrated a correlation between immunological markers and clinical presentation. Long-term outcome is significantly influenced by delay of diagnosis and treatment and the presence of chronic inflammatory complications. While immunoglobulin replacement therapy plus antibiotics can control infections in most cases, patients with non-infectious inflammatory complications such as granulomatous inflammation, interstitial lung disease, inflammatory bowel disease, lymphoproliferation and developing malignancies still represent a therapeutic challenge. In this review we provide a systematic overview of the immunological, clinical, diagnostic and therapeutic aspects of CVID and highlight recent developments in these fields.

Background: Common variable immunodeficiency (CVID) comprises heterogeneous antibody deficiency disorders. To classify this heterogeneous syndrome, clinical as well as immunologic parameters have been combined. Flowcytometric analysis of circulating T and B lymphocyte subpopulations has become an important tool in this endeavor of disease classification.Methods: Multicolor flowcytometric analysis of circulating lymphocytes.Results: The flowcytometric analysis of B and T cell subpopulations in the blood of CVID patients has contributed significantly to the identification of separate groups within the CVID population. In addition, the flowcytometric analysis of the inducible costimulator on activated T cells, CD19 and BAFF‐R on B cells are valid screening methods for three of the four known genetic defects associated with CVID. Only TACI deficiency can not be sufficiently detected by flowcytometric measures.Conclusions: Flowcytometric classification of patients with CVID has become a standard procedure during the diagnostic work up. This should be performed according to common guidelines to guarantee world wide comparability between different immunodeficiency centers. © 2008 Clinical Cytometry Society