Common Variable Immunodeficiency at the End of a Prospering Decade: Towards Novel Gene Defects and Beyond

Hermann Eibel; Ulrich Salzer; Klaus Warnatz

Disclosures

Curr Opin Allergy Clin Immunol. 2010;10(6):526-533. 

In This Article

CD21low B Cells and Ca-signaling

In addition to the 'traditional' peripheral B-cell subsets, transitional, naïve, marginal zone, and switched memory B cells, a new subset termed CD21low cells has been identified, which is most prominent in HIV infected individuals[48] and in specific subgroups of CVID patients.[49••] In CVID, the atypical expression of cell surface markers rendered it difficult to determine their differentiation stage. Since IgM and IgD are expressed on nearly all CD21low B cells they were characterized as mature, pregerminal center cells. They are larger, express higher levels of CD86 and have undergone more divisions in vivo than their naïve counterparts as a sign of activation in vivo.[49••] This activated stage however is associated with a decreased function in vitro and therefore, Fauci had termed the analogous CD21low subset in HIV patients an exhausted B-cell population.[50] Isnardi et al.[51••] confirmed the findings of Rakhmanov et al.[49••] and suggested an anergic status of CD21low B cells. Having demonstrated an increased proportion of autoreactive B cells among CD21low B cells the authors hypothesized that anergy is an expression of defective negative selection during maturation. Alternatively, due to their close resemblance to the recently described tissue like memory B cells in tonsils[52] and their strong accumulation in the bronchoalveolar space of patients with CVID (and other diseases), Rakhmanov et al. [49••] propose an inadequate activation of these cells in the periphery and subsequent exhaustion. Interestingly, the expansion of CD21low B cells in the peripheral blood is significantly associated with a deficiency in activating the calcium pathway.[53••] This deficiency is not restricted to the CD21low B-cell population but affects all mature B cells of EUROClass 21low/Freiburg Ia patients suggesting an underlying predisposition. The dissection of the different steps leading to the calcium influx across the plasma membrane revealed a phosphorylated status of PLCγ2 and normal internal store release while the step of transmembrane calcium influx was severely reduced.

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