CD21low B cells in common variable immunodeficiency do not show defects in receptor editing, but resemble tissue-like memory B cells

M Rakhmanov, S Gutenberger, B Keller… - Blood, The Journal …, 2010 - ashpublications.org
M Rakhmanov, S Gutenberger, B Keller, M Schlesier, HH Peter, K Warnatz
Blood, The Journal of the American Society of Hematology, 2010ashpublications.org
We read with great interest the article by Isnardi et al1 wherein the authors showed very
similar phenotypic and genotypic features of CD21/lo B cells as previously reported. 2 In
view of the polyreactivity, increased autoreactivity, and strongly reduced calcium response
and proliferative capacity of CD21/lo Bcells—reminiscent of anergic B cells in mouse models—
the authors propose that CD21/lo B cells represent anergic human Bcells. 1 Moreover, they
showed that the majority of highly HEp2-reactive CD21/lo B-cell clones express kappa () …
We read with great interest the article by Isnardi et al1 wherein the authors showed very similar phenotypic and genotypic features of CD21/lo B cells as previously reported. 2 In view of the polyreactivity, increased autoreactivity, and strongly reduced calcium response and proliferative capacity of CD21/lo Bcells—reminiscent of anergic B cells in mouse models—the authors propose that CD21/lo B cells represent anergic human Bcells. 1 Moreover, they showed that the majority of highly HEp2-reactive CD21/lo B-cell clones express kappa () light chains and suggested that the receptor editing using lambda () light chains might not be induced in those clones serving as a mechanism to silence autoreactive B cells. We would like to suggest a different interpretation of the origin of CD21low B cells. Anergy in CD21low Bcells in patients with common variable immunodeficiency (CVID) is not complete. In the original model of hen egg lysozyme–transgenic mice, 3 anergy in B cells represents a mechanism of central tolerance caused by Bcell receptor (BCR)–induced hyporesponsiveness, which is associated with down-regulated BCR, poor calcium response, defective up-regulation of CD86, failure of antibody production, and impaired proliferation. 3, 4 Although poor Ca response and impaired proliferation are both features that CD21low B cells share with anergic mouse B cells, CD21low B cells of CVID patients have not down-regulated their surface BCR (Figure 1A-B) and are able to up-regulate activation markers like CD86 (unpublished data) as well as ICOS-L, TACI, and Fas surface expression upon BCR stimulation. 1 Even more importantly, CD21low B cells produce higher levels of IgM than naive B cells after stimulation in vitro. 2 In addition, a comparison of gene-expression profiles of mouse anergic B cells3, 4 and human CD21low B cells2 showed only little overlap: only 3 (11.5%) of 26 genes describing the signature of anergic mouse Bcells were identically expressed in CD21low B cells. In contrast, these cells closely resemble2 the recently characterized tissue memory-like Bcells in tonsils5 and circulating “exhausted” CD21low B cells in HIV patients, suggesting rather a mechanism of activation-driven peripheral exhaustion underlying this anergic phenotype. 6 This would also better explain the accumulation of CD21low B cells in the bronchoalveolar fluid of CVID patients or the synovial fluid of rheumatoid arthritis patients. 2 In addition, in our cohort of CVID patients we cannot confirm a defect in secondary editing and light chain usage. We actually found that CD21low B cells preferentially express-chains compared with the naive B cells of CVID patients, which was also the case in 1 of the 3 CVID samples shown in Figure 2D of Isnardi and colleagues’ article. 1 In our experience the/ratio in CD21 naive B cells (1.24 0.03; n 4) of CVID patients was within the normal range (1.0-2.1), whereas CD21low B cells showed a
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