Activated memory B cell subsets correlate with disease activity in systemic lupus erythematosus: Delineation by expression of CD27, IgD, and CD95

Abstract

Objective. Analysis of peripheral B cell subsets in patients with systemic lupus erythematosus (SLE) has provided evidence of specific alterations, such as an expansion of CD27؉؉ plasma cells/blasts and transitional B cells. However, memory B cells in lupus have not been thoroughly investigated, and only recently a CD27؊ memory B cell subset was identified in the peripheral blood of lupus patients. Focusing on CD27؊ B cells, this study aimed to identify abnormalities in peripheral B cell subsets in patients with SLE.Methods. Three independent cohorts of lupus patients were used to characterize CD27؊ memory B cells, using multiparameter flow cytometry and singlecell reverse transcription-polymerase chain reaction of heavy-chain transcripts.Results. We identified a homogeneous subset of CD27؊,IgD؊,CD95؉ memory B cells with an activated phenotype that was increased in patients with disease flares and that correlated with disease activity and serologic abnormalities. In contrast, the entire subset of CD27؊,IgD؊ B cells was found to be heterogeneous, did not correlate significantly with lupus activity, and was also increased in patients with bacterial infections. Conclusion. We conclude that CD95 is a useful marker to identify CD27؊ memory B cells with an activated phenotype, which might serve as a biomarker for lupus activity and as a target of further investigations aiming to elucidate the pathogenic potential of these cells and the mechanisms involved in the generation as well as regulation of this CD27؊,IgD؊,CD95؉ memory B cell subset.B cell monitoring has been extensively used recently to assess the effect of B cell-depleting or B cell-modulating therapies and the reconstitution of the peripheral blood B cell repertoire after treatment with B cell-depleting drugs. Expression of CD27 has been particularly useful to discriminate B cell subsets. Although CD27 was originally thought to distinguish between memory B cells and plasma cells and between memory B cells and naive B cells (1,2), more recently the heterogeneity of CD27Ϫ B cells has become apparent. The contribution of transitional B cells to this subpopulation has been shown to be high in some patients with systemic lupus erythematosus (SLE) (3). In this regard, after B cell depletion, immature and transitional B cells dominate the peripheral blood for months (4). Conversely, a recent analysis of B cell subsets in patients with Sjögren's syndrome demonstrated a predominance of CD27Ϫ B cells, of which ϳ10% were B cells with

Aiolos Overexpression in Systemic Lupus Erythematosus B Cell Subtypes and BAFF-Induced Memory B Cell Differentiation Are Reduced by CC-220 Modulation of Cereblon Activity

“…The alterations in BAFF, IL-2, and IL-21 in SLE indicate a dysregulation of these factors. Our data in this study demonstrate the B cell differentiation-inducing potential of these factors on memory and DN B cells, which may have an impact in SLE where B cells are known to be in an activated state (106).…”

“…There are several hypotheses on the origin of DN B cells including that they are exhausted memory B cells that have downregulated CD27 (109), memory B cell precursors that have not acquired CD27 yet (111), or an entirely new B cell population that has undergone low levels of somatic hypermutation (111,112). DN B cells show an activated phenotype where levels of these cells are associated with higher levels of circulating autoantibodies in SLE (8,106) and have a proinflammatory phenotype in Alzheimer's disease (110). Because of the phenotypic similarity to CD27 + memory B cells defined by cell surface markers such as CD95 shown in this study (Fig.…”

Activation of TLR7 increases CCND3 expression via the downregulation of miR-15b in B cells of systemic lupus erythematosus

“…3,4 Our data showed the activation of TLR7 also increased the percentage of GC formation and PCs in mice spleens. In addition, it was reported that expanded PCs, which were generated through GCs in both the peripheral and bone marrow in SLE patients, 45,46 are responsible for the production of an array of autoantibodies against soluble and cellular constituents that are most commonly nuclear antigens. 47 Consistent with previous reports, the expression of CCND3 is significantly higher in GC B cells than in non-GC B cells, 7,8 and the expression of miR-15b in IMQ-treated GC B cells is significantly lower than IMQ-treated and wild-type non-GC B cells.…”

Delayed acquisition of somatic hypermutations in repopulated IGD+CD27+ memory B cell receptors after rituximab treatment

“…Memory B cells in humans are characterized by the CD27 surface molecule, which is the key marker for these B cells (13), although more recently IgDϪCD27Ϫ B cells that carry features of memory cells have been identified in SLE (14,15). Memory B cells undergo somatic hypermutation in Ig V-region genes, generating Ig rapidly and vigorously in secondary immune responses (16).…”