Measurement of circulating CD21−CD27− B lymphocytes in SLE patients is associated with disease activity independently of conventional serological biomarkers

Abstract

Determining disease activity in systemic lupus erythematosus (SLE) patients is challenging and limited by the lack of reliable biomarkers. Abnormally activated B cells play a key role in the pathogenesis of SLE, but their measure in clinical practice is currently not recommended. Here, we studied peripheral B cells to identify a valid biomarker. We analyzed peripheral B cells in a discovery cohort of 30 SLE patients compared to 30 healthy controls (HC) using mass cytometry and unsupervised clustering analysis. The relevant B cell populations were subsequently studied by flow cytometry in a validation cohort of 63 SLE patients, 28 autoimmune diseases controls and 39 HC. Our data show an increased frequency of B cell populations with activated phenotype in SLE compared to healthy and autoimmune diseases controls. These cells uniformly lacked the expression of CD21 and CD27. Measurement of CD21−CD27− B cells in the blood identified patients with active disease and their frequency correlated with disease severity. Interestingly, we did not observe an increase in the frequency of CD21−CD27− B cells in patients with clinically inactive disease but with elevated conventional biomarkers (anti-dsDNA and complement levels). Accordingly, measurement of CD21−CD27− B cells represents a robust and easily accessible biomarker to assess the activity of the disease in SLE patients.

Immunophenotyping identifies distinct cellular signatures for systemic lupus erythematosus and lupus nephritis

“…Consistent with prior reports 19 the proportion of T regulatory (Treg, CD4 + CD25 + CD127 lo ) cells were strikingly elevated in the LN group (Figure 3D). In our cohort, there was no significant differences in proportions of total CD8+ T cells, activated CD8+ T cells and activated CD4+ T cell populations between SLE, LN, and HBD groups.…”

“…In murine models of lupus, MZBs are increased and thought to progress to the follicle for maturation, Increased activated CD4+ 23 Increased activation over course of disease 16 Decreased naïve CD4+ 23 Increased initially, but diminishing over time 16 Increased Tfh 25 Increased Tfh 26 mDC expansion 23 Reduced, 27 normal, 28 or increased 29 mDC pDC expansion 23 Reduced 30 or increased 31 pDC Increased B cell activation 23 Increased plasmablast 19 and memory B cell 20 Increased GC formation 32 Increased GC formation 33 Abbreviations: GC, germinal centers; mDC, myeloid dendritic cells; pDC, plasmacytoid dendritic cells; SLE, systemic lupus erythematosus; Tfh, T follicular helper cells. suggesting antibody products of this process are more likely to be auto-reactive.…”

“…18 Th17 cells have previously been shown to be expanded in SLE patients and interleukin (IL)-17 levels reported to correlate with lupus disease activity. 18 B cell phenotypes are more heterogeneous in SLE, yet most studies have noted an increase in plasmablasts, CD21 − CD27 − subsets 19 and IgD CD95 expressing memory B cells. 20 We investigated the peripheral immuno-phenotypes of individuals with SLE who developed LN and those without LN, in an observational study of a SLE/LN cohort using flow cytometry.…”

Altered Circulating Follicular T Helper Cell Subsets and Follicular T Regulatory Cells Are Indicators of a Derailed B Cell Response in Lupus, Which Could Be Modified by Targeting IL-21R

“…Characterization of distinct B cell populations revealed some under-represented cell types, including DN B cells, which mainly consist of primed antibody-secreting cell precursors arisen through the extrafollicular differentiation pathway [ 64 ]. The increased ratio of these cells in SLE was associated with higher SLEDAI scores and an anamnestic history of kidney injury [ 65 , 66 , 67 ]. Corresponding results were found in our study, as the percentages of DN B cells increased to a greater degree in patients with nephritis, compared to patients with cutaneous lupus, although the difference was not statistically significant.…”

Integrated Multi-omics Analyses of NFKB1 patients B cells points towards an up regulation of NF-κB network inhibitors

“…The expression of SERPINE2 in CD21-low B cells could indicate that these cells may be the consequence of an insufficient germinal center reaction not only in NF-B1-insufficient patients, but possibly also in other patients with increased levels of CD21-low B cells, such as in patients with systemic lupus or HIV infection 126,127 . SERPINE2 is known to be expressed in cells undergoing homologous recombination DNA repair 128 .…”