Plasmablast‐like Phenotype Among Antigen‐Experienced CXCR5–CD19^low B Cells in Systemic Lupus Erythematosus

Abstract

Objective. Altered composition of the B cell compartment in the pathogenesis of systemic lupus erythematosus (SLE) is characterized by expanded plasmablast and IgD-CD27-double-negative B cell populations. Previous studies showed that double-negative B cells represent a heterogeneous subset, and further characterization is needed.Methods. We analyzed 2 independent cohorts of healthy donors and SLE patients, using a combined approach of flow cytometry (for 16 healthy donors and 28 SLE patients) and mass cytometry (for 18 healthy donors and 24 SLE patients) and targeted RNA-Seq analysis. To compare B cell subset formation during the acute immune response versus that during autoimmune disease, we investigated healthy donors at various time points after receipt of the BNT162b2 messenger RNA COVID-19 vaccine and patients with acute SARS-CoV-2 infection, using flow cytometry.Results. We found that IgD-CD27+ switched and atypical IgD-CD27-memory B cells, the levels of which were increased in SLE patients, represented heterogeneous populations composed of 3 different subsets each. CXCR5+ CD19 intermediate , CXCR5-CD19 high , and CXCR5-CD19 low populations were found in the switched memory and double-negative compartments, suggesting the relatedness of IgD-CD27+ and IgD-CD27-B cells. We characterized a hitherto unknown and antigen-experienced CXCR5-CD19 low subset that was enhanced in SLE patients, had a plasmablast phenotype with diminished B cell receptor responsiveness, and expressed CD38, CD95, CD71, PRDM1, XBP1, and IRF4. Levels of CXCR5-CD19 low subsets were increased and correlated with plasmablast frequencies in SLE patients and in healthy donors who received BNT162b2, suggesting their interrelationship and contribution to plasmacytosis. The detection of CXCR5-CD19 low B cells among both CD27+ and CD27-populations calls into question the role of CD27 as a reliable marker of B cell differentiation.Conclusion. Our data suggest that CXCR5-CD19 low B cells are precursors of plasmablasts. Thus, cotargeting this subset may have therapeutic value in SLE.

Pathogenesis of systemic lupus erythematosus: risks, mechanisms and therapeutic targets

“…Consistent with important roles for IFN-I and signalling through TLR7, pDCs and RNA-containing immune complexes generate B cells with the double negative CD27 − IgD − B-cell phenotype characteristic of ABCs 218. A more fine-tuned description of the most relevant B cells in patients with SLE was recently reported, with the CXCR5 − CD19 low phenotype most consistent with plasmablast frequencies 219. The relevance of this line of investigation is that it is defining the cell surface features as well as required stimuli that characterise those B cells that go on to produce lupus autoantibodies, thereby defining potential therapeutic targets.…”

UNC93B1 variants underlie TLR7-dependent autoimmunity

“…4′,6-Diamidino-2-phenylindole was added before sample acquisition to allow dead cell exclusion. Gating of plasmablasts was performed as previously described ( 49 ). Healthy controls data were from Ferreira-Gomes et al ( 50 ).…”

Glucocorticoids selectively affect the memory T cell response to SARS-Cov2 spike in vaccinated and post-infected patients with systemic lupus erythematosus

“…The latter point is consistent with our report that the early stage of the humoral response is affected, which provides an argument to interrupt anti-metabolite drugs in the 2 weeks following COVID-19 vaccination as recently suggested [ 30 ]. Moreover, IgG anti-Spike Ab positivity with the presence of anti-dsDNA, anti-SSA/Ro 52 kDa, and anti-CL Abs together with sustained immune response after 50 days post immunization may reflect a post-vaccine expansion and survival of plasmablasts as previously reported in SLE [ 31 , 32 ]. In our study, immunosuppressive drugs did not significantly affect anti-Spike humoral response, which is in agreement with previous reports regarding glucocorticoids, hydroxychloroquine and belimumab [ 27 , 33 ].…”