Increased Frequency of a Unique Spleen Tyrosine Kinase Bright Memory B Cell Population in Systemic Lupus Erythematosus

Abstract

Objective. Systemic lupus erythematosus (SLE) is characterized by B cell hyperactivity and autoantibody production. As spleen tyrosine kinase (Syk) is pivotal in B cell activation, these experiments aimed to examine the extent to which Syk was abnormally expressed in SLE B cells and the nature of the B cell subset that differently expressed Syk.Methods. B cells from healthy donors and SLE patients were analyzed by flow cytometry to assess basal expression of Syk and phosphorylated Syk. B cell subsets expressing higher levels of Syk were found, and their detailed phenotype, in vitro differentiation into plasmablasts/plasma cells, and Syk induction by cytokines were determined. Conclusion. SLE patients exhibit an increased frequency of hitherto unknown CD27؊Syk؉؉ memorylike B cells, indicating that intracellular Syk density could distinguish CD27؊ memory B cells from truly naive B cell subsets. Furthermore, the CD27؊Syk؉؉ subset is a candidate for a source of increased plasma cells in SLE.B cell activation is a complex process involving different soluble and cellular components and, most importantly, if antigen-dependent, binding of the antigen to the B cell receptor (BCR). After BCR ligation, reorganization of autoregulatory BCR clusters with recruitment of intracellular kinases and subsequent internalization of the cognate antigen (1) initiate an intracellular signaling cascade by phosphorylation of the associated BCR molecules CD79␣ and CD79␤. In this process, other signaling molecules, such as Lyn, spleen tyrosine kinase (Syk), Bruton's tyrosine kinase (BTK), and phospholipase C␥2 (PLC␥2) are recruited and activated in an ordered manner to fine-tune BCR signaling. After BCR engagement, Syk becomes phosphorylated (tyrosine residues Y 348 and Y 352 ), induced by immunoreceptor tyrosine-based activation motifs (ITAMs) on the cytosolic tail of the BCRϪCD79 complex (2).Several studies have linked the development of murine lupus to abnormalities of BCR-associated signalSupported by the DFG (SFB650 project TP16, SFB633 A14, SPP ImmunoBone DFG Do491/8-2, and DFG project Do491/7-3).

Enhanced Tyrosine Phosphatase Activity Underlies Dysregulated B Cell Receptor Signaling and Promotes Survival of Human Lupus B Cells

“…Since it has been shown that naive and memory B cells have different BCR activation thresholds , further analyses were performed using conventional CD27− naive and CD27+ memory B cells. Of note, the recently published memory‐like CD27−Syk++ B cell subset was excluded from the CD27− naive B cell compartment and analyzed separately (Supplementary Figure , online at http://onlinelibrary.wiley.com/doi/10.1002/art.39559/abstract). Interestingly, cells from healthy donors, but not those from SLE patients, exhibited increased pSyk (Y 352 ) MFI values upon BCR stimulation in CD27+ versus CD27− B cells (Figure A).…”

CNS Aquaporin‐4‐specific B cells connect with multiple B‐cell compartments in neuromyelitis optica spectrum disorder

“…DN B cells are thought to represent a transient memory subset that may originate from incomplete germinal centers or extrafollicular reactions21, providing an expanded source of IgG+ plasmablasts 22. CD27 + and CD27‐ DN class‐switched memory cells share overlapping clones23, and the transition of B cells between these memory pools may be due to downregulation of CD27 secondary to chronic antigen stimulation 24.…”

TGF-β3 Inhibits Antibody Production by Human B Cells

“…TGF-β3 has been suggested to be therapeutic in a mouse model of SLE[25], and the findings of this study suggest that TGF-β3 modifying therapy may be therapeutic in human autoimmune diseases with B cell dysregulation. It has been suggested that B cells with increased Syk phosphorylation might be a source for pathogenic plasma cells in SLE[52], and TGF-β3, which inhibits phosphorylation of Syk and ASC differentiation, may be able to inhibit those B cells as well as their differentiation into pathogenic plasma cells.…”