Similar CD19 Dysregulation in Two Autoantibody-Associated Autoimmune Diseases Suggests a Shared Mechanism of B-Cell Tolerance Loss

Abstract

: We report here that dysregulation of CD19, a coreceptor that augments B-cell receptor (BCR) signaling, occurs at two B-cell differentiative stages in patients with systemic lupus erythematosus (SLE) and antineutrophil cytoplasmic autoantibody (ANCA) associated small vessel vasculitis (SVV). The naïve B cells of nearly all SLE and ANCA-SVV patients express approximately 20% less CD19 than healthy control (HC) B cells. In contrast, a subset of memory B cells of some SLE and ANCA-SVV Pts (25-35%) express two to fourfold more CD19 than HC B cells. These CD19(hi) memory B cells are activated and exhibit evidence of antigen selection. Proteome array analysis of 67 autoantigens indicates that CD19(hi) SLE Pts exhibit a distinct autoantibody profile characterized by high levels of antibodies to small nuclear ribonucleoproteins and low levels of antiglomerular autoantibodies. These findings have implications for autoreactive B-cell activation and suggest a shared mechanism of B-cell tolerance loss in these two diseases.

Dermatan Sulfate Interacts with Dead Cells and Regulates CD5+ B-Cell Fate

“…Third, in transgenic mouse models, CD19 has been thought to be required for the development and maintenance of B-1a cells, 19 and CD19 dysregulation has been linked to autoantibody-associated autoimmune disorders, including systemic lupus erythematosus and antineutrophil cytoplasmic auotantibodies. 20 However, when B cells from CD19-deficient mice 17 were cultured, DS stimulated the expansion of CD5 ϩ B220 ϩ CD19 Ϫ B cells ( Figure 2E). This finding argues against a requirement for CD19 in the DS stimulation pathway.…”

Altered expression of signalling lymphocyte activation molecule (SLAM) family receptors CS1 (CD319) and 2B4 (CD244) in patients with systemic lupus erythematosus

“…3). According to a recent study, the majority of CD19 + B cells are IgD + and CD27 -, indicating naive B cells [52]. They also reported CD19-high B cells as autoreactive memory B cells, and the frequency of this population correlates with disease activity [52,53].…”

“…According to a recent study, the majority of CD19 + B cells are IgD + and CD27 -, indicating naive B cells [52]. They also reported CD19-high B cells as autoreactive memory B cells, and the frequency of this population correlates with disease activity [52,53]. Also, active SLE disease has been shown to correlate with a high frequency of plasma cells, which express high levels of CD27 and low levels of CD19 [54,55].…”

A novel subset of memory B cells is enriched in autoreactivity and correlates with adverse outcomes in SLE

“…In addition, we, and others, have shown a population of B cells which have 2-3 fold increased levels of CD19 compared to other B cells from the same patient or to healthy control B cells (CD19 hi cells) in SLE, ANCA-SVV, and CVID patients [30;32;33]. We previously reported that these CD19 hi B cells have an activated memory phenotype, are class switched, and show evidence of antigen selection [30]. We propose that the increased CD19 expression on CD19 hi memory B cells decreases their activation threshold leading to enhanced proliferation, survival, and plasma cell differentiation.…”

“…Five of the 10 patients from this study were patients continuing from the original study [30], and the other five were newly identified. Patients were included in this study after informed consent in accordance with our institutional internal review board, and fulfilled at least four of the established American College of Rheumatology 1997 revised criteria for SLE.…”