Phospholipase D4 as a signature of toll-like receptor 7 or 9 signaling is expressed on blastic T-bet + B cells in systemic lupus erythematosus.

BACKGROUND: In systemic lupus erythematosus (SLE), autoreactive B cells are thought to develop by-passing immune checkpoints and contribute to its pathogenesis. Toll-like receptor (TLR) 7 and 9 signaling have been implicated in their development and differentiation. Although some B cell subpopulations such as T-bet + double negative 2 (DN2) cells have been identified as autoreactive in the past few years, because the upregulated surface markers of those cells are not exclusive to them, it is still challenging to specifically target autoreactive B cells in SLE patients. METHODS: Our preliminary expression analysis revealed that phospholipase D4 (PLD4) is exclusively expressed in plasmacytoid dendritic cells (pDCs) and B cells in peripheral blood mononuclear cells (PBMCs) samples. Monoclonal antibodies against human PLD4 were generated, and flow cytometry analyses were conducted for PBMCs from 23 healthy donors (HDs) and 40 patients with SLE. In vitro cell culture was also performed to study the conditions that induce PLD4 in B cells from HDs. Finally, recombinant antibodies were synthesized from subpopulations of PLD4 + B cells from a patient with SLE, and their antinuclear activity was measured through enzyme-linked immunosorbent assay. RESULTS: pDCs from both groups showed comparable frequency of surface PLD4 expression. PLD4 + B cells accounted for only a few percent of HD B cells, whereas they were significantly expanded in patients with SLE (2.1% ± 0.4% vs. 10.8% ± 1.2%, P < 0.005). A subpopulation within PLD4 + B cells whose cell size was comparable to CD38 + CD43 + plasmablasts was defined as "PLD4 + blasts," and their frequencies were significantly correlated with those of plasmablasts (P < 0.005). PLD4 + blasts phenotypically overlapped with double negative 2 (DN2) cells, and, in line with this, their frequencies were significantly correlated with several clinical markers of SLE. In vitro assay using healthy PBMCs demonstrated that TLR7 or TLR9 stimulation was sufficient to induce PLD4 on the surface of the B cells. Finally, two out of three recombinant antibodies synthesized from PLD4 + blasts showed antinuclear activity. CONCLUSION: PLD4 + B cells, especially "blastic" ones, are likely autoreactive B cells undergoing TLR stimulation. Therefore, PLD4 is a promising target marker in SLE treatment.

Protein-losing gastroenteropathy with severe hypoalbuminemia associated with Sjögren's syndrome: A case report and review of the literature.

A 30-year-old man with severe hypoalbuminemia (serum albumin: 0.9 g/dL) was admitted with severe bilateral leg edema and unilateral pleural effusion. Serum anti-SS-A and SS-B antibody levels were abnormally elevated, and his symptoms fulfilled the diagnostic criteria for Sjögren's syndrome. Technetium-99m albumin scintigraphy revealed protein leakage from a large area of the small intestine. Immunohistochemistry revealed perivascular deposition of C1q, C3d, and immunoglobulin G in the duodenal mucosa. The patient was diagnosed with protein-losing gastroenteropathy associated with Sjögren's syndrome. Within 2 months of treatment with oral prednisolone and mycophenolate mofetil, the clinical symptoms of hypoalbuminemia and Sjögren's syndrome disappeared completely.

Interferon α Enhances B Cell Activation Associated With FOXM1 Induction: Potential Novel Therapeutic Strategy for Targeting the Plasmablasts of Systemic Lupus Erythematosus.

Systemic lupus erythematosus (SLE) is an autoimmune disease. It is characterized by the production of various pathogenic autoantibodies and is suggested to be triggered by increased type I interferon (IFN) signature. Previous studies have identified increased plasmablasts in the peripheral blood of SLE patients. The biological characteristics of SLE plasmablasts remain unknown, and few treatments that target SLE plasmablasts have been applied despite the unique cellular properties of plasmablasts compared with other B cell subsets and plasma cells. We conducted microarray analysis of naïve and memory B cells and plasmablasts (CD38+CD43+ B cells) that were freshly isolated from healthy controls and active SLE (n = 4, each) to clarify the unique biological properties of SLE plasmablasts. The results revealed that all B cell subsets of SLE expressed more type I IFN-stimulated genes. In addition, SLE plasmablasts upregulated the expression of cell cycle-related genes associated with higher FOXM1 and FOXM1-regulated gene expression levels than that in healthy controls. This suggests that a causative relationship exists between type I IFN priming and enhanced proliferative capacity through FOXM1. The effects of pretreatment of IFNα on B cell activation and FOXM1 inhibitor FDI-6 on B cell proliferation and survival were investigated. Pretreatment with IFNα promoted B cell activation after stimulation with anti-IgG/IgM antibody. Flow cytometry revealed that pretreatment with IFNα preferentially enhanced the Atk and p38 pathways after triggering B cell receptors. FDI-6 inhibited cell division and induced apoptosis in activated B cells. These effects were pronounced in activated B cells pretreated with interferon α. This study can provide better understanding of the pathogenic mechanism of interferon-stimulated genes on SLE B cells and an insight into the development of novel therapeutic strategies.

Seven-day (24-h) ambulatory blood pressure monitoring, self-reported depression and quality of life scores.

OBJECTIVE: Effects of environmental conditions on blood pressure (BP) and heart rate (HR) variations as putative factors underlying the onset of vascular events. METHODS: BP and HR were monitored around the clock for 7 days on 54 residents from Urausu, Hokkaido, Japan. Daytime, night-time, and 24-h means served to identify dippers and non-dippers. Questionnaire-assessed depression and subjective quality of life were related to BP and HR by analyses of variance and linear regression. Statistical significance was at 5%. RESULTS: A circaseptan (about 7-day) component characterizes the 24-h mean and standard deviation (SD) of HR, and the daytime and day-night ratio of systolic BP. The SD of HR is higher on weekends and lower on Mondays and Thursdays. When awake, systolic BP is lowest on Sundays and the day-night ratio is optimal on weekends (Saturdays: 15.7 +/- 9.4%; Sundays: 14.0 +/- 13.2%). Depression was detected in 15 subjects, who had higher mean systolic and diastolic BP values (systolic BP: P = 0.028 Fridays, P = 0.021 Tuesdays; diastolic BP: P = 0.022 Mondays, P = 0.006 daytime Mondays) and a lower day-night ratio of diastolic BP (P = 0.012 Tuesdays, P = 0.005 Wednesdays, and P = 0.038 Thursdays). A depressive mood correlated positively with 24-h averages of systolic (P = 0.037) and diastolic (P = 0.030) BP. CONCLUSIONS: Depression (and subjective quality of life) can affect BP and HR variability. The results indicate the role that psychological factors may play in the pathogenesis of cardiovascular disease. Therapeutic implications are suggested for primary and secondary prevention.