Urine Proteomics Differentiate Primary Thrombotic Antiphospholipid Syndrome From Obstetric Antiphospholipid Syndrome.

Antiphospholipid syndrome (APS) is a multisystem disorder characterized by thrombosis and/or recurrent fetal loss. This clinical phenotype heterogeneity may result in differences in response to treatment and prognosis. In this study, we aimed to identify primary thrombotic APS (TAPS) from primary obstetric APS (OAPS) using urine proteomics as a non-invasive method. Only patients with primary APS were enrolled in this study from 2016 to 2018 at a single clinical center in Shanghai. Urine samples from 15 patients with TAPS, 9 patients with OAPS, and 15 healthy controls (HCs) were collected and analyzed using isobaric tags for relative and absolute quantification (iTRAQ) labeling combined with liquid chromatography-tandem mass spectrometry analysis to identify differentially expressed proteins. Cluster analysis of urine proteomics identified differentiated proteins among the TAPS, OAPS, and HC groups. Urinary proteins were enriched in cytokine and cytokine receptor pathways. Representative secreted cytokines screened out (fold change >1.20, or <0.83, p<0.05) in these differentiated proteins were measured by enzyme-linked immunosorbent assay in a validation cohort. The results showed that the levels of C-X-C motif chemokine ligand 12 (CXCL12) were higher in the urine of patients with TAPS than in those with OAPS (p=0.035), while the levels of platelet-derived growth factor subunit B (PDGFB) were lower in patients with TAPS than in those with OAPS (p=0.041). In addition, correlation analysis showed that CXCL12 levels were positively correlated with immunoglobulin G anti-ß2-glycoprotein I antibody (r=0.617, p=0.016). Our results demonstrated that urinary CXCL12 and PDGFB might serve as potential non-invasive markers to differentiate primary TAPS from primary OAPS.

Multiple injections of anti-mouse ß2glycoprotein 1 antibody induce FcRγ-dependent fetal growth restriction (FGR) in mice.

OBJECTIVES: The antiphospholipid syndrome (APS) is characterized by the presence of circulating antiphospholipid antibodies (aPLs), is a leading cause for thromboembolic events, repeated miscarriage, fetal loss and is a major risk factor for fetal growth restriction (FGR) and preeclampsia. In human, anti-ß2 glycoprotein I (aß2GPI) antibody is one of the aPLs and considered to be a specific and important marker for APS. However, pathophysiological changes induced by aß2GPI antibodies in FGR are largely unknown. METHODS: In the present study, we developed a murine FGR model induced by multiple injections of WBCAL-1, a well-characterized mouse aß2GPI monoclonal antibody. RESULTS: Administration of WBCAL-1, but not the isotype control antibody and saline, into pregnant mice specifically decreased the size of fetuses and placentas without affecting the number of delivered pups. Also, a significant increase in urinary albumin and electron microscopic changes, such as splitting layers of basal membranes in the placental labyrinth and rearrangement of pores in glomerular endothelial cells, were observed in WBCAL-1 treated mice. WBCAL-1 injection did not induce any changes in blood pressure and typical parameters of blood thromboembolic symptoms. Furthermore, FcRγ deficiency protected the fetuses from aß2GPI antibody-induced injuries. CONCLUSIONS: Our present findings suggest that proteinuria is a symptom associated with APS-related FGR with placental and renal tissue injuries, and that FcRγ might be a molecular target for prevention of aß2GPI antibody-mediated obstetrical pathologies.

[A case of antiphospholipid antibody syndrome with variable renal histological change despite of poor changes in urinalysis].

We experienced a case of lupus nephritis with antiphospholipid antibody syndrome. A renal biopsy specimen from this patient showed various renal histological changes, but the results of urinalysis were almost normal. The patient was a 56-year-old woman diagnosed as having systemic lupus erythematosus with antiphospholipid antibody syndrome in 1983. In 1998, she had diarrhea and blood gas analysis showed metabolic acidosis. Therefore, she was admitted to our hospital and underwent renal function examination. The glomerular filtration rate was reduced(GFR: 40/ml/min), but urinalysis was almost normal. To examine her renal dysfunction, we performed open renal biopsy. Her renal tissues showed global glomerular sclerosis, mesangial cell proliferation and infiltration of cells in the tubulointerstitial area(WHO II). Furthermore, some arterioles showed organized thrombus formation and recanalization due to the antiphospholipid antibody syndrome. Renal biopsy of patients with lupus nephritis is useful not only for precise diagnosis, but also for the selection of appropriate treatment.