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Antiphospholipid syndrome

In addition to its role in calcium homeostasis and bone formation, a modulatory role of the active form of vitamin D on cells of the immune system, particularly T lymphocytes, has been described. The effects of vitamin D on the production and action of several cytokines has been intensively investigated in recent years. In this connection, deficiency of vitamin D has been associated with several autoimmune diseases, including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), antiphospholipid syndrome (APS), Hashimoto Thyroiditis (HT), and multiple sclerosis (MS). In a successful pregnancy, the maternal immune response needs to adapt to accommodate the semiallogeneic fetus. Disturbances in maternal tolerance are implicated in infertility and pregnancy complications such as miscarriages (RM) and preeclampsia (PE). It is well-known that a subset of T lymphocytes, regulatory T cells (Tregs) exhibit potent suppressive activity, and have a crucial role in curtailing the destructive response of the immune system during pregnancy, and preventing autoimmune diseases. Interestingly, vitamin D deficiency is common in pregnant women, despite the widespread use of prenatal vitamins, and adverse pregnancy outcomes such as RM, PE, intrauterine growth restriction have been linked to hypovitaminosis D during pregnancy. Research has shown that autoimmune diseases have a significant prevalence within the female population, and women with autoimmune disorders are at higher risk for adverse pregnancy outcomes. Provocatively, dysregulation of T cells plays a crucial role in the pathogenesis of autoimmunity, and adverse pregnancy outcomes where these pathologies are also associated with vitamin D deficiency. This article reviews the immunomodulatory role of vitamin D in autoimmune diseases and pregnancy. In particular, we will describe the role of vitamin D from conception until delivery, including the health of the offspring. This review highlights an observational study where hypovitaminosis D was correlated with decreased fertility, increased disease activity, placental insufficiency, and preeclampsia in women with APS.

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Immunomodulatory Effects of Vitamin D in Pregnancy and Beyond.

Association between neutrophil extracellular traps (NETs) and thrombosis in antiphospholipid syndrome.

The role of inflammation in thrombotic complications of primary antiphospholipid syndrome (PAPS) is controversial. The aim of this study was to evaluate levels of inflammation and coagulation markers in patients with thrombotic PAPS (t-PAPS). Patients with t-PAPS and individuals with no history of thrombosis were enrolled. The association of t-PAPS with levels of tumor necrosis factor (TNF)-α, C-reactive protein (hs-CRP), interferon (IFN)-α, interleukins (IL)-6, -8, factor VIII (FVIII), von Willebrand factor (VWF) and tissue factor (TF) was evaluated by regression models. The levels of these markers were also compared between controls and subgroups of t-PAPS patients with triple positivity, recently diagnosed thrombosis, recurrent thrombosis and venous thrombosis. Patients with t-PAPS (n = 101) had a 8.6-fold increased levels of TNF-α, 90% increased levels of hs-CRP, 80% increased levels of IL-6, 30% increased levels of FVIIIAg, 50% increased levels of VWF and 66% increased levels of TF as compared to controls (n = 131), and the differences did not change after adjustments for sex, age and cardiovascular risk factors. Inflammatory markers were elevated in t-PAPS regardless of the aPL profile, number of previous thrombosis or time elapsed since diagnosis. TNF-α and IL-8 levels were higher in t-PAPS patients with venous thrombosis, in comparison with those with arterial thrombosis and controls. Patients with t-PAPS presented with increased levels of inflammatory and coagulation markers, which suggests that t-PAPS is associated not only with hypercoagulability but also with a persistent inflammatory state.

Inflammatory markers in thrombosis associated with primary antiphospholipid syndrome

In recent years, tumor microenvironment (TME) has been recognized as potential targets for tumor treatment and the tumor vascular system is one of such targets. Fusing truncated tissue factor (tTF) with pH low insertion peptides (pHLIP), tTF-pHLIP, can target tumor vessels owing to its acidic TME and cause tumor vessel occlusion by blood clotting and subsequently effectively inhibit tumor growth. To evaluate its bioeffects, we exposed the tTF-pHLIP to normal mice and mice xenograft with B16F10 tumor and analyzed the metabolic profiling of various tissues and biofluids including plasma and urine from mice treated with and without tTF-pHLIP. A combination of nuclear magnetic resonance (NMR) and gas chromatography-mass spectrometry and ultra-high-performance liquid chromatography-mass spectrometry was employed in the study. We found that tTF-pHLIP treatment can effectively reduce tumor size and concurrently ameliorate tumor-induced alterations in the TCA cycle metabolism and lipid metabolism. In addition, we found that toxicity of tTF-pHLIP to normal mice is minor and exposure of the tTF-pHLIP induced oxidative stress to the system. Hence, we concluded that tTF-pHLIP is of low toxicity and effective in reducing tumor size as well as rebalancing tumor-induced metabolic derailment.

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Metabonomic Investigation of Biological Effects of a New Vessel Target Protein tTF-pHLIP in a Mouse Model

Circulating levels of tissue factor and the risk of thrombosis associated with antiphospholipid syndrome.

Tissue factor (TF) is a procoagulant protein associated with increased risk of thrombotic events in antiphospholipid syndrome (t-APS). The mechanisms by which TF levels are increased in APS have not yet been established. The aim of this study was to investigate whether TF mRNA expression is associated with TF levels and thrombosis in APS. We compared levels of circulating TF and high sensitivity C-reactive protein (hs-CRP) between t-APS and controls (individuals without thrombosis). The association between TF mRNA expression, quantified by real time quantitative polymerase chain reaction, and t-APS was accessed using regression analysis. We included 41 controls and 42 t-APS patients, mean age was 41 years old (SD 14) in both groups. Hs-CRP and TF levels were higher in t-APS patients (mean hs-CRP levels 0.81 mg/dL [SD 1.88] and median TF levels 249.0 pg/mL [IQR 138.77–447.61]) as compared to controls (mean hs-CRP levels 0.24 mg/dL [SD 0.26] and median TF levels 113.0 pg/mL [IQR 81.17–161.53]; P = 0.02 and P < 0.0001, respectively). There was no correlation between TF mRNA expression and TF levels in t-APS (r − 0.209, P = 0.19). TF mRNA expression was not associated with t-APS (adjusted OR 1.16; 95%CI 0.72–1.87). Despite circulating TF levels being higher in patients with t-APS than in controls, TF mRNA expression was similar between groups. The results demonstrate that TF mRNA expression is not associated with levels of circulating TF and hypercoagulability in t-APS.

Fernanda Talge Arantes

Papers

Circulating levels of tissue factor and the risk of thrombosis associated with antiphospholipid syndrome.

Inflammatory markers in thrombosis associated with primary antiphospholipid syndrome

Expression of tissue factor mRNA in thrombosis associated with antiphospholipid syndrome