Vitamin D and Anti-Phospholipid Antibody Syndrome: A Comprehensive Review

Roberta Gualtierotti1, 2, *, Alessio Di Giacomo3, Elena Raschi3, Maria Orietta Borghi2, 3, Pier Luigi Meroni3
1 Lupus Clinic, Department of Rheumatology and Clinical Sciences, ASST Pini-CTO, Milan, Italy
2 Department of Clinical Sciences and Community Health, University of Milan, Cardinal Ferrari, 1 20122, Milan, Italy
3 Immunorheumatology Research Laboratory, Instituto Auxologico Italiano, IRCCS, Milan, Italy

Article Metrics

CrossRef Citations:
Total Statistics:

Full-Text HTML Views: 193
Abstract HTML Views: 111
PDF Downloads: 87
ePub Downloads: 99
Total Views/Downloads: 490
Unique Statistics:

Full-Text HTML Views: 143
Abstract HTML Views: 74
PDF Downloads: 65
ePub Downloads: 72
Total Views/Downloads: 354

© 2018 Gualtierotti et al.

open-access license: This is an open access article distributed under the terms of the Creative Commons Attribution 4.0 International Public License (CC-BY 4.0), a copy of which is available at: ( This license permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

* Address correspondence to this author at the Department of Clinical Sciences and Community Health, University of Milan, Cardinal Ferrari, 1 20122, Milano, Italy; Tel: 0258296272; E-mail:


Vitamin D is a steroid hormone that exerts a variety of biological effects that range from the well-known regulation of bone metabolism to the modulation of cellular growth, of apoptosis, and the regulation of both innate and adaptive immunity. Evidence supports a correlation between low vitamin D levels and a high risk to develop chronic inflammatory diseases including autoimmune diseases.

Anti-phospholipid antibody (aPL) syndrome (APS) is an autoimmune chronic condition characterized by recurrent arterial and/or venous thrombosis and/or obstetric complications associated with persistent aPL positivity. Secondary prevention of thrombosis is widely accepted in these patients and relies on life-long anticoagulant drugs. On the contrary, primary prevention in isolated aPL positivity in healthy carriers and treatment of obstetric manifestations in APS are still debated.

Epidemiological data have shown that vitamin D deficiency (serum levels <30 ng/ml) is frequent in APS patients and that it may be associated with an increased risk of thrombosis in these patients. Experimental data show that vitamin D is able to reduce the expression of adhesion molecules, of toll-like receptors and the secretion of proinflammatory chemokines, thus playing a protective role on endothelial activation and the subsequent development of thrombosis in APS.

Although these observations need to be confirmed in prospective studies and randomized clinical trials, it is tempting to speculate that vitamin D supplementation could be very useful for the prevention of clinical manifestations in APS patients, in particular as a primary prevention countermeasure in aPL carriers.

Keywords: Anti-phospholipid syndrome, Vitamin D, Endothelial cells, Inflammation, Toll-like receptor, TLR, Adhesion molecules, IFN.


Vitamin D is a steroid hormone generated by cholesterol, exerting a wide variety of biological effects that go beyond the well-known role in the regulation of bone metabolism and calcium homeostasis [1, 2]. Vitamin D has been later recognized as responsible for many non-skeletal effects, mainly based on observational studies conducted in large cohorts showing a significant association between low levels of vitamin D (i.e., <20 ng/mL of 25-hydroxy-vitamin D) and the risk of developing cardiovascular (CV), metabolic, neoplastic and autoimmune diseases [3-6].

The biological activity of the active form of vitamin D is triggered by its interaction with the high-affinity Vitamin D Receptor (VDR), which belongs to the superfamily of nuclear hormone receptors [7, 8]. After interaction with its ligand, VDR behaves as a transcription factor binding another receptor, Retinoid X Receptor (RXR), and thus generating a heterodimeric complex that recognizes specific DNA sequences. The VDR is also found in caveoles, invaginations of the plasma membrane with high concentrations of sphingolipids and steroids. Vitamin D binds its specific receptor also at this level, but the transduction pathway of this signal is currently unknown [9]. Activation of VDR induces not only osteometabolic responses, but also a wide variety of biological effects, such as modulation of cellular growth, proliferation, apoptosis, and immune cell activation [10]. Vitamin D regulates both innate and adaptive immunity by means of VDR, which is present in almost all immune cells [2, 11-13]. Furthermore, the presence of VDR allelic polymorphisms has been associated with a major susceptibility to develop an autoimmune disease such as Systemic Lupus Erythematosus (SLE) and Rheumatoid Arthritis (RA) [14, 15].

1.1. Immunomodulatory Effects of Vitamin D

Evidence speaks in favor of a regulatory role of vitamin D both for innate and adaptive immunity [16, 17]. VDR is constitutively expressed in Antigen Presenting Cells (APC), such as macrophages and Dendritic Cells (DC), and is inducible in activated T lymphocytes [11, 18]. Vitamin D promotes a balance of innate and adaptive immunity [19] by regulating molecules related to immune activation such as MHC class II and CD40 among others and the production of Interleukin (IL)-1β, IL-6, IL-12, Tumor Necrosis Factor (TNF)-α, and Macrophage-Colony Stimulating Factor (M-CSF) [20-22]. In addition, vitamin D receptor agonists favor DC proliferation and tolerance [16].

Furthermore, vitamin D can modulate Toll Like Receptor (TLR) response to bacterial infections, with an immunosuppressive effect due to the reduction of the expression of TLR2 and TLR4 on monocytes/macrophages [23-25]. Moreover, vitamin D inhibits lipopolysaccharide (LPS)-induced TNF-α production in a concentration-dependent manner [26-28]. Vitamin D is capable of inhibiting LPS-mediated production of various inflammatory chemokines and cytokines and TLR4 and 5 signaling in myometrial smooth muscle cells; in contrast, IL-10 and TLR10 expression increases in response to treatment with vitamin D, suggesting an inhibitory role in infection-related inflammation [29]. In addition, VDR is expressed also on trophoblast cells, which are influenced by the locally synthesized 1,25(OH)2D, either in an autocrine or paracrine way [30-32]. The local synthesis of active vitamin D seems to play a key role in placental innate immunity regulation [30]. In addition, there is evidence that vitamin D exerts an anti-inflammatory role on trophoblast cells isolated both from normal and preeclampsia subjects [33, 34].

1.2. Anti-Phospholipid Antibody Syndrome (APS)

APS is characterized by arterial or venous thrombosis and/or pregnancy morbidity with persistent positivity of aPL detected by means of three formal diagnostic assays: anti-cardiolipin (aCL), anti-β2glycoprotein I (anti-β2GPI) and Lupus Anticoagulant (LA) [35-37]. The reactivity with the LA assay is mainly mediated by antibodies directed against prothrombin and β2GPI, whereas aCL positivity is mainly caused by β2GPI-dependent aPL. Despite persistent positivity of aPL antibodies, thrombotic events in patients with APS occur occasionally. Based on this clinical observation, a “two hit” hypothesis has been proposed in which the antibody (representing the first hit) induces a thrombophilic state, and the presence of another thrombophilic condition provides the second hit, triggering clotting [36].

Immunoglobulin G (IgG) from APS patients are able to induce endothelial dysfunction, monocyte and platelet activation, as well as overexpression of Tissue Factor (TF), adhesion molecules, and proinflammatory cytokines through activation of TLR4 [38, 39]. There is evidence that aPL may also activate endothelial cells via TLR2- and TLR4-mediated signaling [40, 41]. LPS is the natural ligand of TLR4 and experimental data demonstrate that LPS increases the expression of β2GPI in vascular tissues and triggers aPL-mediated thrombosis [42]. It is well known that the second hit can be provided by several triggers, such as surgery, inflammatory and infectious processes [36, 43]. In particular, the combination of a second hit plus the perturbation of endothelial cells mediated by aPL may overcome the threshold for triggering thrombosis [38, 41].

It is widely recognized that pathogenic mechanisms in obstetric APS are different from those involved in thrombotic manifestations. Intraplacental thrombosis, with subsequent impairment of maternal-fetal blood exchange, was initially suggested as the main pathogenic mechanism of aPL-induced fetal loss and heparin was introduced in the treatment of pregnant APS patients based on this assumption. Indeed, in vitro studies have shown that aPL may induce a procoagulant state at the placental level through several mechanisms [44, 45]. However, it has become clear that thrombotic mechanisms do not fully explain recurrent fetal loss in these patients, and proinflammatory rather than prothrombotic mechanisms have been advocated, such as complement activation, inhibition of trophoblast proliferation, differentiation and migration, defective angiogenesis, embryonal toxicity on preimplantation embryo, decreased production of human Chorionic Gonadotropin (hCG) and human placental lactogen, decreased expression of annexin V as well as acute placental inflammation [36, 46-55]. Furthermore, aPL have been shown to specifically destroy trophoblast, inhibit syncytium formation, halt hCG production, and limit trophoblast invasion [56, 57]. The effect of heparin in the management of patients with obstetric APS seems to be based on mechanisms of action other than anticoagulation [58, 59].

The clinical spectrum of APS actually comprises non-criteria manifestations such as APS nephropathy and Central Nervous System (CNS) symptoms (epilepsy and cognitive abnormalities). Also in this case, clinical manifestations are not fully explained by ischemic mechanisms. A direct effect of aPL on glomerular microcirculation and on neuronal cells has been proposed [60, 61].

1.3. Management of APS and Primary Prevention in aPL Carriers

Due to the risk of relapse after the first episode of thrombosis, the management of patients with APS envisages long-term anticoagulation [62]. Bleeding complications may occur as a result of anticoagulation therapy, thrombocytopenia, use of NSAIDs and congenital or acquired hemorrhagic syndromes such as the rare but possible Lupus anticoagulant-hypoprothrombinemia syndrome [63, 64]. Non-pharmacological management of APS is aimed at managing other CV risk factors such as arterial hypertension, obesity (body mass index >30 kg/m2), diabetes mellitus, smoking, active or treated cancer, use of oral contraceptives, underlying systemic autoimmune diseases and genetic hypercoagulable states [65], or venous prothrombotic factors [66].

Isolated positivity of aPL in healthy carriers is often a conundrum for clinicians. Primary prophylaxis in aPL carriers with Low Dose Aspirine (LDA) remains controversial due to the lack of relevant evidence-based data. In particular, it is unclear whether the benefits of LDA in a low-risk population may outweigh the increased risk of bleeding [67]. Based on aPL specificity and isotype, it is possible to stratify patients, with LA and triple positivity bearing the highest risk for a first thrombotic event [68]. In particular, LA raises the risk of thrombosis by approximately 4-fold [69] and aPL IgG isotype is considered clinically more meaningful compared to IgM isotype [70]. Although hydroxychloroquine has been demonstrated to reduce the risk for venous thromboembolism in SLE [71-73], and to have a CV protective effect [74], evidence is controversial for primary prevention of thrombotic events [75]. Also statins have been advocated as effective drugs for primary and secondary prevention of thrombotic events in APS, not only due to their lipid-lowering effect, but also because of their pleiotropic immunomodulatory, anti-inflammatory, and antithrombotic properties [76]. However, in the absence of sound evidence, statins cannot be recommended in APS patients in the absence of hyperlipidemia [58]. Therefore, primary prevention in aPL carriers is still an unmet need.

1.4. Endothelial Perturbation in Anti-Phospholipid Antibody Syndrome

It is widely accepted that anti-β2GPI antibodies, in the presence of β2GPI, can induce endothelial cell perturbation [77, 78]. In the past, our group has demonstrated that anti-β2GPI is able to induce a proinflammatory phenotype with up-regulation of Endothelial-Leukocyte Adhesion Molecule 1 (ELAM-1) and Intercellular Adhesion Molecule 1 (ICAM-1) [42]. Although the precise mechanism of aPL-induced activation of endothelial cells remains to be determined, TLR4 has been demonstrated to play a central role [36, 79]. More recently, other TLRs have been investigated as potentially involved in APS pathogenesis. TLR3 activation via polyinosinic:polycytidylic acid (Poly I:C) seems to enhance LPS/TLR4-induced production of Interferon (IFN) [80]. TLR9 recognizes viral and bacterial DNA, which contain unmethylated CpG dinucleotides. CpG DNA was found to exert potent proinflammatory actions, such as the expression of adhesion molecules, IL-8, and monocyte chemoattractant protein-1 in Human Endothelial Cells (HUVECs), thus facilitating leukocyte trafficking [81, 82]. Evidence suggests that aPL can also directly activate neutrophils, as a consequence of enhanced granule release, oxidative burst, and increase IL-8 production [83, 84]. After activation, adhesion to endothelial cells and transmigration, neutrophils further amplify the inflammatory process. Furthermore, after stimulation within endosomes TLRs activate transcription factors Interferon Regulatory Factor (IRF)3 or IRF7 and induce type I IFNs [85].

1.5. Vitamin D and the Anti-Phospholipid Antibody Syndrome

The role of vitamin D in immune system regulation could contribute to APS pathogenesis. To date, no data are available regarding VDR polymorphisms and APS. Vitamin D deficiency (<10–20 ng/ml) and insufficiency (<30 ng/mL) are relatively common in autoimmune diseases [86], including APS [87]. Vitamin D deficiency has been reported to be significantly correlated with arterial and venous thrombosis as well as with non-criteria APS manifestations such as neurological and ophthalmic manifestations, pulmonary hypertension, livedo reticularis and skin ulcerations in APS patients [88-90]. Similarly, in a large Swedish study an increase of 50% in the risk of venous and arterial thrombosis was observed during winter compared with other seasons, whereas a significantly lower risk of thrombosis was reported in women who were more sun-exposed [91].

Vitamin D is able to suppress the expression of TLRs such as TLR4, which is responsible for the activation of nuclear factor κB and the signaling cascade that ultimately induces a prothrombotic state in endothelial cells by aPL. Reduced expression of TLRs is accompanied by impaired nuclear factor κB translocation to the nucleus and by reduced TLR-dependent signal transduction [63]. Vitamin D can reduce TF expression induced by proinflammatory stimuli such as TNF-α or LPS on monocytes [92, 93].

Vitamin D deficiency has been linked to a three-fold increase in preeclampsia risk [94, 95]. In a cross-sectional study conducted in women with recurrent pregnancy loss, an association between low vitamin D levels and positivity for aPL was found [96]. In particular, during weeks 24-26 of pregnancy, women with low serum levels of vitamin D have significantly increased risk [97].

Vitamin D can inhibit TLR4 signaling in peripheral blood monocytes of pregnant women at risk for preeclampsia, thereby down-regulating inflammatory pathways and reducing the risk of endothelial cell damage [98]. Notably, Gysler et al. found that vitamin D, either alone or in combination with low molecular weight heparin, is able to attenuate the inflammatory response in trophoblast cells after exposure to a monoclonal murine anti-human β2GPI [99].

1.6. Vitamin D and Endothelial Perturbation in Anti-Phospholipid Syndrome

There is evidence that vitamin D is able to directly modulate endothelial perturbation due to its anti-inflammatory effect. Vitamin D was shown to reduce the expression of adhesion molecules such as ELAM-1 and ICAM-1 on endothelial cells [100]. Equils et al. found that pretreatment of human microvessel endothelial cells with vitamin D inhibited LPS-induced activation of transcription factor NF-κB and secretion of IL-8 [101]. Furthermore, a reduction of IL-8 secretion was shown in coronary artery endothelial cells [102]. Despite the well-known role of endothelial cell perturbation in APS, evidence of a direct role of vitamin D on aPL-mediated endothelial cell perturbation is still scarce. Indeed, Agmon-Levin et al reported that vitamin D is a potent inhibitor of the in vitro expression of TF in endothelial cells stimulated by anti-β2GPI antibodies derived from APS patients [88].

With this as background, we investigated the expression of ELAM-1 and ICAM-1, of TLR3 and 9, the secretion of the proinflammatory chemokine IL-8 and the expression of type I IFNs (IFN-α, IFN-β) in cultures of HUVEC pretreated with vitamin D and incubated with inflammatory stimuli such as LPS, TNF-α or anti-β2GPI IgG isolated by APS subjects. After informed consent, we recruited two subjects with high titer of anti-β2GPI and aCL IgG and IgM and with LA activity fulfilling APS 2006 criteria [35]. Polyclonal IgG from five age- and sex-matched healthy subjects were included as controls (HD). Serum IgG were isolated as as previously described [103].

ELAM-1 is one of the main endothelial activation markers whose expression is up-regulated in response to inflammatory stimuli (e.g. LPS and TNF-α) and to anti-β2GPI antibodies [104]. Overnight pre-treatment with vitamin D significantly reduced ELAM-1 expression induced by both inflammatory stimuli (LPS and TNF-α) and anti-β2GPI IgG (p<0.05) in our in vitro model. We observed no changes in ELAM-1 expression in all other experimental conditions (Fig. 1). ICAM-1 is an adhesion molecule whose expression is both constitutive and up-regulated in response to inflammatory stimuli (e.g. LPS and TNF-α) or antibodies to anti-β2GPI [104]. Overnight pre-treatment with vitamin D significantly reduced ICAM-1 transcription induced by inflammatory stimuli (LPS and TNF-α) and anti-β2GPI polyclonal IgG (p<0.05) (data not shown).

IL-8 is a proinflammatory chemokine whose secretion is up-regulated in response to inflammatory stimuli. It is one of the key regulators of leukocyte trafficking/activation in inflammation and it is also involved in tissue injury, fibrosis and angiogenesis [105]. IL-8 secretion increases in response to LPS and aPL [84]. In agreement with previous studies, we found that overnight pre-treatment with vitamin D resulted in a significant reduction of IL-8 concentration in supernatants from HUVEC cultures stimulated with LPS, Poly I:C and aPL IgG (p<0.05) (Fig. 2).

Fig. (1). ELAM-1 expression in endothelial cells treated with APS IgG and vitamin D. Overnight pretreatment with vitamin D (1α,25-dihydroxy-vitamin D3, 1,25-OH-D3; SIGMA-Aldrich - Saint Louis, MI, USA) 80 nM significantly reduced the expression of Endothelial-Leukocyte Adhesion Molecule 1 (ELAM-1) induced by inflammatory stimuli (LPS and TNF-α) and anti-β2GPI IgG. No changes were detected in all other experimental conditions. Human umbilical vein endothelial cells (HUVECs) isolated from the umbilical cord vein were cultured in E199 (Gibco-Life Technologies - Groningen, The Netherlands), supplemented with 20% heat-injected Fetal Bovine Serum (FBS, PAA-GE Healthcare - Buckinghamshire, United Kingdom) in the presence of LPS (100 ng/mL, SIGMA-Aldrich - Saint Louis, MI, USA); TNF-α (40 ng/mL, R&D Systems – Minneapolis, MN, USA); or polyclonal IgG directed against β2GPI isolated from APS patient sera and IgG (200 μg/mL) from a pool of Healthy Donor (HD) sera respectively. IgG were isolated on a protein-G-Sefarose column (HiTrap Protein G, GE Healthcare Bio-Science AB, Uppsala, Sweden) as previously described by Tincani et al (97). A cyto-ELISA monoclonal IgG murine antibody was used to detect human ELAM-1 (R&D systems - Minneapolis, MN, USA). The choice of the doses and regimens was based on previous unpublished experimental data from our laboratory.
anti-b2GPI: Anti-b2glycoprotein I; HD: Healthy Donor; LPS: lipopolysaccharide; NT: No Treatment; TNF: Tumor Necrosis Factor-alpha. (*p <0.05)

Fig. (2). IL-8 secretion in endothelial cells treated with APS IgG and vitamin D Overnight pretreatment with vitamin D (1α,25-dihydroxy-vitamin D3, 1,25-OH-D3; SIGMA-Aldrich - Saint Louis, MI, USA) 80 nM resulted in a significant reduction of upregulated levels of interleukin (IL)-8 (R&D Systems – Minneapolis, MN, USA). No significant difference was observed after treatment with Healthy Donor (HD) IgG and culture medium alone. Human Umbilical Vein Endothelial Cells (HUVECs) cultured in E199 (Gibco-Life Technologies - Groningen, The Netherlands), supplemented with 20% heat-injected Fetal Bovine Serum (FBS, PAA-GE Healthcare - Buckinghamshire, United Kingdom) in the presence of LPS (100 ng/mL, SIGMA-Aldrich - Saint Louis, MI, USA); Poly (I:C) (20 μg/mL, InvivoGen - San Diego, CA, USA); polyclonal IgG directed against β2GPI isolated from APS patient sera and HD IgG (200 μg/mL) from a pool of HD sera respectively. IgG were isolated on a protein-G-Sefarose column (HiTrap Protein G, GE Healthcare Bio-Science AB, Uppsala, Sweden) as previously described by Tincani et al., (97). The choice of the doses and regimens was based on previous unpublished experimental data from our laboratory
anti-b2GPI: anti-b2glycoprotein I, HD: Healthy Donor, IL-8: Interleukin-8, LPS: Lipopolysaccharide, NT: No Treatment, Poly (I:C): Polyinosinic:polycytidylic acid. (*p <0.05).

Both TLR3 and TLR9 are expressed on the endosomal membranes [85]. Therefore, we studied gene expression of these two receptors. The expression of TLR3 was significantly increased by Poly I:C and LPS, but not by anti-β2GPI, and was reduced by overnight pretreatment with vitamin D (p<0.05). TLR9 was up-regulated by LPS and IgG of patients with APS, but not in the presence of culture medium alone. A slight increase was found in the presence of HD IgG compared to the only culture medium. Overnight pretreatment with vitamin D resulted in increased TLR9 transcription in basal conditions, but significantly reduced receptor expression levels in the presence of LPS, anti-β2GPI IgG (p <0.01) and HD IgG (p <0.05) (data not shown).

Type I IFNs (IFN-α, IFN-β) are important mediators of the immune response that modulate the differentiation and proliferation of immune system cells and contribute to the pathogenesis of several autoimmune diseases [106]. For example, patients with SLE display high and constant levels of IFN-α, responsible for disease activity and organ damage [107, 108]. The analysis of IFN-α and IFN-β mRNA expression showed that pathological Poly I:C, LPS and IgG from APS patients resulted in a significant increase in transcription of both cytokines and a slight increase was also observed in the presence of HD IgG compared to the culture medium alone. The expression of type I IFNs was reduced after overnight pretreatment with vitamin D in all experimental conditions (p<0.01 for LPS and anti-β2GPI IgG; p<0.05 for Poly I:C and HD IgG) (data not shown).


The therapeutic role of vitamin D supplementation, including the dosage and definition of treatment targets (among which the standardization of the definition of “vitamin D deficiency”) in aPL-positive patients is still to be determined in prospective studies and randomized clinical trials.

Based on the available literature, the administration of vitamin D with a target serum level of vitamin D >30 ng/ml may be beneficial in APS patients. Vitamin D may act as a further countermeasure for secondary prevention in full-blown APS because of its ability to interfere with the prothrombotic mechanisms mediated by aPL. Inflammatory conditions, such as infectious events, may favor the occurrence of the first thrombotic event in asymptomatic aPL carriers [66, 70]. In these patients, vitamin D could provide a potential new pharmacological approach for primary prevention. Finally, its ability to interfere with the mechanisms leading to miscarriages may be useful in preventing clinical manifestations also in obstetric patients. Indeed, vitamin D supplementation should be considered in all APS patients showing vitamin D deficiency and insufficiency [62].

Our experimental data, although preliminary, are in agreement with previous reports. We used an in vitro model of endothelial cell activation with HUVEC stimulated with proinflammatory stimuli - TNF-α and TLR specific agonists such as LPS and Poly I:C - or with anti-β2GPI IgG from APS patients compared with medium culture and HD IgG. We showed that vitamin D can reduce the expression of adhesion molecules such as ELAM-1 and ICAM-1, both expressed as a consequence of an inflammatory stimulus or incubation with aPL IgG [42, 100]. Furthermore, the secretion of IL-8, a proinflammatory chemokine which increases in response to aPL and LPS and is involved in leukocyte recruitment was significantly reduced [84]. TLR9 has been involved in the pathogenesis of APS, whereas TLR3 role has never been investigated in APS pathogenesis [42, 109]. TLR9 was significantly increased both in the presence of inflammatory stimuli and IgG isolated from APS patients and was completely inhibited by pretreatment with vitamin D. Conversely, the expression of TLR3, although reduced by overnight pretreatment with vitamin D, was significantly increased by Poly I:C and LPS, but not by anti-β2GPI. Based on this observation, we assume that TLR9 may be involved in the pathogenesis of APS and could provide a possible target of vitamin D whereas TLR3 may not be directly involved in APS pathogenesis.

TLRs are able to up-regulate expression of type I IFNs; in particular IFN-α transcription is dependent on TLR9 while IFN-β depends on TLR3 and TLR4 activation [110-112]. We observed an increased gene expression of both IFN-α and IFN-β in the presence of both TLR specific agonists and IgG isolated from APS patients and a significant reduction with pretreatment with vitamin D, further confirming its anti-inflammatory effect.

Although our results are preliminary and should be validated with larger experiments and cohort studies, they further support the hypothesis that vitamin D may display a protective effect on endothelial cell perturbation in APS.


The anti-inflammatory and antithrombotic role of vitamin D is supported by epidemiological data on vitamin D deficiency in APS subjects, in particular in those with thrombotic manifestations.

It is tempting to speculate that aPL carriers, who do not have an indication for antiplatelet and anticoagulation, may benefit from vitamin D supplementation. Vitamin D may be considered in addition to standard care for obstetric and thrombotic APS patients.

Future mechanistic research should be aimed at investigating the potential effects of vitamin D in APS.


Not applicable.


The authors declare no conflict of interest, financial or otherwise.


Gruppo LES Italiano provided a grant for RG to run the Lupus Clinic


[1] Anderson PH, Vitamin D. Vitamin D activity and metabolism in bone. Curr Osteoporos Rep 2017; 15(5): 443-9.
[2] Cutolo M, Pizzorni C, Sulli A. Vitamin D endocrine system involvement in autoimmune rheumatic diseases. Autoimmun Rev 2011; 11(2): 84-7.
[3] Dobnig H, Pilz S, Scharnagl H, et al. Independent association of low serum 25-hydroxyvitamin d and 1,25-dihydroxyvitamin d levels with all-cause and cardiovascular mortality. Arch Intern Med 2008; 168(12): 1340-9.
[4] Pittas AG, Lau J, Hu FB, Dawson-Hughes B. The role of vitamin D and calcium in type 2 diabetes. A systematic review and meta-analysis. J Clin Endocrinol Metab 2007; 92(6): 2017-29.
[5] Giovannucci E, Liu Y, Rimm EB, et al. Prospective study of predictors of vitamin D status and cancer incidence and mortality in men. J Natl Cancer Inst 2006; 98(7): 451-9.
[6] Hewison M. Vitamin D and innate immunity. Curr Opin Investig Drugs 2008; 9(5): 485-90.
[7] Zehnder D, Bland R, Williams MC, et al. Extrarenal expression of 25-hydroxyvitamin d(3)-1 alpha-hydroxylase. J Clin Endocrinol Metab 2001; 86(2): 888-94.
[8] Adams JS, Hewison M. Extrarenal expression of the 25-hydroxyvitamin D-1-hydroxylase. Arch Biochem Biophys 2012; 523(1): 95-102.
[9] Huhtakangas JA, Olivera CJ, Bishop JE, Zanello LP, Norman AW. The vitamin D receptor is present in caveolae-enriched plasma membranes and binds 1 alpha,25(OH)2-vitamin D3 in vivo and in vitro. Mol Endocrinol 2004; 18(11): 2660-71.
[10] Peelen E, Knippenberg S, Muris AH, et al. Effects of vitamin D on the peripheral adaptive immune system: A review. Autoimmun Rev 2011; 10(12): 733-43.
[11] Penna G, Amuchastegui S, Giarratana N, et al. 1,25-Dihydroxyvitamin D3 selectively modulates tolerogenic properties in myeloid but not plasmacytoid dendritic cells. J Immunol 2007; 178(1): 145-53.
[12] Chen S, Sims GP, Chen XX, Gu YY, Chen S, Lipsky PE. Modulatory effects of 1,25-dihydroxyvitamin D3 on human B cell differentiation. J Immunol 2007; 179(3): 1634-47.
[13] Almerighi C, Sinistro A, Cavazza A, Ciaprini C, Rocchi G, Bergamini A. 1Alpha,25-dihydroxyvitamin D3 inhibits CD40L-induced pro-inflammatory and immunomodulatory activity in human monocytes. Cytokine 2009; 45(3): 190-7.
[14] Xiong J, He Z, Zeng X, Zhang Y, Hu Z. Association of vitamin D receptor gene polymorphisms with systemic lupus erythematosus: A meta-analysis. Clin Exp Rheumatol 2014; 32(2): 174-81.
[15] Mosaad YM, Hammad EM, Fawzy Z, et al. Vitamin D receptor gene polymorphism as possible risk factor in rheumatoid arthritis and rheumatoid related osteoporosis. Hum Immunol 2014; 75(5): 452-61.
[16] Yang CY, Leung PS, Adamopoulos IE, Gershwin ME. The implication of vitamin D and autoimmunity: A comprehensive review. Clin Rev Allergy Immunol 2013; 45(2): 217-26.
[17] Adorini L, Penna G. Control of autoimmune diseases by the vitamin D endocrine system. Nat Clin Pract Rheumatol 2008; 4(8): 404-12.
[18] Veldman CM, Cantorna MT, DeLuca HF. Expression of 1,25-dihydroxyvitamin D(3) receptor in the immune system. Arch Biochem Biophys 2000; 374(2): 334-8.
[19] Wang TT, Nestel FP, Bourdeau V, et al. Cutting edge: 1,25-dihydroxyvitamin D3 is a direct inducer of antimicrobial peptide gene expression. J Immunol 2004; 173(5): 2909-12.
[20] Boltz-Nitulescu G, Willheim M, Spittler A, Leutmezer F, Tempfer C, Winkler S. Modulation of IgA, IgE, and IgG Fc receptor expression on human mononuclear phagocytes by 1 alpha,25-dihydroxyvitamin D3 and cytokines. J Leukoc Biol 1995; 58(2): 256-62.
[21] Spittler A, Willheim M, Leutmezer F, et al. Effects of 1 alpha,25-dihydroxyvitamin D3 and cytokines on the expression of MHC antigens, complement receptors and other antigens on human blood monocytes and U937 cells: Role in cell differentiation, activation and phagocytosis. Immunology 1997; 90(2): 286-93.
[22] Sochorová K, Budinský V, Rozková D, et al. Paricalcitol (19-nor-1,25-dihydroxyvitamin D2) and calcitriol (1,25-dihydroxyvitamin D3) exert potent immunomodulatory effects on dendritic cells and inhibit induction of antigen-specific T cells. Clin Immunol 2009; 133(1): 69-77.
[23] Gambhir V, Kim J, Siddiqui S, et al. Influence of 1,25-dihydroxy vitamin D3 on TLR4-induced activation of antigen presenting cells is dependent on the order of receptor engagement. Immunobiology 2011; 216(9): 988-96.
[24] Verma R, Jung JH, Kim JY. 1,25-Dihydroxyvitamin D3 up-regulates TLR10 while down-regulating TLR2, 4, and 5 in human monocyte THP-1. J Steroid Biochem Mol Biol 2014; 141: 1-6.
[25] Sadeghi K, Wessner B, Laggner U, et al. Vitamin D3 down-regulates monocyte TLR expression and triggers hyporesponsiveness to pathogen-associated molecular patterns. Eur J Immunol 2006; 36(2): 361-70.
[26] Cohen ML, Douvdevani A, Chaimovitz C, Shany S. Regulation of TNF-alpha by 1alpha,25-dihydroxyvitamin D3 in human macrophages from CAPD patients. Kidney Int 2001; 59(1): 69-75.
[27] Giovannini L, Panichi V, Migliori M, et al. 1,25-dihydroxyvitamin D(3) dose-dependently inhibits LPS-induced cytokines production in PBMC modulating intracellular calcium. Transplant Proc 2001; 33(3): 2366-8.
[28] Takahashi K, Horiuchi H, Ohta T, Komoriya K, Ohmori H, Kamimura T. 1 alpha,25-dihydroxyvitamin D3 suppresses interleukin-1beta-induced interleukin-8 production in human whole blood: An involvement of erythrocytes in the inhibition. Immunopharmacol Immunotoxicol 2002; 24(1): 1-15.
[29] Thota C, Farmer T, Garfield RE, Menon R, Al-Hendy A. Vitamin D elicits anti-inflammatory response, inhibits contractile-associated proteins, and modulates Toll-like receptors in human myometrial cells. Reprod Sci 2013; 20(4): 463-75.
[30] Evans KN, Bulmer JN, Kilby MD, Hewison M. Vitamin D and placental-decidual function. J Soc Gynecol Investig 2004; 11(5): 263-71.
[31] Liu N, Kaplan AT, Low J, et al. Vitamin D induces innate antibacterial responses in human trophoblasts via an intracrine pathway. Biol Reprod 2009; 80(3): 398-406.
[32] Pospechova K, Rozehnal V, Stejskalova L, et al. Expression and activity of vitamin D receptor in the human placenta and in choriocarcinoma BeWo and JEG-3 cell lines. Mol Cell Endocrinol 2009; 299(2): 178-87.
[33] Díaz L, Noyola-Martínez N, Barrera D, et al. Calcitriol inhibits TNF-alpha-induced inflammatory cytokines in human trophoblasts. J Reprod Immunol 2009; 81(1): 17-24.
[34] Noyola-Martínez N, Díaz L, Avila E, Halhali A, Larrea F, Barrera D. Calcitriol downregulates TNF-α and IL-6 expression in cultured placental cells from preeclamptic women. Cytokine 2013; 61(1): 245-50.
[35] Miyakis S, Lockshin MD, Atsumi T, et al. International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). J Thromb Haemost 2006; 4(2): 295-306.
[36] Meroni PL, Borghi MO, Raschi E, Tedesco F. Pathogenesis of antiphospholipid syndrome: Understanding the antibodies. Nat Rev Rheumatol 2011; 7(6): 330-9.
[37] Giannakopoulos B, Krilis SA. The pathogenesis of the antiphospholipid syndrome. N Engl J Med 2013; 368(11): 1033-44.
[38] Lambrianides A, Carroll CJ, Pierangeli SS, et al. Effects of polyclonal IgG derived from patients with different clinical types of the antiphospholipid syndrome on monocyte signaling pathways. J Immunol 2010; 184(12): 6622-8.
[39] Kornberg A, Blank M, Kaufman S, Shoenfeld Y. Induction of tissue factor-like activity in monocytes by anti-cardiolipin antibodies. J Immunol 1994; 153(3): 1328-32.
[40] Alard JE, Gaillard F, Daridon C, Shoenfeld Y, Jamin C, Youinou P. TLR2 is one of the endothelial receptors for beta 2-glycoprotein I. J Immunol 2010; 185(3): 1550-7.
[41] Borghi MO, Raschi E, Grossi C, Chighizola CB, Meroni PL. Toll-like receptor 4 and β2 glycoprotein I interaction on endothelial cells. Lupus 2014; 23(12): 1302-4.
[42] Raschi E, Chighizola CB, Grossi C, et al. β2-glycoprotein I, lipopolysaccharide and endothelial TLR4: Three players in the two hit theory for anti-phospholipid-mediated thrombosis. J Autoimmun 2014; 55: 42-50.
[43] Shoenfeld Y, Blank M, Cervera R, Font J, Raschi E, Meroni PL. Infectious origin of the antiphospholipid syndrome. Ann Rheum Dis 2006; 65(1): 2-6.
[44] Peaceman AM, Rehnberg KA. The effect of immunoglobulin G fractions from patients with lupus anticoagulant on placental prostacyclin and thromboxane production. Am J Obstet Gynecol 1993; 169(6): 1403-6.
[45] Nayar R, Lage JM. Placental changes in a first trimester missed abortion in maternal systemic lupus erythematosus with antiphospholipid syndrome; A case report and review of the literature. Hum Pathol 1996; 27(2): 201-6.
[46] Girardi G, Berman J, Redecha P, et al. Complement C5a receptors and neutrophils mediate fetal injury in the antiphospholipid syndrome. J Clin Invest 2003; 112(11): 1644-54.
[47] Girardi G, Fraser J, Lennen R, Vontell R, Jansen M, Hutchison G. Imaging of activated complement using Ultrasmall Superparamagnetic Iron Oxide particles (USPIO): Conjugated vectors: An in vivo in utero non-invasive method to predict placental insufficiency and abnormal fetal brain development. Mol Psychiatry 2015; 20(8): 1017-26.
[48] Shamonki JM, Salmon JE, Hyjek E, Baergen RN. Excessive complement activation is associated with placental injury in patients with antiphospholipid antibodies. Am J Obstet Gynecol 2007; 196(2) :167 e1-5.
[49] Breen KA, Seed P, Parmar K, Moore GW, Stuart-Smith SE, Hunt BJ. Complement activation in patients with isolated antiphospholipid antibodies or primary antiphospholipid syndrome. Thromb Haemost 2012; 107(3): 423-9.
[50] Van Horn JT, Craven C, Ward K, Branch DW, Silver RM. Histologic features of placentas and abortion specimens from women with antiphospholipid and antiphospholipid-like syndromes. Placenta 2004; 25(7): 642-8.
[51] Berman J, Girardi G, Salmon JE. TNF-alpha is a critical effector and a target for therapy in antiphospholipid antibody-induced pregnancy loss. J Immunol 2005; 174(1): 485-90.
[52] Redecha P, Tilley R, Tencati M, et al. Tissue factor: A link between C5a and neutrophil activation in antiphospholipid antibody induced fetal injury. Blood 2007; 110(7): 2423-31.
[53] Mulla MJ, Brosens JJ, Chamley LW, et al. Antiphospholipid antibodies induce a pro-inflammatory response in first trimester trophoblast via the TLR4/MyD88 pathway. Am J Reprod Immunol 2009; 62(2): 96-111.
[54] Kwak-Kim J, Agcaoili MS, Aleta L, et al. Management of women with recurrent pregnancy losses and antiphospholipid antibody syndrome. Am J Reprod Immunol 2013; 69(6): 596-607.
[55] Pantham P, Abrahams VM, Chamley LW. The role of anti-phospholipid antibodies in autoimmune reproductive failure. Reproduction 2016; 151(5): R79-90.
[56] Rote NS, Vogt E, DeVere G, Obringer AR, Ng AK. The role of placental trophoblast in the pathophysiology of the antiphospholipid antibody syndrome. Am J Reprod Immunol 1998; 39(2): 125-36.
[57] McIntyre JA. Antiphospholipid antibodies in implantation failures. Am J Reprod Immunol 2003; 49(4): 221-9.
[58] Han CS, Mulla MJ, Brosens JJ, et al. Aspirin and heparin effect on basal and antiphospholipid antibody modulation of trophoblast function. Obstet Gynecol 2011; 118(5): 1021-8.
[59] Girardi G, Redecha P, Salmon JE. Heparin prevents antiphospholipid antibody-induced fetal loss by inhibiting complement activation. Nat Med 2004; 10(11): 1222-6.
[60] Shoenfeld Y, Meroni PL, Toubi E. Antiphospholipid syndrome and systemic lupus erythematosus: Are they separate entities or just clinical presentations on the same scale? Curr Opin Rheumatol 2009; 21(5): 495-500.
[61] Katzav A, Shoenfeld Y, Chapman J. The pathogenesis of neural injury in animal models of the antiphospholipid syndrome. Clin Rev Allergy Immunol 2010; 38(2-3): 196-200.
[62] Erkan D, Aguiar CL, Andrade D, et al. 14th International Congress on Antiphospholipid Antibodies: Task force report on antiphospholipid syndrome treatment trends. Autoimmun Rev 2014; 13(6): 685-96.
[63] Erkan D, Bateman H, Lockshin MD. Lupus anticoagulant-hypoprothrombinemia syndrome associated with systemic lupus erythematosus: Report of 2 cases and review of literature. Lupus 1999; 8(7): 560-4.
[64] Cugno M, Gualtierotti R, Tedeschi A, Meroni PL. Autoantibodies to coagulation factors: From pathophysiology to diagnosis and therapy. Autoimmun Rev 2014; 13(1): 40-8.
[65] Raso S, Sciascia S, Kuzenko A, Castagno I, Marozio L, Bertero MT. Bridging therapy in antiphospholipid syndrome and antiphospholipid antibodies carriers: Case series and review of the literature. Autoimmun Rev 2015; 14(1): 36-42.
[66] Legault KJ, Ugarte A, Crowther MA, Ruiz-Irastorza G. Prevention of recurrent thrombosis in antiphospholipid syndrome: Different from the general population? Curr Rheumatol Rep 2016; 18(5): 26.
[67] Arnaud L, Conti F, Massaro L, Denas G, Chasset F, Pengo V. Primary thromboprophylaxis with low-dose aspirin and antiphospholipid antibodies: Pro’s and Con’s. Autoimmun Rev 2017; 16(11): 1103-8.
[68] Galli M, Luciani D, Bertolini G, Barbui T. Anti-beta 2-glycoprotein I, antiprothrombin antibodies, and the risk of thrombosis in the antiphospholipid syndrome. Blood 2003; 102(8): 2717-23.
[69] de Groot PG, Lutters B, Derksen RH, Lisman T, Meijers JC, Rosendaal FR. Lupus anticoagulants and the risk of a first episode of deep venous thrombosis. J Thromb Haemost 2005; 3(9): 1993-7.
[70] Ruffatti A, Del Ross T, Ciprian M, et al. Risk factors for a first thrombotic event in antiphospholipid antibody carriers. A multicentre, retrospective follow-up study. Ann Rheum Dis 2009; 68(3): 397-9.
[71] Ruiz-Irastorza G, Egurbide MV, Pijoan JI, et al. Effect of antimalarials on thrombosis and survival in patients with systemic lupus erythematosus. Lupus 2006; 15(9): 577-83.
[72] Tektonidou MG, Laskari K, Panagiotakos DB, Moutsopoulos HM. Risk factors for thrombosis and primary thrombosis prevention in patients with systemic lupus erythematosus with or without antiphospholipid antibodies. Arthritis Rheum 2009; 61(1): 29-36.
[73] Becker-Merok A, Nossent J. Prevalence, predictors and outcome of vascular damage in systemic lupus erythematosus. Lupus 2009; 18(6): 508-15.
[74] Fasano S, Pierro L, Pantano I, Iudici M, Valentini G. Longterm hydroxychloroquine therapy and low-dose aspirin may have an additive effectiveness in the primary prevention of cardiovascular events in patients with systemic lupus erythematosus. J Rheumatol 2017; 44(7): 1032-8.
[75] Petri M. Use of hydroxychloroquine to prevent thrombosis in systemic lupus erythematosus and in antiphospholipid antibody-positive patients. Curr Rheumatol Rep 2011; 13(1): 77-80.
[76] Danesh FR, Anel RL, Zeng L, Lomasney J, Sahai A, Kanwar YS. Immunomodulatory effects of HMG-CoA reductase inhibitors. Arch Immunol Ther Exp (Warsz) 2003; 51(3): 139-48.
[77] Allen KL, Fonseca FV, Betapudi V, Willard B, Zhang J, McCrae KR. A novel pathway for human endothelial cell activation by antiphospholipid/anti-β2 glycoprotein I antibodies. Blood 2012; 119(3): 884-93.
[78] Cugno M, Borghi MO, Lonati LM, et al. Patients with antiphospholipid syndrome display endothelial perturbation. J Autoimmun 2010; 34(2): 105-10.
[79] Laplante P, Fuentes R, Salem D, et al. Antiphospholipid antibody-mediated effects in an arterial model of thrombosis are dependent on Toll-like receptor 4. Lupus 2016; 25(2): 162-76.
[80] Koch SR, Lamb FS, Hellman J, Sherwood ER, Stark RJ. Potentiation and tolerance of toll-like receptor priming in human endothelial cells. Transl Res 2017; 180(53): 53-67. e4
[81] El Kebir D, József L, Pan W, Wang L, Filep JG. Bacterial DNA activates endothelial cells and promotes neutrophil adherence through TLR9 signaling. J Immunol 2009; 182(7): 4386-94.
[82] József L, Khreiss T, El Kebir D, Filep JG. Activation of TLR-9 induces IL-8 secretion through peroxynitrite signaling in human neutrophils. J Immunol 2006; 176(2): 1195-202.
[83] Arvieux J, Jacob MC, Roussel B, Bensa JC, Colomb MG. Neutrophil activation by anti-beta 2 glycoprotein I monoclonal antibodies via Fc gamma receptor II. J Leukoc Biol 1995; 57(3): 387-94.
[84] Gladigau G, Haselmayer P, Scharrer I, et al. A role for Toll-like receptor mediated signals in neutrophils in the pathogenesis of the anti-phospholipid syndrome. PLoS One 2012; 7(7): e42176.
[85] Lee BL, Barton GM. Trafficking of endosomal Toll-like receptors. Trends Cell Biol 2014; 24(6): 360-9.
[86] Agmon-Levin N, Theodor E, Segal RM, Shoenfeld Y. Vitamin D in systemic and organ-specific autoimmune diseases. Clin Rev Allergy Immunol 2013; 45(2): 256-66.
[87] Orbach H, Zandman-Goddard G, Amital H, et al. Novel biomarkers in autoimmune diseases: Prolactin, ferritin, vitamin D, and TPA levels in autoimmune diseases. Ann N Y Acad Sci 2007; 1109: 385-400.
[88] Agmon-Levin N, Blank M, Zandman-Goddard G, et al. Vitamin D: an instrumental factor in the anti-phospholipid syndrome by inhibition of tissue factor expression. Ann Rheum Dis 2011; 70(1): 145-50.
[89] Andreoli L, Piantoni S, Dall’Ara F, Allegri F, Meroni PL, Tincani A. Vitamin D and antiphospholipid syndrome. Lupus 2012; 21(7): 736-40.
[90] Piantoni S, Andreoli L, Allegri F, Meroni PL, Tincani A. Low levels of vitamin D are common in primary antiphospholipid syndrome with thrombotic disease. Reumatismo 2012; 64(5): 307-13.
[91] Lindqvist PG, Epstein E, Olsson H. Does an active sun exposure habit lower the risk of venous thrombotic events? A D-lightful hypothesis. J Thromb Haemost 2009; 7(4): 605-10.
[92] Chung J, Koyama T, Ohsawa M, Shibamiya A, Hoshi A, Hirosawa S. 1,25(OH)(2)D(3) blocks TNF-induced monocytic tissue factor expression by inhibition of transcription factors AP-1 and NF-kappaB. Lab Invest 2007; 87(6): 540-7.
[93] Ohsawa M, Koyama T, Yamamoto K, Hirosawa S, Kamei S, Kamiyama R. 1alpha,25-dihydroxyvitamin D(3) and its potent synthetic analogs downregulate tissue factor and upregulate thrombomodulin expression in monocytic cells, counteracting the effects of tumor necrosis factor and oxidized LDL. Circulation 2000; 102(23): 2867-72.
[94] Wei SQ, Audibert F, Hidiroglou N, et al. Longitudinal vitamin D status in pregnancy and the risk of pre-eclampsia. BJOG 2012; 119(7): 832-9.
[95] Robinson CJ, Alanis MC, Wagner CL, Hollis BW, Johnson DD. Plasma 25-hydroxyvitamin D levels in early-onset severe preeclampsia. Am J Obstet Gynecol 2010; 203(4) :366 e1-6
[96] Ota K, Dambaeva S, Han AR, Beaman K, Gilman-Sachs A, Kwak-Kim J. Vitamin D deficiency may be a risk factor for recurrent pregnancy losses by increasing cellular immunity and autoimmunity. Hum Reprod 2014; 29(2): 208-19.
[97] Baker AM, Haeri S, Camargo CA Jr, Espinola JA, Stuebe AM. A nested case-control study of midgestation vitamin D deficiency and risk of severe preeclampsia. J Clin Endocrinol Metab 2010; 95(11): 5105-9.
[98] Qian L, Wang H, Wu F, Li M, Chen W, Lv L. Vitamin D3 alters Toll-like receptor 4 signaling in monocytes of pregnant women at risk for preeclampsia. Int J Clin Exp Med 2015; 8(10): 18041-9.
[99] Gysler SM, Mulla MJ, Stuhlman M, et al. Vitamin D reverses aPL-induced inflammation and LMWH-induced sFlt-1 release by human trophoblast. Am J Reprod Immunol 2015; 73(3): 242-50.
[100] Chen SF. 1 alpha, 25-Dihydroxyvitamin D3 decreased ICAM-1 and ELAM-1 expressions on pulmonary microvascular endothelial cells and neutrophil motivation. J Steroid Biochem Mol Biol 1995; 52(1): 67-70.
[101] Equils O, Naiki Y, Shapiro AM, et al. 1,25-Dihydroxyvitamin D inhibits lipopolysaccharide-induced immune activation in human endothelial cells. Clin Exp Immunol 2006; 143(1): 58-64.
[102] Kudo K, Hasegawa S, Suzuki Y, et al. 1α,25-Dihydroxyvitamin D(3) inhibits vascular cellular adhesion molecule-1 expression and interleukin-8 production in human coronary arterial endothelial cells. J Steroid Biochem Mol Biol 2012; 132(3-5): 290-4.
[103] Tincani A, Spatola L, Prati E, et al. The anti-beta2-glycoprotein I activity in human anti-phospholipid syndrome sera is due to monoreactive low-affinity autoantibodies directed to epitopes located on native beta2-glycoprotein I and preserved during species’ evolution. J Immunol 1996; 157(12): 5732-8.
[104] Betapudi V, Lominadze G, Hsi L, Willard B, Wu M, McCrae KR. Anti-β2GPI antibodies stimulate endothelial cell microparticle release via a nonmuscle myosin II motor protein-dependent pathway. Blood 2013; 122(23): 3808-17.
[105] Russo RC, Garcia CC, Teixeira MM, Amaral FA. The CXCL8/IL-8 chemokine family and its receptors in inflammatory diseases. Expert Rev Clin Immunol 2014; 10(5): 593-619.
[106] Di Domizio J, Cao W. Fueling autoimmunity: Type I interferon in autoimmune diseases. Expert Rev Clin Immunol 2013; 9(3): 201-10.
[107] Rönnblom LE, Alm GV, Oberg KE. Autoimmunity after alpha-interferon therapy for malignant carcinoid tumors. Ann Intern Med 1991; 115(3): 178-83.
[108] Eloranta ML, Lövgren T, Finke D, et al. Regulation of the interferon-alpha production induced by RNA-containing immune complexes in plasmacytoid dendritic cells. Arthritis Rheum 2009; 60(8): 2418-27.
[109] Aguilar-Valenzuela R, Nickerson K, Romay-Penabad Z. Involvement of TLR7 and TLR9 in the production of antiphospholipid antibodies. Arthritis Rheum 2011; 63(10): s281.
[110] Simons KH, Peters HAB, Jukema JW, de Vries MR, Quax PHA. A protective role of IRF3 and IRF7 signalling downstream TLRs in the development of vein graft disease via type I interferons. J Intern Med 2017; 282(6): 522-36.
[111] Crow MK. Type I interferon in the pathogenesis of lupus. J Immunol 2014; 192(12): 5459-68.
[112] Lövgren T, Eloranta ML, Kastner B, Wahren-Herlenius M, Alm GV, Rönnblom L. Induction of interferon-alpha by immune complexes or liposomes containing systemic lupus erythematosus autoantigen- and Sjögren’s syndrome autoantigen-associated RNA. Arthritis Rheum 2006; 54(6): 1917-27.