Effects of anti‐β2‐GPI antibodies on cytokine production in normal first‐trimester trophoblast cells

Azuma, Hiromitsu; Yamamoto, Tatsuo; Chishima, Fumihisa

doi:10.1111/jog.12993

Cited by 4 publications

(5 citation statements)

References 23 publications

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“…Serum IL-8 levels were also higher in those with severe versus mild pre-eclampsia (29). Although we saw no correlation of aPL with pregnancy morbidity in our patients, recent in-vitro studies have shown that aPL can induce IL-8 and IL-6 secretion in trophoblasts (30). Vitamin D treatment alone or in combination with low molecular weight heparin has also been shown to attenuate the aPL-mediated proinflammatory response in trophoblast cultures (31).…”

Section: Discussioncontrasting

confidence: 86%

“…29 Although we saw no correlation of aPL with pregnancy morbidity in our patients, recent in vitro studies have shown that aPL can induce IL-8 and IL-6 secretion in trophoblasts. 30 Vitamin D treatment alone or in combination with low molecular weight heparin has also been shown to attenuate the aPL-mediated proinflammatory response in trophoblast cultures. 31 It should be noted, however, that while currently available clinical evidence indicates no association between hypovitaminosis D and obstetric APS manifestations, a recent cross-sectional study of women with recurrent pregnancy loss reported an association between low vitamin D levels and increased odds of positive aPL.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Clinical associations of proinflammatory cytokines, oxidative biomarkers and vitamin D levels in systemic lupus erythematosus

Smikle

DeCeulaer

Romay-Penabad³

et al. 2017

Lupus

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Background The abnormal biological activity of cytokines plays an important role in the pathophysiology of both systemic lupus erythematosus (SLE) and antiphospholipid syndrome (APS). Several studies have highlighted the association of vitamin D and certain pro-inflammatory cytokines with disease activity in SLE. However, there are limited data on the association of vitamin D and antiphospholipid antibodies (aPL) with various proinflammatory biomarkers in these patients and their relative impact on clinical outcomes. Methods The serum levels of several aPL, 25-hydroxy vitamin D, pro-inflammatory cytokines including IFNα, IL-1β, IL-6, IL-8, IP10, sCD40L, TNFα and VEGF were measured in 312 SLE patients from the Jamaican (n-=45) and Hopkins (n=267) Lupus cohorts using commercial Milliplex and ELISA assays. Oxidized LDL/β2glycoprotein antigenic complexes (oxLβ2Ag) and their associated antibodies were also measured in the Jamaican cohort. Healthy controls for oxidative marker and cytokine testing were utilized. Results Abnormally low vitamin D levels were present in 61.4% and 73.3% of Hopkins and Jamaican SLE patients respectively. Median concentrations of IP10, TNFα, sCD40L and VEGF were elevated in both cohorts, oxLβ2Ag and IL-6 were elevated in the Jamaican cohort and IFNα, IL-1β and IL-8 were the same or lower in both cohorts compared to controls. IP10 and VEGF were independent predictors of disease activity, aPL, IP10 and IL-6 were independent predictors of thrombosis and IL-8 and low vitamin D were independent predictors of pregnancy morbidity despite there being no association of vitamin D with pro-inflammatory cytokines. Conclusions Our results indicate that aPL-mediated pro-inflammatory cytokine production is likely a major mechanism of thrombus development in SLE patients. We provide presumptive evidence of the role IL-8 and hypovitaminosis D play in obstetric pathology in SLE but further studies are required to characterize the subtle complexities of vitamin D’s relationship with cytokine production and disease activity in these patients.

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Section: Discussioncontrasting

confidence: 86%

Section: Discussionmentioning

confidence: 99%

Clinical associations of proinflammatory cytokines, oxidative biomarkers and vitamin D levels in systemic lupus erythematosus

Smikle

DeCeulaer

Romay-Penabad³

et al. 2017

Lupus

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“…Studies of obstetric APS have also yielded mixed results with an older study demonstrating no role for TLR4 in an in vivo model of pregnancy loss [35]. In contrast, Azuma and colleagues recently suggested that, at least in vitro, TLR2 and TLR4 facilitate inflammatory cytokine production by trophoblast cells in response to anti-β 2 GPI antibodies [36]. …”

Section: Cell Activation and Signaling Pathways: New Conceptsmentioning

confidence: 99%

Antiphospholipid syndrome: an update for clinicians and scientists

Vreede

Bockenstedt

Knight

2017

Current Opinion in Rheumatology

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Purpose of review Antiphospholipid syndrome (APS) is a leading acquired cause of thrombosis and pregnancy loss. Upon diagnosis (which is not made until at least one morbid event has occurred), anticoagulant medications are typically prescribed in an attempt to prevent future events. This approach is not uniformly effective and does not prevent associated autoimmune and inflammatory complications. The goal of this review is to update clinicians and scientists on mechanistic and clinically-relevant studies from the past 18 months, which have especially focused on inflammatory aspects of APS pathophysiology. Recent findings How antiphospholipid antibodies leverage receptors and signaling pathways to activate cells are being increasingly defined. While established mediators of disease pathogenesis (like endothelial cells and the complement system) continue to receive intensive study, emerging concepts (such as the role of neutrophils) are also receiving increasing attention. In vivo animal studies and small clinical trials are demonstrating how repurposed medications (hydroxychloroquine, statins, rivaroxaban) may have clinical benefit in APS, with these concepts importantly supported by mechanistic data. Summary As anticoagulant medications are not uniformly effective and do not comprehensively target the underlying pathophysiology of APS, there is a continued need to reveal the inflammatory aspects of APS, which may be modulated by novel and repurposed therapies.

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“…When the antiphospholipid antibody binds to β 2 GPI, the antibody complex interacts with a number of receptors, like annexin A2, Toll‐like receptor family, glycoprotein Ibα, low‐density lipoprotein receptor‐related protein 8 and low‐density lipoprotein receptor family. The result is the activation of endothelial cells, platelets, monocytes, 7 and trophoblasts 8,9 . The inflammation and clotting that follow could lead to vascular thrombosis or pregnancy‐related complications 10,11 …”

Section: Introductionmentioning

confidence: 99%

“…The result is the activation of endothelial cells, platelets, monocytes, 7 and trophoblasts. 8,9 The inflammation and clotting that follow could lead to vascular thrombosis or pregnancyrelated complications. 10,11 On β 2 GPI, the domain I is the antigenic epitope specifically bound by the antiphospholipid antibody.…”

Section: Introductionmentioning

confidence: 99%

Cardiolipin interacts with beta‐2‐glycoprotein I and forms an open conformation–Mechanisms analyzed using hydrogen/deuterium exchange

Tang

Chen

et al. 2021

Protein Science

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Beta‐2‐glycoprotein I (β2GPI) is the major antigen for the antiphospholipid antibodies in the antiphospholipid syndrome. The exposed epitope in domain I of β2GPI can be recognized by the anti‐β2GPI antibody. Here, we prepared the anionic di‐oleoyl‐phosphatidylserine (DOPS) and cardiolipin (CL) liposomes to interact with the β2GPI. The conformational changes of β2GPI upon binding with the liposomes were analyzed using hydrogen/deuterium exchange mass spectrometry. The exchange level of sequences 21–27 significantly increased after β2GPI had interacted with DOPS. This change indicated a reduced interaction between domain I and domain V, inferring to a protrusion of the sequences 21–27 from the ring conformation. After β2GPI had interacted with CL for 30 min, the exchange levels in 4 of the 5 domains increased significantly. The deuteration levels of sequences 1–20, 21–27, 196–205, 273–279 and 297–306 increased, suggesting that these regions had become more exposed, and the domain I was no longer in contact with domain V. The increasing deuteration levels in sequences 70–86, 153–162, 191–198, 196–205 and 273–279 indicated β2GPI undergoing conformational changes to expose these inner regions, suggesting a structural transition. Overall, DOPS and CL induced minor conformational changes of β2GPI at sequences 21–27 and forms an intermediate conformation after 10 min of interaction. After a complete protein–lipid interaction, high negatively charged CL membrane induced a major conformation transition of β2GPI.

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Effects of anti‐β2‐GPI antibodies on cytokine production in normal first‐trimester trophoblast cells

Abstract: We suspect that aβ2-GPIAb might increase cytokine production by binding to TLR2 or TLR4. The increased cytokine production in response to aβ2-GPIAb might play a role in the increased inflammatory response in the placenta.

Cited by 4 publications

References 23 publications

Clinical associations of proinflammatory cytokines, oxidative biomarkers and vitamin D levels in systemic lupus erythematosus

Clinical associations of proinflammatory cytokines, oxidative biomarkers and vitamin D levels in systemic lupus erythematosus

Antiphospholipid syndrome: an update for clinicians and scientists

Cardiolipin interacts with beta‐2‐glycoprotein I and forms an open conformation–Mechanisms analyzed using hydrogen/deuterium exchange

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