Significance of Anti-Phosphatidylethanolamine Antibodies in the Pathogenesis of Recurrent Pregnancy Loss

Yonezawa, Mirei; Kuwabara, Yoshimitsu; Ono, Sachiko; Ouchi, Noriaki; Ichikawa, Tomoko; Takeshita, Toshiyuki

doi:10.1007/s43032-020-00208-4

Cited by 12 publications

(6 citation statements)

References 15 publications

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“…In an earlier study, patients with APS who tested positive for anti-PE antibody showed high granulysin levels, and when this persisted for more than 12 weeks, the miscarriage rate was found to be high [50]. PE is an anti-in ammatory lipid [51]; therefore, anti-PE antibody-positive patients may show higher levels of in ammation, increased immune activity (including granulysin production), and a higher risk of miscarriage.…”

Section: Discussionmentioning

confidence: 96%

Upregulated Serum Granulysin Levels in Women With Antiphospholipid Syndrome-Associated Recurrent Miscarriages Are Downregulated by Heparin Treatment

Ichikawa

Negishi

Kasano

et al. 2021

Preprint

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Background Antiphospholipid antibody syndrome is the major cause of recurrent pregnancy loss (RPL) and associated with inflammation. Granulysin is a cytotoxic protein secreted by cytotoxic T cells, natural killer cells, and natural killer T cells that is present in abundance in the decidua. It activates innate and cellular immunity simultaneously, and also induces miscarriage. As a treatment, heparin is widely used for the patients with RPL, and exhibits the antithrombotic and anti-inflammatory activities, and angiogenesis. Methods We hypothesized that granulysin is an important factor in inducing miscarriage. Here, we evaluated the changes of serum granulysin level before and 1 week after the commencement of heparin treatment for the patients with RPL. Results The serum granulysin levels before heparin treatment were significantly higher in women who tested positive for one or more types of antiphospholipid antibody (2.75 ± 1.03 vs. 2.44 ± 0.69; P = 0.0341 by Welch’s t-test), particularly anti-phosphatidylethanolamine antibodies (IgG: 2.98 ± 1.09 vs. 2.51 ± 0.86; P = 0.0013, IgM: 2.85 ± 1.09 vs. 2.47 ± 0.77; P = 0.0024 by Welch’s t-test). After heparin treatment for 1 week, the serum granulysin levels were reduced significantly (P = 0.0017 by paired t-test). The miscarriage rate was significantly higher in women whose serum granulysin levels were not reduced by heparin treatment (P = 0.0086 by Fisher’s exact probability test). Conclusions These results suggest that heparin may reduce the incidence of miscarriages by suppressing the serum granulysin levels.

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Section: Discussionmentioning

confidence: 96%

Upregulated Serum Granulysin Levels in Women With Antiphospholipid Syndrome-Associated Recurrent Miscarriages Are Downregulated by Heparin Treatment

Ichikawa

Negishi

Kasano

et al. 2021

Preprint

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“…Previous studies have shown that aPE occurs signi cantly more frequently in unexplained early fetal loss patients than in explained early fetal loss patients or in healthy women [14]. There is increasing evidence that aPE is a higher independent risk factor for unexplained fetal loss than aCL or aβ2GPI antibodies [15][16][17]. The pathogenic role of aPE in pregnancy complications may be related to a signi cant increase in placenta cell apoptosis [14].…”

Section: Discussionmentioning

confidence: 99%

“Non-criteria” antiphospholipid antibodies aid risk stratification in autoimmune recurrent pregnancy loss

Zhao

Huang

et al. 2023

Preprint

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Recurrent pregnancy loss (RPL) is a serious pregnancy disease caused by a variety of factors. Obstetric antiphospholipid syndrome (OAPS) is the most prevalent treatable cause of RPL. Although some RPL patients do not meet the diagnosis of OAPS, they may benefit from the standard treatment of OAPS. However, the diagnosis and treatment of these patients are controversial. To evaluate the value of “non-criteria” antiphospholipid antibodies (aPLs) in RPL patients, and to assess whether RPL patients with “criteria”/ “non-criteria” aPL positivity could benefit from treatment with low-molecular-weight heparin (LMWH) and low-dose aspirin (LDA), we profiled five “criteria” and ten “non-criteria” aPLs, namely LA, aCL IgG/M, aβ2GPI IgG/M, aPS/PT IgG/M, aANXA5, aANXA2, aVIM, aβ2GPI-D1, aPE, aPI IgG/M, aPS IgG, in 11 OAPS, 65 “non-criteria” OAPS (NOAPS), 31 OAPS carrier, 90 connective tissue disease-RPL (CTD-RPL), 75 unexplained RPL (URPL), 45 thrombotic APS (TAPS) patients, and 81 healthy controls (HCs). Our results showed that aPS/PT IgG/M, aANXA5, aANXA2, aVIM, aβ2GPI-D1, aPE, aPI IgG/M, and aPS IgG were associated with RPL. We found that aPS/PT IgG was positively correlated with the number of “criteria” aPL positivity in APS patients. Importantly, “non-criteria” aPL-positive RPL patients could benefit from the treatment with LMWH and LDA. Combined aPE, aANXA2, aVIM, and aβ2GPI-D1 could distinguish OAPS, NOAPS, OAPS carrier, CTD-RPL, and URPL group from HCs. Our study demonstrates the utility of “non-criteria” aPLs in identifying RPL women with clinical features of OAPS, which is expected to provide tailored treatment management for RPL patients and ultimately improve obstetric outcomes.

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“…In an earlier study, patients with APS who tested positive for anti‐PE antibodies showed high granulysin levels, and when this persisted for more than 12 weeks, the miscarriage rate was found to be high. 45 PE is an anti‐inflammatory lipid 46 ; therefore, anti‐PE antibody‐positive patients may show higher levels of inflammation, increased immune activity (including granulysin production), and a higher risk of miscarriage. The mechanism by which heparin reduces granulysin levels in anti‐PE antibody‐positive patients is unclear.…”

Section: Discussionmentioning

confidence: 99%

Upregulated serum granulysin levels in women with antiphospholipid antibody‐associated recurrent miscarriage are downregulated by heparin treatment

Ichikawa

Negishi

Kasano

et al. 2022

Reprod Medicine & Biology

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Purpose Granulysin is a cytotoxic protein that simultaneously activates innate and cellular immunity. The authors aimed to evaluate whether granulysin is associated with the antiphospholipid antibody syndrome and whether heparin changes the granulysin levels. Methods A cohort study was performed with women with antiphospholipid antibody‐positive recurrent pregnancy loss (RPL). The authors examined granulysin levels under RPL and evaluated the changes in serum granulysin levels before and 1 week after the commencement of heparin treatment. Results Serum granulysin levels before heparin treatment were significantly higher in women who tested positive for one or more types of antiphospholipid antibodies (2.75 ± 1.03 vs. 2.44 ± 0.69, p = 0.0341 by Welch's t test), particularly anti‐phosphatidylethanolamine antibodies (IgG: 2.98 ± 1.09 vs. 2.51 ± 0.86, p = 0.0013; IgM: 2.85 ± 1.09 vs. 2.47 ± 0.77, p = 0.0024 by Welch's t test). After heparin treatment for 1 week, serum granulysin levels were significantly reduced ( p = 0.0017 by the paired t test). The miscarriage rate was significantly higher in women whose serum granulysin levels were not reduced by heparin treatment ( p = 0.0086 by Fisher's exact probability test). Conclusion The results suggest that heparin may reduce the incidence of miscarriage by suppressing serum granulysin levels.

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Significance of Anti-Phosphatidylethanolamine Antibodies in the Pathogenesis of Recurrent Pregnancy Loss

Cited by 12 publications

References 15 publications

Upregulated Serum Granulysin Levels in Women With Antiphospholipid Syndrome-Associated Recurrent Miscarriages Are Downregulated by Heparin Treatment

Upregulated Serum Granulysin Levels in Women With Antiphospholipid Syndrome-Associated Recurrent Miscarriages Are Downregulated by Heparin Treatment

“Non-criteria” antiphospholipid antibodies aid risk stratification in autoimmune recurrent pregnancy loss

Upregulated serum granulysin levels in women with antiphospholipid antibody‐associated recurrent miscarriage are downregulated by heparin treatment

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