CD39 and CD73 activity are protective in a mouse model of antiphospholipid antibody-induced miscarriages

Anushka N. Samudra, Karen M. Dwyer, Carly Selan, Susanna Freddi, Lisa Murray-Segal, Mandana Nikpour, Michael J. Hickey, Karlheinz Peter, Simon C. Robson, Maithili Sashindranath, Peter J. Cowan, Harshal H. Nandurkar

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Objective: Antiphospholipid syndrome (APS) is a systemic autoimmune disorder of young adults associated with devastating pregnancy complications (recurrent miscarriages, preeclampsia and low birth weight) and vascular complications including thrombosis. The key components implicated in pathogenesis of APS are the complement cascade and tissue factor (TF) activity causing inflammation and coagulation. Purinergic signalling involving catabolism of ATP to adenosine by cell-surface enzymes CD39 and CD73 has anti-inflammatory and anti-thrombotic effects. We studied whether activities of CD39 and CD73 are important in preventing the development of miscarriages in APS. Methods: We studied frequency of miscarriages and decidual pathology following passive transfer of human aPL-ab to pregnant wildtype mice, and mice deficient in CD39 and CD73, and also transgenic mice exhibiting 2-3X higher CD39 activity. Results: aPL-ab infusion in pregnant CD39-or CD73-knockout mice triggers an increase in miscarriages, associated with increased TF expression and complement deposition as well as elevated oxidative stress and pro-inflammatory TNF-α and IL-10 expression within the placental decidua. In contrast, aPL-ab induced miscarriages are prevented in mice over-expressing CD39, with reduced decidual TF expression and C3d deposition, diminished lipid peroxidation (4-hydroxynonenal or 4-HNE positive lipid adducts), and reduced TNF-α expression. Conclusion: We demonstrate a protective role for CD39 in APS and provide rationale for both the development of endothelial cell-targeted soluble CD39 as a novel therapeutic for APS and analysis of perturbations in the purinergic pathway to explain human disease.

LanguageEnglish
Pages131-138
Number of pages8
JournalJournal of Autoimmunity
Volume88
DOIs
Publication statusPublished - Mar 2018

Cite this

Samudra, Anushka N. ; Dwyer, Karen M. ; Selan, Carly ; Freddi, Susanna ; Murray-Segal, Lisa ; Nikpour, Mandana ; Hickey, Michael J. ; Peter, Karlheinz ; Robson, Simon C. ; Sashindranath, Maithili ; Cowan, Peter J. ; Nandurkar, Harshal H. / CD39 and CD73 activity are protective in a mouse model of antiphospholipid antibody-induced miscarriages. In: Journal of Autoimmunity. 2018 ; Vol. 88. pp. 131-138.
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abstract = "Objective: Antiphospholipid syndrome (APS) is a systemic autoimmune disorder of young adults associated with devastating pregnancy complications (recurrent miscarriages, preeclampsia and low birth weight) and vascular complications including thrombosis. The key components implicated in pathogenesis of APS are the complement cascade and tissue factor (TF) activity causing inflammation and coagulation. Purinergic signalling involving catabolism of ATP to adenosine by cell-surface enzymes CD39 and CD73 has anti-inflammatory and anti-thrombotic effects. We studied whether activities of CD39 and CD73 are important in preventing the development of miscarriages in APS. Methods: We studied frequency of miscarriages and decidual pathology following passive transfer of human aPL-ab to pregnant wildtype mice, and mice deficient in CD39 and CD73, and also transgenic mice exhibiting 2-3X higher CD39 activity. Results: aPL-ab infusion in pregnant CD39-or CD73-knockout mice triggers an increase in miscarriages, associated with increased TF expression and complement deposition as well as elevated oxidative stress and pro-inflammatory TNF-α and IL-10 expression within the placental decidua. In contrast, aPL-ab induced miscarriages are prevented in mice over-expressing CD39, with reduced decidual TF expression and C3d deposition, diminished lipid peroxidation (4-hydroxynonenal or 4-HNE positive lipid adducts), and reduced TNF-α expression. Conclusion: We demonstrate a protective role for CD39 in APS and provide rationale for both the development of endothelial cell-targeted soluble CD39 as a novel therapeutic for APS and analysis of perturbations in the purinergic pathway to explain human disease.",
author = "Samudra, {Anushka N.} and Dwyer, {Karen M.} and Carly Selan and Susanna Freddi and Lisa Murray-Segal and Mandana Nikpour and Hickey, {Michael J.} and Karlheinz Peter and Robson, {Simon C.} and Maithili Sashindranath and Cowan, {Peter J.} and Nandurkar, {Harshal H.}",
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CD39 and CD73 activity are protective in a mouse model of antiphospholipid antibody-induced miscarriages. / Samudra, Anushka N.; Dwyer, Karen M.; Selan, Carly; Freddi, Susanna; Murray-Segal, Lisa; Nikpour, Mandana; Hickey, Michael J.; Peter, Karlheinz; Robson, Simon C.; Sashindranath, Maithili; Cowan, Peter J.; Nandurkar, Harshal H.

In: Journal of Autoimmunity, Vol. 88, 03.2018, p. 131-138.

Research output: Contribution to journalArticleResearchpeer-review

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AU - Samudra, Anushka N.

AU - Dwyer, Karen M.

AU - Selan, Carly

AU - Freddi, Susanna

AU - Murray-Segal, Lisa

AU - Nikpour, Mandana

AU - Hickey, Michael J.

AU - Peter, Karlheinz

AU - Robson, Simon C.

AU - Sashindranath, Maithili

AU - Cowan, Peter J.

AU - Nandurkar, Harshal H.

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N2 - Objective: Antiphospholipid syndrome (APS) is a systemic autoimmune disorder of young adults associated with devastating pregnancy complications (recurrent miscarriages, preeclampsia and low birth weight) and vascular complications including thrombosis. The key components implicated in pathogenesis of APS are the complement cascade and tissue factor (TF) activity causing inflammation and coagulation. Purinergic signalling involving catabolism of ATP to adenosine by cell-surface enzymes CD39 and CD73 has anti-inflammatory and anti-thrombotic effects. We studied whether activities of CD39 and CD73 are important in preventing the development of miscarriages in APS. Methods: We studied frequency of miscarriages and decidual pathology following passive transfer of human aPL-ab to pregnant wildtype mice, and mice deficient in CD39 and CD73, and also transgenic mice exhibiting 2-3X higher CD39 activity. Results: aPL-ab infusion in pregnant CD39-or CD73-knockout mice triggers an increase in miscarriages, associated with increased TF expression and complement deposition as well as elevated oxidative stress and pro-inflammatory TNF-α and IL-10 expression within the placental decidua. In contrast, aPL-ab induced miscarriages are prevented in mice over-expressing CD39, with reduced decidual TF expression and C3d deposition, diminished lipid peroxidation (4-hydroxynonenal or 4-HNE positive lipid adducts), and reduced TNF-α expression. Conclusion: We demonstrate a protective role for CD39 in APS and provide rationale for both the development of endothelial cell-targeted soluble CD39 as a novel therapeutic for APS and analysis of perturbations in the purinergic pathway to explain human disease.

AB - Objective: Antiphospholipid syndrome (APS) is a systemic autoimmune disorder of young adults associated with devastating pregnancy complications (recurrent miscarriages, preeclampsia and low birth weight) and vascular complications including thrombosis. The key components implicated in pathogenesis of APS are the complement cascade and tissue factor (TF) activity causing inflammation and coagulation. Purinergic signalling involving catabolism of ATP to adenosine by cell-surface enzymes CD39 and CD73 has anti-inflammatory and anti-thrombotic effects. We studied whether activities of CD39 and CD73 are important in preventing the development of miscarriages in APS. Methods: We studied frequency of miscarriages and decidual pathology following passive transfer of human aPL-ab to pregnant wildtype mice, and mice deficient in CD39 and CD73, and also transgenic mice exhibiting 2-3X higher CD39 activity. Results: aPL-ab infusion in pregnant CD39-or CD73-knockout mice triggers an increase in miscarriages, associated with increased TF expression and complement deposition as well as elevated oxidative stress and pro-inflammatory TNF-α and IL-10 expression within the placental decidua. In contrast, aPL-ab induced miscarriages are prevented in mice over-expressing CD39, with reduced decidual TF expression and C3d deposition, diminished lipid peroxidation (4-hydroxynonenal or 4-HNE positive lipid adducts), and reduced TNF-α expression. Conclusion: We demonstrate a protective role for CD39 in APS and provide rationale for both the development of endothelial cell-targeted soluble CD39 as a novel therapeutic for APS and analysis of perturbations in the purinergic pathway to explain human disease.

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