Mulla, Melissa J., Brosens, Jan J., Chamley, Larry W., Giles, Ian, Pericleous, Charis, Rahman, Anisur, Joyce, Shawna K., Panda, Britta, Paidas, Michael J. and Abrahams, Vikki M.. (2009) ORIGINAL ARTICLE : Antiphospholipid antibodies induce a pro-inflammatory response in first trimester trophoblast via the TLR4/MyD88 pathway. American Journal of Reproductive Immunology, Vol.62 (No.2). pp. 96-111. ISSN 10467408

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Abstract

Problem  Women with antiphospholipid antibodies (aPL) are at risk for recurrent miscarriage, pre-eclampsia, and pre-term labor. aPL target the placenta directly by binding to beta2-glycoprotein I (β2GPI) expressed on the surface of trophoblast cells. The objective of this study was to determine the effects of aPL on trophoblast function and the mechanisms involved. Method of study  First trimester trophoblast cells were treated with anti-β2GPI monoclonal antibodies and patient-derived aPL, after which cell survival and function was evaluated. Results  We report that anti-β2GPI antibodies trigger an inflammatory response in trophoblast, characterized by increased secretion of interleukin (IL)-8, MCP-1, GRO-α, and IL-1β, and that this occurs in a TLR-4/MyD88-dependent manner. At high concentrations, these antibodies also induce caspase-mediated cell death. This was attenuated upon disabling of the MyD88 pathway, suggesting that anti-β2GPI-induced inflammatory mediators compromise trophoblast survival by acting in an autocrine/paracrine manner. Enhanced IL-8, GRO-α, and IL-1β secretion also occurred when trophoblast cells were incubated with antibodies from patients with antiphospholipid syndrome. Heparin, which acts as a pro-survival factor in human trophoblast, attenuated the anti-β2GPI antibody-mediated cell death, and also the pro-inflammatory response, but only at high concentrations. Conclusion  These findings demonstrate that aPL triggers a placental inflammatory response via the TLR-4/MyD88 pathway, which in turn compromises trophoblast survival. Thus, the TLR-4/MyD88 pathway may provide a new therapeutic target to improve pregnancy outcome in antiphospholipid syndrome patients.

Item Type:	Journal Article
Subjects:	R Medicine > R Medicine (General)
Divisions:	Faculty of Medicine > Warwick Medical School > Reproductive Health Faculty of Medicine > Warwick Medical School
Journal or Publication Title:	American Journal of Reproductive Immunology
Publisher:	Wiley-Blackwell Publishing, Inc.
ISSN:	10467408
Date:	August 2009
Volume:	Vol.62
Number:	No.2
Page Range:	pp. 96-111
Identification Number:	10.1111/j.1600-0897.2009.00717.x
Status:	Peer Reviewed
Publication Status:	Published
Access rights to Published version:	Restricted or Subscription Access
URI:	http://wrap.warwick.ac.uk/id/eprint/45194

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