Antiphospholipid antibodies induce a pro-inflammatory response in first trimester trophoblast via the TLR4/MyD88 pathway.

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 beta(2)-glycoprotein I (beta(2)GPI) 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-beta(2)GPI monoclonal antibodies and patient-derived aPL, after which cell survival and function was evaluated.

RESULTS:

We report that anti-beta(2)GPI antibodies trigger an inflammatory response in trophoblast, characterized by increased secretion of interleukin (IL)-8, MCP-1, GRO-alpha, and IL-1beta, 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-beta(2)GPI-induced inflammatory mediators compromise trophoblast survival by acting in an autocrine/paracrine manner. Enhanced IL-8, GRO-alpha, and IL-1beta 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-beta(2)GPI 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.

• Authors: Melissa J Mulla, Jan J Brosens, Larry W Chamley, Ian Giles, Charis Pericleous, Anisur Rahman, Shawna K Joyce, Britta Panda, Michael J Paidas, Vikki M Abrahams
• Journal: American journal of reproductive immunology (New York, N.Y. : 1989) (Am J Reprod Immunol) Vol. 62 Issue 2 Pg. 96-111 (Aug 2009) ISSN: 1600-0897 [Electronic] Denmark
• PMID: 19614626 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies, Antiphospholipid
• Antibodies, Monoclonal
• CXCL1 protein, human
• Chemokine CXCL1
• Cytokines
• MYD88 protein, human
• Myeloid Differentiation Factor 88
• TLR4 protein, human
• Toll-Like Receptor 4
• beta 2-Glycoprotein I
• Heparin

Topics

• Adult
• Aged
• Antibodies, Antiphospholipid (immunology)
• Antibodies, Monoclonal (immunology)
• Antiphospholipid Syndrome (immunology)
• Apoptosis
• Cell Line
• Cell Survival (drug effects, physiology)
• Cells, Cultured
• Chemokine CXCL1 (metabolism)
• Cytokines (drug effects, metabolism)
• Female
• Heparin (immunology, metabolism)
• Humans
• Inflammation (immunology)
• Middle Aged
• Myeloid Differentiation Factor 88 (metabolism)
• Pregnancy
• Pregnancy Trimester, First (immunology)
• Toll-Like Receptor 4 (metabolism)
• Trophoblasts (immunology)
• beta 2-Glycoprotein I (immunology)