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Abstract Number: 872

Interferon-α and Angiogenic Dysregulation in Pregnant Lupus Patients Destined for Preeclampsia

Danieli Andrade1, Mimi Kim2, Luz P. Blanco3, S. Ananth Karumanchi4, Gloria Koo5, Patricia M. Redecha6, Kyriakos A. Kirou1, Angela M. Alvarez7, Melissa J. Mulla7, Mary K. Crow8, Vikki Abrahams7, Mariana J. Kaplan3 and Jane E. Salmon9, 1Hospital for Special Surgery, New York, NY, 2Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY, 3Systemic Autoimmunity Branch, Intramural Research Program, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, 4Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, 5Autoimmunity & Inflammation, Hospital for Special Surgery, New York, NY, 6Rheumatology Research, Hospital for Special Surgery, New York, NY, 7Yale School of Medicine, New Haven, CT, 8Department of Medicine, Hospital for Special Surgery, New York, NY, 9Rheumatology, Hospital for Special Surgery, New York, NY

Meeting: 2014 ACR/ARHP Annual Meeting

Keywords: interferons, pregnancy and vasculogenesis, SLE

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Session Information

Session Title: Systemic Lupus Erythematosus - Human Etiology and Pathogenesis I: Pathways of Inflammation/Injury

Session Type: Abstract Submissions (ACR)

Background/Purpose: Pregnant patients with SLE are at increased risk of placental insufficiency and preeclampsia, disorders associated with angiogenic factor imbalance. IFN-α, a critical element in SLE pathogenesis, is a potent antiangiogenic factor.  In a case-control longitudinal study of lupus pregnancies from PROMISSE (Predictors of Pregnancy Outcome: Biomarkers In Antiphospholipid Antibody Syndrome and Systemic Lupus Erythematosus), we investigated whether elevated IFN-α early in pregnancy might be associated with poor pregnancy outcomes.

Methods: Each of 28 SLE patients with poor pregnancy outcome was matched to an SLE patient with an uncomplicated pregnancy and to a pregnant healthy control. Serum samples obtained monthly through pregnancy were assayed for IFN-α activity using a reporter cell assay, and for antiangiogenic factor, sFlt1, and proangiogenic factor, placenta growth factor (PlGF).  Human umbilical vein endothelial cells (HUVEC) were cultured in the presence of IFN-α and/or sFlt1, and gene expression assessed by q-RT PCR. The effect of IFN-α and sFlt1 on endothelial-trophoblast interactions was assessed in an in vitro model of spiral artery transformation in which the capacity of human first trimester extravillous trophoblasts to stabilize endometrial endothelial cell tube structures is measured.

Results: Compared to SLE patients with uncomplicated pregnancies, those with preeclampsia had increased IFN-α before clinical symptoms. Non-autoimmune patients destined for preeclampsia did not have increased IFN-α. In SLE patients with low IFN-α, marked angiogenic imbalance (higher sFlt1, lower PlGF and higher sFlt1/PLGF ratios) precedes maternal manifestations of preeclampsia, whereas in SLE with high IFN-α, preeclampsia occurs without evidence of systemic angiogenic imbalance.  To investigate this result, we treated HUVEC with exogenous sFlt1 and IFN-α.  Treatment with sFlt1 induced the expression of sFlt1 mRNA, and IFN-α dramatically amplified the endothelial response to sFlt1, leading to a local positive feedback loop.  Furthermore, in an in vitro  model of spiral artery transformation, only IFN-α and sFlt1 together disrupted the ability of trophoblast cells to remodel endothelial tube structures.

Conclusion: Our studies identify a new mechanism by which IFN-α induces an antiangiogenic milieu in the vasculature leading to inadequate spiral artery remodeling and poor placentation early in pregnancy and maternal endothelial dysfunction presenting as preeclampsia later in pregnancy. They suggest that elevated IFN-α may contribute to the pathogenesis of preeclampsia in some pregnant women with SLE.


Disclosure:

D. Andrade,
None;

M. Kim,
None;

L. P. Blanco,
None;

S. A. Karumanchi,

Aggamin Pharmaceuticals,

1,

Thermofisher,

2,

Siemens Diagnostics,

5,

Beth Israel Deaconness Medical Center,

7;

G. Koo,
None;

P. M. Redecha,
None;

K. A. Kirou,
None;

A. M. Alvarez,
None;

M. J. Mulla,
None;

M. K. Crow,
None;

V. Abrahams,
None;

M. J. Kaplan,
None;

J. E. Salmon,
None.

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