Interferon-alpha and angiogenic dysregulation in pregnant lupus patients destined for preeclampsia
Bibliographic record
Abstract
Pregnant patients with SLE are at increased risk of placental insufficiency and preeclampsia, disorders associated with angiogenic factor imbalance. IFNα, 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 IFNα early in pregnancy might be associated with poor pregnancy outcomes. 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 IFNα 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 IFNα and/or sFlt1, and gene expression assessed by q-RT PCR. The effect of IFNα 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. Compared with SLE patients with uncomplicated pregnancies, those with preeclampsia had increased IFNα before clinical symptoms. Nonautoimmune patients destined for preeclampsia did not have increased IFNα. In SLE patients with low IFNα, marked angiogenic imbalance (higher sFlt1, lower PlGF and higher sFlt1/PLGF ratios) precedes maternal manifestations of preeclampsia, whereas in SLE with high IFNα, preeclampsia occurs without evidence of systemic angiogenic imbalance. To investigate this result, we treated HUVEC with exogenous sFlt1 and IFNα. Treatment with sFlt1 induced the expression of sFlt1 mRNA, and IFNα 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 IFNα and sFlt1 together disrupted the ability of trophoblast cells to remodel endothelial tube structures. Our studies identify a new mechanism by which IFNα 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 IFNα may contribute to the pathogenesis of preeclampsia in some pregnant women with SLE.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.002 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".