Female mouse fetal loss mediated by maternal autoantibody

Wang, Li; Zhou, Dun; Lee, Ji; Niu, Haitao; Faust, Thomas W.; Frattini, Stephen A.; Kowal, Czeslawa; Huerta, Patricio T.; Volpe, Bruce T.; Diamond, Betty

doi:10.1084/jem.20111986

Cited by 43 publications

(55 citation statements)

References 27 publications

(40 reference statements)

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“…This is consistent with our previous analysis of OSLER data showing a substantially greater male-tofemale ratio among live offspring of mothers with SLE as compared to controls (OR 1.18 [95% CI 1.01, 1.38]) (12), although this has not yet been confirmed in a large population-based study. Our findings are supported by recent experimental evidence suggesting that a subset of anti-DNA antibodies cross-reacting with the N-methyl-D-aspartate receptors can bind brainstem neuronal receptors and induce apoptosis, resulting in a marked preferential loss of female fetuses in murine models of SLE (13).…”

Section: Discussionsupporting

confidence: 87%

Brief Report: Causes of Stillbirths in Women With Systemic Lupus Erythematosus

Vinet

Genest

Scott

et al. 2016

Arthritis & Rheumatology

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Objective. There are few precise or recent estimates of the risk or causes of stillbirths in women with systemic lupus erythematosus (SLE). Thus, we undertook the present study to examine causes of stillbirths in mothers with SLE versus those without SLE.Methods. The Offspring of SLE Mothers Registry (OSLER) is a large population-based cohort, identified through Quebec's health care databases , including all women who had ‡1 hospitalization for delivery after SLE diagnosis, and a randomly selected control group of women matched for age and year of delivery. We identified stillbirths and ascertained the cause of death as indicated on death certificates. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated, and multivariate logistic regression analysis was performed to estimate the risk of stillbirth in women with SLE versus controls.Results. In our cohort, 509 women with SLE had 729 births, including 9 stillbirths, while 5,829 matched controls had 8,541 births, including 47 stillbirths. We observed more stillbirths in mothers with SLE than in controls (1.24% versus 0.55%, difference 0.69% [95% CI 0.03, 1.88]). Women with SLE had an increased risk of stillbirth compared to controls (adjusted OR 2.13 [95% CI 1.02, 4.45]). We also observed a trend toward more stillbirths due to placenta-mediated pregnancy complications in mothers with SLE than in controls (44% [95% CI 14, 79] versus 15% [95% CI 6, 28]).Conclusion. Compared to women from the general population, women with SLE have an increased risk of stillbirth. Stillbirths in women with SLE might be more often caused by placenta-mediated pregnancy complications compared to stillbirths in mothers without SLE.It is believed that pregnant women with systemic lupus erythematosus (SLE) have an increased risk of stillbirth, although there are few precise or recent estimates of the magnitude of the effect of SLE on stillbirth risk. Observational studies of pregnant women with SLE, most retrospective in design and including a limited number of subjects, have shown a wide-ranging prevalence of stillbirths, with estimates between 1% and 3% (1). In addition, these studies have mainly been conducted in tertiary care centers, and have not directly compared stillbirths occurring in women with SLE to a general population control group.Moreover, no study to date has investigated the causes of stillbirths in women with SLE. Pregnant women with SLE have an increased risk of certain placenta-mediated complications, such as preeclampsia and small-for-gestational-age (SGA) babies, as well as an increased risk of adverse obstetric outcomes, including premature rupture of membranes and preterm births (2). There are no data on the relative importance of these events as the cause of stillbirth in SLE. Therefore, using the Offspring of SLE Mothers Registry (OSLER), we examined causes of stillbirths in mothers with SLE versus in those without SLE. PATIENTS AND METHODSStudy design and subjects. OSLER is a populationbased cohort of 728 births occurring in mothers with SLE, ...

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Section: Discussionsupporting

confidence: 87%

Brief Report: Causes of Stillbirths in Women With Systemic Lupus Erythematosus

Vinet

Genest

Scott

et al. 2016

Arthritis & Rheumatology

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“…Embryos were harvested at E15.5 and processed for sex identification (described in ref. 27) and fetal brain pathology. Additional pregnancies were allowed to reach full-term.…”

Section: Methodsmentioning

confidence: 99%

Caspr2-reactive antibody cloned from a mother of an ASD child mediates an ASD-like phenotype in mice

et al. 2016

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Autism spectrum disorder (ASD) occurs in 1 in 68 births, preferentially affecting males. It encompasses a group of neurodevelopmental abnormalities characterized by impaired social interaction and communication, stereotypic behaviors and motor dysfunction. Although recent advances implicate maternal brain-reactive antibodies in a causative role in ASD, a definitive assessment of their pathogenic potential requires cloning of such antibodies. Here, we describe the isolation and characterization of monoclonal brain-reactive antibodies from blood of women with brain-reactive serology and a child with ASD. We further demonstrate that male but not female mice exposed in utero to the C6 monoclonal antibody, binding to contactin-associated protein-like 2 (Caspr2), display abnormal cortical development, decreased dendritic complexity of excitatory neurons and reduced numbers of inhibitory neurons in the hippocampus, as well as impairments in sociability, flexible learning and repetitive behavior. Anti-Caspr2 antibodies are frequent in women with brain-reactive serology and a child with ASD. Together these studies provide a methodology for obtaining monclonal brain-reactive antibodies from blood B cells, demonstrate that ASD can result from in utero exposure to maternal brain-reactive antibodies of single specificity and point toward the exciting possibility of prognostic and protective strategies.

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“…New experimental evidence suggests that a subset of anti-DNA antibodies cross-reacting with the N-methyl-D-aspartate (NMDA) receptor can bind brainstem neuronal receptors, induce apoptosis, and result in a marked preferential loss of female fetuses in murine models of systemic lupus erythematosus (SLE) (1). Observational studies assessing the sex of offspring born to women with SLE are scant and limited by their sample size (2).…”

Section: To the Editormentioning

confidence: 99%

Increased Male‐to‐Female Ratio Among Children Born to Women With Systemic Lupus Erythematosus: Comment on the Article by Lockshin et al

Vinet¹,

Bernatsky²,

Pineau³

et al. 2013

Arthritis & Rheumatism

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New experimental evidence suggests that a subset of anti-DNA antibodies cross-reacting with the N-methyl-D-aspartate (NMDA) receptor can bind brainstem neuronal receptors, induce apoptosis, and result in a marked preferential loss of female fetuses in murine models of systemic lupus erythematosus (SLE) (1). Observational studies assessing the sex of offspring born to women with SLE are scant and limited by their sample size (2). In a recent study of 281 liveborn children of mothers with SLE, Lockshin et al did not observe an increased male-to-female ratio in offspring of antiphospholipid antibody-negative mothers with SLE compared with the general population (2). Thus, in a large population-based study, we aimed to determine the sex ratio of children born to women with SLE compared with children born to women without SLE.We identified all women with at least 1 hospitalization for a delivery (either for a stillbirth or a live birth) after SLE diagnosis, using Quebec's physician billing and hospitalization databases (from January 1, 1989 to December 31, 2009). These administrative databases capture all fee-for-service outpatient and hospital medical visits in a universal health care system within the province of Quebec, Canada (population ϳ7.5 million). Women were defined as having SLE if they had either been hospitalized at least once with an SLE diagnosis recorded prior to or at the time of delivery, or if they had at least 2 physician visits with a diagnosis of SLE, occurring 2 months to 2 years apart, up to the time of delivery. This way of defining cases of SLE has been previously shown to have high specificity (99.9%) (3). We randomly selected a general population control group, composed of women matched at least 4:1 for age and year of delivery, who had not been diagnosed as having SLE prior to or at the time of delivery.Quebec's administrative databases contain valid data on the sex of newborns (4), which we used to calculate the male-to-female ratios for all births occurring in SLE patients and in non-SLE subjects. We performed multivariate logistic regression analysis, with the offspring's sex as the dependent variable, adjusting for the potential effect of preeclampsia (previously shown to increase the male-to-female ratio in the general population [5]) and race/ethnicity. As administrative databases do not provide data on antibody profiles (i.e., anti-DNA antibodies) and as anti-NMDA receptor antibodies are not commercially available, we could not assess the independent effect of autoantibodies on the sex of the offspring.Among this population, 512 women with SLE had 729 births after diagnosis, while 5,836 matched control women had 8,541 births. In unadjusted estimates, the male-to-female ratio was higher among children born to women with SLE (odds ratio [OR] 1.26, 95% confidence interval [95% CI] 1.09-1.46) versus controls (OR 1.06, 95% CI 1.02-1.11), resulting in an unadjusted OR of 1.18 (95% CI 1.01-1.38). In multivariate analysis with adjustment for the effect of preeclampsia and race/ethnicity, wo...

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Female mouse fetal loss mediated by maternal autoantibody

Abstract: In mouse models of systemic lupus erythematosus, antibodies that cross-react with double-stranded DNA and the NR2A subunit of the NMDAR cause apoptosis of NR2A-expressing neurons within the brainstem of developing female fetuses, resulting in a gender bias.

Cited by 43 publications

References 27 publications

Brief Report: Causes of Stillbirths in Women With Systemic Lupus Erythematosus

Brief Report: Causes of Stillbirths in Women With Systemic Lupus Erythematosus

Caspr2-reactive antibody cloned from a mother of an ASD child mediates an ASD-like phenotype in mice

Increased Male‐to‐Female Ratio Among Children Born to Women With Systemic Lupus Erythematosus: Comment on the Article by Lockshin et al

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