Female mouse fetal loss mediated by maternal autoantibody

Systemic lupus erythematosus (SLE), a disease of women during childbearing years, is characterized by the production of double-stranded DNA antibodies. A subset of these antibodies, present in 40% of patients, cross-reacts with the NR2A and NR2B subunits of the N-methyl-d-aspartate receptor (NMDAR)....

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Published inThe Journal of experimental medicine Vol. 209; no. 6; pp. 1083 - 1089
Main Authors Wang, Li, Zhou, Dun, Lee, Ji, Niu, Haitao, Faust, Thomas W, Frattini, Stephen, Kowal, Czeslawa, Huerta, Patricio T, Volpe, Bruce T, Diamond, Betty
Format Journal Article
LanguageEnglish
Published United States The Rockefeller University Press 04.06.2012
Subjects
Animals
Animals, Newborn
Antibodies, Antinuclear - immunology
Apoptosis - genetics
Apoptosis - immunology
Autoantibodies - immunology
Brain - embryology
Brain - pathology
Brief Definitive Report
Female
Fetal Death - immunology
Gene Expression Regulation, Developmental
Humans
Lupus Erythematosus, Systemic - immunology
Male
Mice
Mice, Inbred BALB C
Neurons - immunology
Oligopeptides - immunology
Oligopeptides - pharmacology
Pregnancy
Receptors, N-Methyl-D-Aspartate - genetics
Sex Factors
Sex Ratio
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Summary:Systemic lupus erythematosus (SLE), a disease of women during childbearing years, is characterized by the production of double-stranded DNA antibodies. A subset of these antibodies, present in 40% of patients, cross-reacts with the NR2A and NR2B subunits of the N-methyl-d-aspartate receptor (NMDAR). In this study, we show that, in mouse models, these antibodies cause a loss of female fetus viability by inducing apoptosis of NR2A-expressing neurons within the brainstem late in fetal development; gender specificity derives from a time-dependent increased expression of NR2A in female brainstem or increased vulnerability of female fetal neurons to signaling through NR2A-containing NMDARs. This paradigm is consistent with available data on the sex ratio of live births of women with SLE. It represents a novel mechanism by which maternal autoantibodies can severely affect fetal health in a gender-specific fashion and raises the question of how many maternal antibodies affect brain development or exhibit gender-specific fetal effects.
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B.T. Volpe and B. Diamond contributed equally to this paper.
ISSN:0022-1007
1540-9538
DOI:10.1084/jem.20111986