Letter | Published:

Neurotoxic autoantibodies mediate congenital cortical impairment of offspring in maternal lupus

Nature Medicine volume 15, pages 9196 (2009) | Download Citation

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Abstract

Systemic lupus erythematosus (SLE) is an autoimmune disease mediated by autoantibodies and preferentially affecting women of childbearing age. Because the offspring of mothers with SLE show a high frequency of learning disorders1,2,3,4,5, we hypothesized that maternally transferred autoantibodies that bind DNA and the N-methyl-D-aspartate receptor (NMDAR)6,7,8,9,10,11,12 could have a pathogenic role during fetal brain development. Here we describe a maternal SLE mouse model wherein pregnant dams harbored DNA-specific, NMDAR-specific autoantibodies throughout gestation. High titers of these autoantibodies in maternal circulation led to histological abnormalities in fetal brain and subsequent cognitive impairments in adult offspring. These data support a paradigm in which in utero exposure to neurotoxic autoantibodies causes abnormal brain development with long-term consequences. This paradigm may apply to multiple congenital neuropsychiatric disorders.

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Acknowledgements

The work was supported by grants from the US National Institutes of Health (B.D., P.T.H. and B.T.V.) and the Alliance for Lupus Research (B.T.V.). We are grateful to L. DeGiorgio, S. Loncar, T. Huerta and R. Berlin for technical assistance; M. Scharff, E. Chang and T. Faust for suggestions on the manuscript; and S. Jones for help in preparing the manuscript.

Author information

Author notes

    • Ji Y Lee
    •  & Patricio T Huerta

    These authors contributed equally to this study.

Affiliations

  1. Albert Einstein College of Medicine, Department of Microbiology & Immunology, 1300 Morris Park Avenue, Bronx, New York 10461, USA.

    • Ji Y Lee
    • , Czeslawa Kowal
    •  & Betty Diamond
  2. Weill Medical College of Cornell University, Department of Neurology & Neuroscience, Burke Cornell Medical Research Institute, 785 Mamaroneck Avenue, White Plains, New York 10605, USA.

    • Patricio T Huerta
    •  & Bruce T Volpe
  3. The Feinstein Institute for Medical Research, Autoimmune & Musculoskeletal Disease Center, 350 Community Drive, Manhasset, New York 11030, USA.

    • Jie Zhang
    • , Czeslawa Kowal
    • , Eva Bertini
    •  & Betty Diamond
  4. University of Genoa, Department of Experimental Medicine, Viale Benedetto XV.3, Genoa 16132, Italy.

    • Eva Bertini

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Contributions

J.Y.L. initiated this project, performed the studies of histology in E15 mice and analyzed negative geotaxis in newborn pups. P.T.H. performed all of the behavioral analyses. J.Z. generated the human monoclonal antibodies. C.K. performed all of the studies of antibody transfer to fetal brain and participated in several studies of antibody titers in immunized mice. E.B. performed the studies of immunohistology with monoclonal antibodies and peptide inhibition. B.T.V. contributed to the design of the study and performed histological analyses of adult brain. B.D. participated in the design of the studies. All authors contributed to data analysis.

Corresponding author

Correspondence to Betty Diamond.

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DOI

https://doi.org/10.1038/nm.1892

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