Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

Neurotoxic autoantibodies mediate congenital cortical impairment of offspring in maternal lupus

Nature Medicine volume 15, pages 91–96 (2009)Cite this article

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.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: MP brains exposed to maternal NMDAR-specific autoantibodies in utero show morphological abnormalities at E15.
Figure 2: Morphological abnormalities in E15 brains exposed to murine anti-NMDAR autoantibodies in utero.
Figure 3: Morphological abnormalities in E15 brains exposed to human lupus NMDAR-specific autoantibodies in utero.
Figure 4: Congenital impairments in neonatal reflexes and cognitive tasks.

Similar content being viewed by others

References

  1. Lahita, R.G. Systemic lupus erythematosus: learning disability in the male offspring of female patients and relationship to laterality. Psychoneuroendocrinology 13, 385–396 (1988).

    Article  CAS  Google Scholar 

  2. McAllister, D.L. et al. The influence of systemic lupus erythematosus on fetal development: cognitive, behavioral, and health trends. J. Int. Neuropsychol. Soc. 3, 370–376 (1997).

    CAS  PubMed  Google Scholar 

  3. Neri, F. et al. Neuropsychological development of children born to patients with systemic lupus erythematosus. Lupus 13, 805–811 (2004).

    Article  CAS  Google Scholar 

  4. Ross, G., Sammaritano, L., Nass, R. & Lockshin, M. Effects of mothers' autoimmune disease during pregnancy on learning disabilities and hand preference in their children. Arch. Pediatr. Adolesc. Med. 157, 397–402 (2003).

    Article  Google Scholar 

  5. Tincani, A. et al. Impact of in utero environment on the offspring of lupus patients. Lupus 15, 801–807 (2006).

    Article  CAS  Google Scholar 

  6. DeGiorgio, L.A. et al. A subset of lupus anti-DNA antibodies cross-reacts with the NR2 glutamate receptor in systemic lupus erythematosus. Nat. Med. 7, 1189–1193 (2001).

    Article  CAS  Google Scholar 

  7. Kowal, C. et al. Human lupus autoantibodies against NMDA receptors mediate cognitive impairment. Proc. Natl. Acad. Sci. USA 103, 19854–19859 (2006).

    Article  CAS  Google Scholar 

  8. Yoshio, T., Onda, K., Nara, H. & Minota, S. Association of IgG anti-NR2 glutamate receptor antibodies in cerebrospinal fluid with neuropsychiatric systemic lupus erythematosus. Arthritis Rheum. 54, 675–678 (2006).

    Article  CAS  Google Scholar 

  9. Omdal, R. et al. Neuropsychiatric disturbances in SLE are associated with antibodies against NMDA receptors. Eur. J. Neurol. 12, 392–398 (2005).

    Article  CAS  Google Scholar 

  10. Lapteva, L. et al. Anti–N-methyl-d-aspartate receptor antibodies, cognitive dysfunction and depression in systemic lupus erythematosus. Arthritis Rheum. 54, 2505–2514 (2006).

    Article  CAS  Google Scholar 

  11. Husebye, E.S. et al. Autoantibodies to a NR2A peptide of the glutamate/NMDA receptor in sera of patients with systemic lupus erythematosus. Ann. Rheum. Dis. 64, 1210–1213 (2005).

    Article  CAS  Google Scholar 

  12. Steup-Beekman, G.M., Steens, S.C., van Buchem, M.A. & Huizinga, T.W. Anti-NMDA receptor autoantibodies in patients with systemic lupus erythematosus and their first-degree relatives. Lupus 16, 329–334 (2007).

    Article  CAS  Google Scholar 

  13. Hanly, J.G. New insights into central nervous system lupus: a clinical perspective. Curr. Rheumatol. Rep. 9, 116–124 (2007).

    Article  Google Scholar 

  14. Fragoso-Loyo, H. et al. Serum and cerebrospinal fluid autoantibodies in patients with neuropsychiatric lupus erythematosus. Implications for diagnosis and pathogenesis. PLoS ONE published online 6 Oct., doi:10.1371/journal.pone.0003347.

    Article  Google Scholar 

  15. Kowal, C. et al. Cognition and immunity; antibody impairs memory. Immunity 21, 179–188 (2004).

    Article  CAS  Google Scholar 

  16. Huerta, P.T., Kowal, C., DeGiorgio, L.A., Volpe, B.T. & Diamond, B. Immunity and behavior: antibodies alter emotion. Proc. Natl. Acad. Sci. USA 103, 678–683 (2006).

    Article  CAS  Google Scholar 

  17. Morphis, L.G. & Gitlin, D. Maturation of the maternofoetal transport system for human γ-globulin in the mouse. Nature 228, 573 (1970).

    Article  CAS  Google Scholar 

  18. Buyon, J.P. & Clancy, R.M. Neonatal lupus syndromes. Curr. Opin. Rheumatol. 15, 535–541 (2003).

    Article  CAS  Google Scholar 

  19. Putterman, C. & Diamond, B. Immunization with a peptide surrogate for double-stranded DNA (dsDNA) induces autoantibody production and renal immunoglobulin deposition. J. Exp. Med. 188, 29–38 (1998).

    Article  CAS  Google Scholar 

  20. Hanashima, C. et al. Brain factor-1 controls the proliferation and differentiation of neocortical progenitor cells through independent mechanisms. J. Neurosci. 22, 6526–6536 (2002).

    Article  CAS  Google Scholar 

  21. Kriegstein, A.R. & Noctor, S.C. Patterns of neuronal migration in the embryonic cortex. Trends Neurosci. 27, 392–399 (2004).

    Article  CAS  Google Scholar 

  22. Zhang, J. et al. Identification of DNA-reactive B cells in patients with systemic lupus erythematosus. J. Immunol. Methods 338, 79–84 (2008).

    Article  CAS  Google Scholar 

  23. Rafael, J.A., Nitta, Y., Peters, J. & Davies, K.E. Testing of SHIRPA, a mouse phenotypic assessment protocol, on Dmd(mdx) and Dmd(mdx3cv) dystrophin-deficient mice. Mamm. Genome 11, 725–728 (2000).

    Article  CAS  Google Scholar 

  24. Ten, V.S., Bradley-Moore, M., Gingrich, J.A., Stark, R.I. & Pinsky, D.J. Brain injury and neurofunctional deficit in neonatal mice with hypoxic-ischemic encephalopathy. Behav. Brain Res. 145, 209–219 (2003).

    Article  Google Scholar 

  25. Lubics, A. et al. Neurological reflexes and early motor behavior in rats subjected to neonatal hypoxic-ischemic injury. Behav. Brain Res. 157, 157–165 (2005).

    Article  Google Scholar 

  26. Quirk, G.J., Garcia, R. & González-Lima, F. Prefrontal mechanisms in extinction of conditioned fear. Biol. Psychiatry 60, 337–343 (2006).

    Article  Google Scholar 

  27. Barker, G.R. et al. The different effects on recognition memory of perirhinal kainate and NMDA glutamate receptor antagonism: implications for underlying plasticity mechanisms. J. Neurosci. 26, 3561–3566 (2006).

    Article  CAS  Google Scholar 

  28. Goodrich-Hunsaker, N.J., Hunsaker, M.R. & Kesner, R.P. Dissociating the role of the parietal cortex and dorsal hippocampus for spatial information processing. Behav. Neurosci. 119, 1307–1315 (2005).

    Article  Google Scholar 

  29. Verkhratsky, A. & Kirchhoff, F. NMDA receptors in glia. Neuroscientist 13, 28–37 (2007).

    Article  CAS  Google Scholar 

  30. Salter, M.G. & Fern, R. NMDA receptors are expressed in developing oligodendrocyte processes and mediate injury. Nature 438, 1167–1171 (2005).

    Article  CAS  Google Scholar 

  31. Manent, J.B. et al. A noncanonical release of GABA and glutamate modulates neuronal migration. J. Neurosci. 25, 4755–4765 (2005).

    Article  CAS  Google Scholar 

  32. van Zundert, B., Yoshii, A. & Constantine-Paton, M. Receptor compartmentalization and trafficking at glutamate synapses: a developmental proposal. Trends Neurosci. 27, 428–437 (2004).

    Article  CAS  Google Scholar 

  33. Ritter, L.M., Unis, A.S. & Meador-Woodruff, J.H. Ontogeny of ionotropic glutamate receptor expression in human fetal brain. Brain Res. Dev. Brain Res. 127, 123–133 (2001).

    Article  CAS  Google Scholar 

  34. Shi, L., Fatemi, S.H., Sidwell, R.W. & Patterson, P.H. Maternal influenza infection causes marked behavioral and pharmacological changes in the offspring. J. Neurosci. 23, 297–302 (2003).

    Article  Google Scholar 

  35. Dalton, P. et al. Maternal neuronal antibodies associated with autism and a language disorder. Ann. Neurol. 53, 533–537 (2003).

    Article  Google Scholar 

  36. Martin, L.A. et al. Stereotypies and hyperactivity in rhesus monkeys exposed to IgG from mothers of children with autism. Brain Behav. Immun. 22, 806–816 (2008).

    Article  CAS  Google Scholar 

  37. Galaburda, A.M., Sherman, G.F., Rosen, G.D., Aboitiz, F. & Geschwind, N. Developmental dyslexia: four consecutive patients with cortical anomalies. Ann. Neurol. 18, 222–233 (1985).

    Article  CAS  Google Scholar 

  38. Walsh, C.A. Genetic malformations of the human cerebral cortex. Neuron 23, 19–29 (1999).

    Article  CAS  Google Scholar 

  39. Newman, J., Rice, J.S., Wang, C., Harris, S.L. & Diamond, B. Identification of an antigen-specific B cell population. J. Immunol. Methods 272, 177–187 (2003).

    Article  CAS  Google Scholar 

  40. Wardemann, H. et al. Predominant autoantibody production by early human B cell precursors. Science 301, 1374–1377 (2003).

    Article  CAS  Google Scholar 

Download references

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

  1. Ji Y Lee and Patricio T Huerta: These authors contributed equally to this study.

Authors and Affiliations

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

    Ji Y Lee, Czeslawa Kowal & Betty Diamond

  2. Department of Neurology & Neuroscience, Weill Medical College of Cornell University, Burke Cornell Medical Research Institute, 785 Mamaroneck Avenue, White Plains, 10605, New York, USA

    Patricio T Huerta & Bruce T Volpe

  3. The Feinstein Institute for Medical Research, Autoimmune & Musculoskeletal Disease Center, 350 Community Drive, Manhasset, 11030, New York, USA

    Jie Zhang, Czeslawa Kowal, Eva Bertini & Betty Diamond

  4. Department of Experimental Medicine, University of Genoa, Viale Benedetto XV.3, Genoa 16132, Italy.,

    Eva Bertini

Authors
  1. Ji Y Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Patricio T Huerta
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jie Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Czeslawa Kowal
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Eva Bertini
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Bruce T Volpe
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Betty Diamond
    View author publications

    You can also search for this author in PubMed Google Scholar

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.

Supplementary information

Supplementary Text and Figures

Supplementary Figs. 1–6 and Supplementary Table 1 (PDF 816 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Lee, J., Huerta, P., Zhang, J. et al. Neurotoxic autoantibodies mediate congenital cortical impairment of offspring in maternal lupus. Nat Med 15, 91–96 (2009). https://doi.org/10.1038/nm.1892

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

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

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing