A subset of lupus anti-DNA antibodies cross-reacts with the NR2 glutamate receptor in systemic lupus erythematosus

Abstract

In systemic lupus erythematosus, antibodies against double-stranded DNA are a major contributor to renal disease. We have previously demonstrated that the pentapeptide Asp/Glu-Trp-Asp/Glu-Tyr-Ser/Gly is a molecular mimic of double-stranded DNA. This sequence is also present in the extracellular domain of murine and human NMDA (N-methyl-d-aspartate) receptor subunits NR2a and NR2b. Here we show that the NR2 receptor is recognized by both murine and human anti-DNA antibodies. Moreover, anti-DNA antibodies with this cross-reactivity mediate apoptotic death of neurons in vivo and in vitro. Finally, we show that the cerebrospinal fluid of a patient with systemic lupus erythematosus contains these antibodies and also mediates neuronal death via an apoptotic pathway. These observations indicate that lupus antibodies cross-react with DNA and NMDA receptors, gain access to cerebrospinal fluid and may mediate non-thrombotic and non-vasculitic abnormalities of the central nervous system.

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Figure 1: R4A monoclonal antibody recognizes NR2.
Figure 2: R4A mediates neuron death via apoptosis.
Figure 3: Human anti-peptide antibodies bind DNA.
Figure 4: Human anti-peptide antibody causes neuron death.
Figure 5: R4A and human anti-peptide antibody causes apoptosis in primary neuron cultures.
Figure 6: Lupus CSF has anti-peptide, anti-DNA and ANA activity.

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Acknowledgements

We thank I. Joshi and W. Shen for technical help. This work was supported by grants from the National Institutes of Health, the SLE Foundation and the American Heart Association.

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Correspondence to Betty Diamond.

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