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


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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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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