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.
DeGiorgio
L A
LA
Department of Neurology & Neuroscience, The Burke Medical Research Institute, Weill Medical College of Cornell University, White Plains, New York, USA.
Konstantinov
K N
KN
Lee
S C
SC
Hardin
J A
JA
Volpe
B T
BT
Diamond
B
B
D000818:Animals; D000974:Antibodies, Antinuclear / Q000134:cerebrospinal fluid / Q000276:immunology*; D017209:Apoptosis; D002478:Cells, Cultured; D003429:Cross Reactions; D006801:Humans; D066298:In Vitro Techniques; D008180:Lupus Erythematosus, Systemic / Q000276:immunology* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000276:immunology / Q000473:pathology; D016194:Receptors, N-Methyl-D-Aspartate / Q000276:immunology*
D000974:Antibodies, Antinuclear; D016194:Receptors, N-Methyl-D-Aspartate