Brendan P. Kelley

Systemic lupus erythematosus (SLE) is a complex autoimmune disease with multiorgan involvement due to a number of different immunologic mechanisms. Neuropsychiatric systemic lupus erythematosus (NPSLE) is a general term that encompasses any of the various neuropsychiatric manifestations of the disease. Autoantibodies against double-stranded DNA (dsDNA) are a hallmark of SLE, but their role in NPSLE is not well understood. Our clinical report highlights a series of patients with NPSLE demonstrating striatal inflammation responsive to plasmapheresis with an overall clinical and imaging appearance that is strikingly similar to that of the small subset of patients with anti-N-methyl-D-aspartate receptor (NMDAr) encephalitis with a striatal variant of autoimmune encephalitis (AE). We proposed that the underlying pathophysiology could be related to anti-dsDNA antibodies in these patients with NPSLE cross-reacting with the NR2 subunits of the NMDA receptor (NMDA-NR2) to result in a secondary form of anti-NMDAr encephalitis.

While the cross-reactivity between dsDNA antibodies and NMDA-NR2 antigens has already been established, the pathologic significance of this interaction remains unclear and controversial in the medical literature.¹ The conventional wisdom in AE research is that an NMDA-NR2 antigen–specific immune response is not sufficient to cause the disease.² Despite this limitation, we felt it was important to publish our findings given the favorable treatment response in these patients with NPSLE and are pleased to see our description of striatal encephalitis in neuropsychiatric systemic lupus erythematosus being incorporated into clinical practice.³ Shortly after our clinical report was published, Hirohata and colleagues provided further evidence that cross-reactivity between anti-dsDNA antibodies and NMDA-NR2 antigens in patients with NPSLE does not appear to be sufficient to generate the antigen-specific immune response observed in patients with AE.⁴

Thus, the underlying pathophysiology of striatal encephalitis in NPSLE remains poorly understood, but Hirohata and colleagues provide further insight into the contrasting roles of NMDA-NR1 antibodies in AE and NMDA-NR2 antibodies in NPSLE.

Hirohata and colleagues note that, while it has been established that NMDA-NR1 antibody binding reduces the number of cell-surface NMDA receptors at the neuronal synapse in patients with AE, the downstream effect of NMDA-NR2 antibody binding is less well-characterized but clearly does not result in synaptic remodeling and instead may result in antibody-mediated apoptosis of neurons. They also remind us that SLE pathophysiology is exceedingly complex and encompasses multiple interconnected mechanisms of immune dysfunction, which include antigen-specific immune reactions such as those from NMDA-NR2 antibodies, but also include other immune mechanisms such as polyclonal B cell activation and several elaborate forms of immune network dysregulation. We continue to be inspired and educated by the outstanding research in this field and invite others to join the perpetual effort to improve the diagnosis and treatment of patients with autoimmune CNS disease, who often represent some of the most vulnerable members of our population.

References

1. Lauvsnes MB, Omdal R. Systemic lupus erythematosus, the brain, and anti-NR2 antibodies. J Neurol 2012;259:622–29, 10.1007/s00415-011-6232-5
2. Dalmau J, Gleichman AJ, Hughes EG, et al. Anti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies. Lancet Neurol 2008;7:1091–98, 10.1016/S1474-4422(08)70224-2
3. Nakamura K, Sugiyama A, Shibuya K, et al. Striatal encephalitis in neuropsychiatric systemic lupus erythematosus. Intern Med 2019 Oct 31. [Epub ahead of print]
4. Hirohata S, Tanaka K. Differential expression of antibodies to NMDA receptor in anti-NMDA receptor encephalitis and in neuropsychiatric systemic lupus erythematosus. Lupus Sci Med 2019;6:e000359, 10.1136/lupus-2019-000359

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