Analysis of complement and plasma cells in the brain of patients with anti-NMDAR encephalitis

DISCUSSION

The 2 main findings of this study are the absence of deposits of complement and the presence of abundant CD138+ cells (plasma cells/plasmablasts) in the brain of patients with anti-NMDAR encephalitis. The absence of complement was emphasized in studies comparing in parallel brain and tumor tissue, showing that in contrast to brain, the neural tissue contained in tumors frequently had complement immunoreactivity. Whether the cystic lesions in the brain of patient 3 were caused by complement-mediated toxicity is unclear; we have not identified similar lesions in 400 patients with anti-NMDAR encephalitis.¹

Complement immunoreactivity was identified in 81% of teratomas from patients with anti-NMDAR encephalitis and 62.5% of teratomas from control individuals, suggesting the presence of antibody-dependent and independent mechanisms of complement binding. Indeed, studies using human fetal neurons have shown spontaneous complement activation through the classic pathway in immunoglobulin-deficient serum.⁸ Similar to these experiments, we found linear deposits of complement in 5% of cultured rodent neurons treated with human complement regardless of the presence of neuronal antibody binding (data not shown).

CD138 is a highly specific marker of plasma cells and plasmablasts, which are precursors of plasma cells. Our studies do not clarify whether the brain-infiltrating CD138+ cells were plasma cells or plasmablasts, but both types of cells are known to secrete high amounts of antibodies.^e6 These cells were found in perivascular, interstitial, and Virchow-Robin spaces, providing an explanation for the intrathecal synthesis of antibodies frequently noted in anti-NMDAR encephalitis.^1,4

We postulate that after systemic immune activation by an NMDAR-expressing tumor or unknown mechanisms, antibodies synthesized systemically may cross the blood–brain barrier (BBB) through leaky regions, but activated B cells that are able to cross an intact BBB reach the brain and differentiate into plasmablasts/plasma cells, producing most of the antibodies detected in patients' CNS. These antibodies cause a decrease of cell surface and synaptic NMDAR, as reported.² The lack of complement immunoreactivity in patients' brain is likely due to the low levels of complement in the CNS (estimated 440 times lower than serum levels⁹).

The brain infiltrates of plasma cells/plasmablasts provide a plausible explanation for the prolonged clinical course of anti-NMDAR encephalitis,^1,4 and for the limited response to plasma exchange or IVIg once the peripheral immune response has expanded in the CNS. Accordingly, patients with protracted symptoms usually have persistent levels of antibodies in the CSF.^e7 The half-life of human plasmablasts is believed to be several days, but plasma cells may live many months in an inflammatory environment, such as that provided by B and T cells.^e6,e8,e9 Moreover, plasma cells and most plasmablasts do not express CD20, the target of rituximab. This is important because in current practice, patients who do not improve with IV immunoglobulin, plasma exchange, or corticosteroids are frequently treated with rituximab or cyclophosphamide. These drugs have limited BBB penetration but result in improvement in approximately 70% of those cases.¹ While rituximab causes a decrease of B cells and prevents maturation into antibody-secreting cells,¹⁰ cyclophosphamide reduces all types of inflammatory infiltrates. The distribution of plasma cells/plasmablasts noted in this study suggests that treatment strategies that facilitate BBB penetration, such as high-dose methotrexate, may be useful in patients with refractory symptoms and persistently elevated CSF antibody titers.

Future studies should focus on the analysis of a possibly CNS compartmentalized B cell immune response in patients with anti-NMDAR encephalitis, and how an expansion or retraction of this response may explain maintenance, improvement, or relapse of symptoms.