The pathogenesis of neuropsychiatric systemic lupus erythematosus (NPSLE) is incompletely understood. In a new study, detailed phenotypic analysis has revealed the presence of tertiary lymphoid structures (TLSs) in the choroid plexus of lupus-prone mice and provides evidence that the choroid plexus can serve as a site for lymphocyte migration into the brain.

Credit: Springer Nature Limited

“The prevailing understanding of the pathogenesis of NPSLE implicates dysfunction of brain barriers, consequently exposing the brain to systemic neurotoxic agents,” explains Ayal Ben-Zvi, co-author on the new study. “Most of the focus to date had been on the blood brain barrier; however, the blood-cerebrospinal fluid barrier, at the choroid plexus, has long been implicated in human NPSLE.”

Previous studies had identified extensive cellular infiltrates in the choroid plexus of lupus-prone MRL/lpr mice. “Reports of the presence of TLSs in tissues affected by chronic inflammation in autoimmune diseases led us to hypothesize that the marked cellular infiltration may in fact be consistent with a TLS,” says lead author Ariel Stock.

Immunofluorescence and transcriptomic analysis of these infiltrates revealed important features of TLSs, including follicular helper T cells, germinal centre B cells and IgG-producing plasma cells, as well as cytokine and chemokine signatures associated with lymphoid organization and aggregation.

Using transmission electron microscopy, the investigators also found evidence of lymphocyte transepithelial migration in the choroid plexus, suggesting a possible alternative route into the brain than through the parenchymal blood brain barrier. Histological evaluation of brain autopsy samples from patients with SLE also revealed the choroid plexus as a site of leukocyte migration in some patients.

the investigators… found evidence of lymphocyte transepithelial migration in the choroid plexus

“Although we were able to demonstrate a temporal association between the development of TLSs and the appearance of neuropsychiatric deficits in the mouse model, it will be important in future studies to conclusively establish the pathogenic contribution of these lymphoid structures to NPSLE,” states corresponding author Chaim Putterman.