Background/Purpose: MRL/lpr mice develop an overt neuropsychiatric phenotype including depression and cognitive dysfunction, similar to diffuse neuropsychiatric manifestations of human lupus. Additionally, MRL/lpr mice display a robust infiltration of predominately lymphocytes through the choroid plexus (CP) of the central nervous system. Radiological studies and evaluation of pathological tissue has provided evidence to suggest CP involvement in human lupus as well. There has been, however, little evaluation of the functional features of these infiltrating cells, or their potential contribution to neuropsychiatric disease. Localized tertiary lymphoid structures have been described in various neoplastic and autoimmune models, including the kidneys and peritoneum of spontaneous and inducible lupus models. Given the immunoprivileged nature of the central nervous system and recent studies describing the critical role of the CP in immune surveillance, we evaluated 3D reconstructions of cellular infiltrates, and now hypothesize that the CP infiltrates in MRL/lpr mice consist of tertiary lymphoid structures (including ectopic germinal centers), induced in response to local inflammatory signals.

Methods: We evaluated MRL/lpr and control MRL/+ mice at several time points, beginning at 5 weeks of age. Expression of lymphotoxin-β and CXCL13 were evaluated by RT-qPCR at 8, 12 and 16 weeks of age. Brain tissue was immunofluorescently stained at 5, 8, 12 and 16 weeks of age to determine the phenotypical characteristics of infiltrating cells, as well as the kinetics of their infiltration. High resolution three dimensional reconstructions were generated by confocal microscopy, and both scanning and transmission electron microscopy were used to study regional compartmentalization and local intercellular interactions of infiltrating cells.

Results: We found dramatically increased lymphotoxin-β and CXCL13, key molecules in lymphoid follicle organization, in the CP of MRL/lpr mice. Lymphotoxin-β and CXCL13 were upregulated by 8 weeks of age, well before any significant cellular infiltration was present. Upon detailed examination, we found organizational and phenotypic features of lymphoid follicles, including structural reticular fibers and type I collagen cords, as well as clusters of proliferating (PCNA+) T and B cells, organized according to local chemokine gradients. Furthermore, we identified phenotypically distinct groups of B-Cells (e.g. IgM⁺, GL7⁺, BCL6⁺) and T-Cells (e.g. FoxP3⁺, BCL6⁺, GL7+), as well as follicular dendritic cells. Finally, we found aggregates of CD138⁺plasma cells, in localized regions sharply demarcated from naïve B-cells.

Conclusion: Based on the structural, organizational and phenotypical characteristics of the MRL/lpr CP infiltrate, we conclude that the CP of MRL/lpr mice contain tertiary lymphoid structures with germinal center activity, the pathogenicity of which, including production of neuropathic autoantibodies, remains to be determined.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/choroid-plexus-infiltrates-in-lupus-model-mrllpr-mice-represent-tertiary-lymphoid-structures-shedding-light-on-the-immunological-mechanisms-of-neuropsychiatric-lupus/