{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T16:03:29Z","timestamp":1785859409993,"version":"3.56.0"},"reference-count":53,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,1,13]],"date-time":"2026-01-13T00:00:00Z","timestamp":1768262400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Med."],"abstract":"<jats:p>Neuropsychiatric Systemic Lupus Erythematosus (NPSLE) represents one of the most severe and enigmatic manifestations of SLE, contributing significantly to disease morbidity and mortality. Its clinical presentation is profoundly heterogeneous, encompassing 19 distinct syndromes that pose considerable diagnostic and therapeutic challenges. While historical estimates of its prevalence varied widely, contemporary prospective studies suggest that approximately 56% of SLE patients experience a neuropsychiatric event, with 30\u201350% of these events being directly attributable to SLE-related pathogenic mechanisms. A comprehensive understanding of its multifactorial pathogenesis is critical for developing targeted therapies. The pathogenesis of NPSLE is an integrated neuroimmune process initiated by the disruption of the blood\u2013brain and blood-CSF barriers. This breach permits peripheral autoimmune mediators-including pathogenic autoantibodies (e.g., anti-NMDAR, anti-ribosomal P), pro-inflammatory cytokines (e.g., Type I IFN, IL-6), and innate immune cells such as neutrophils forming Neutrophil Extracellular Traps (NETs)-to enter the central nervous system (CNS). Within the CNS, these insults trigger a robust response from resident glial cells. Microglia polarize to a pro-inflammatory M1 phenotype, driving neuroinflammation and pathological synaptic stripping, while astrocytes transition to a neurotoxic A1 phenotype, losing their neurosupportive functions. These inflammatory pathways are intricately linked with an ischemic\/thrombotic pathway, often mediated by antiphospholipid antibodies, creating a complex pathogenic landscape. The adaptive immune system plays a crucial role in perpetuating the autoimmune attack within the CNS compartment. This involves the infiltration of pathogenic T cell subsets, as identified in animal models like the MRL\/lpr strain, including T follicular helper (Tfh)-like cells in the choroid plexus and senescent\/exhausted Eomes+ double-negative T cells within the brain parenchyma. Furthermore, the CNS can become an active site for B cell responses, supporting the intrathecal clonal expansion of B cells and plasma cells, leading to local production of pathogenic autoantibodies. Deconstructing this cellular and molecular complexity requires high-resolution technologies. Single-cell genomics (scRNA-seq, CITE-seq, scBCR-seq) and spatial transcriptomics are providing unprecedented insights into the specific cell types and states driving the disease. While direct analysis of human NPSLE brain tissue remains rare, a powerful framework is emerging from synthesizing mechanistic data from diverse animal models (e.g., MRL\/lpr and NZB\/W\u202fF1) with findings from human CSF in related neuroinflammatory conditions. The translation of these molecular insights into clinical practice is the ultimate goal. This research paves the way for moving beyond descriptive syndromic classifications toward a mechanism-based stratification using \u201cimmune endophenotypes.\u201d Such an approach promises to enhance biomarker discovery (e.g., NfL, GFAP, CXCL13) and guide the development of targeted therapies, such as Type I IFN receptor blockade and specific B cell-directed agents. By bridging high-resolution discovery with clinical reality, we can advance toward an era of precision medicine for the management of NPSLE.<\/jats:p>","DOI":"10.3389\/fmed.2025.1732805","type":"journal-article","created":{"date-parts":[[2026,1,13]],"date-time":"2026-01-13T06:35:09Z","timestamp":1768286109000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["Advancements in understanding neuropsychiatric lupus: deciphering immune heterogeneity with single-cell 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