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Recently, the meninges, which are filled with CSF, were identified as a neuroimmunological interface, highlighting the potential of exploring central nervous system (CNS) immunity by studying CNS border compartments. Here, we summarize how single-cell transcriptomics of such border compartments advance our understanding of neurological diseases,\u00a0the challenges that remain, and what opportunities novel multi-omic methods offer. Single-cell transcriptomics studies have detected cytotoxic CD4\n                    <jats:sup>+<\/jats:sup>\n                    T cells and clonally expanded T and B cells in the CSF in the autoimmune disease multiple sclerosis; clonally expanded pathogenic CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cells were found in the CSF and in the brain adjacent to \u03b2-amyloid plaques of dementia patients; in patients with brain metastases, CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cell clonotypes were shared between the brain parenchyma and the CSF and persisted after therapy. We also outline how novel multi-omic approaches permit the simultaneous measurements of gene expression, chromatin accessibility, and protein in the same cells, which remain to be explored in the CSF. This calls for multicenter initiatives to create single-cell atlases, posing challenges in integrating patients and modalities across centers. While high-dimensional analyses of CSF cells are challenging, they hold potential for personalized medicine by better resolving heterogeneous diseases and stratifying patients.\n                  <\/jats:p>","DOI":"10.1186\/s13073-022-01097-9","type":"journal-article","created":{"date-parts":[[2022,8,17]],"date-time":"2022-08-17T13:02:38Z","timestamp":1660741358000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":32,"title":["High-dimensional investigation of the cerebrospinal fluid to explore and monitor CNS immune responses"],"prefix":"10.1186","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9568-2790","authenticated-orcid":false,"given":"Michael","family":"Heming","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna-Lena","family":"B\u00f6rsch","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heinz","family":"Wiendl","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4341-4719","authenticated-orcid":false,"given":"Gerd","family":"Meyer zu H\u00f6rste","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2022,8,17]]},"reference":[{"key":"1097_CR1","doi-asserted-by":"publisher","first-page":"581","DOI":"10.1016\/j.tins.2016.07.001","volume":"39","author":"D Raper","year":"2016","unstructured":"Raper D, Louveau A, Kipnis J. 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