{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,17]],"date-time":"2026-07-17T16:52:20Z","timestamp":1784307140322,"version":"3.55.0"},"reference-count":18,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2024,12,13]],"date-time":"2024-12-13T00:00:00Z","timestamp":1734048000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2024,12,13]],"date-time":"2024-12-13T00:00:00Z","timestamp":1734048000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100018936","name":"Universit\u00e4tsklinikum Heidelberg","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100018936","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Arthritis Res Ther"],"abstract":"<jats:title>Abstract<\/jats:title><jats:sec>\n                <jats:title>Objective<\/jats:title>\n                <jats:p>The high potential of CD19.CAR-T cells to treat autoimmune diseases such as Systemic Sclerosis (SSc) supposedly relies on the disappearance of autoantibodies. Here we investigated effects of CAR-T cells on the innate immune system which is an important contributor to pathology in SSc.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>Longitudinal analysis of peripheral blood mononuclear cells from an Scl70\u2009+\u2009SSc patient treated with CAR-T cells sampled over 18 months by 29-color spectral flow cytometry, in vitro experiments using sera from patient cohorts.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>In the patient treated with CAR-T cells, the substantial clinical improvement was paralleled by dynamic changes in innate lymphoid cells, namely Fc\u03b3-receptor IIIA-expressing natural killer (NK) cells. NK cells adopted a more juvenile, less activated, and less differentiated phenotype. In parallel, the potency of serum to form Scl70-containing immune complexes that activate Fc\u03b3-receptor IIIA decreased over time. These observations suggested a mechanistic link between reversal of adaptive autoimmunity and recovering Fc\u03b3-receptor IIIA-expressing innate immune cells after CAR-T cell therapy via regressing immune complex activity. Experiments with sera from the non-CAR-T-treated SSc cohort confirmed that Scl70-containing immune complexes activate Fc\u03b3-receptor IIIA-expressing NK cells in a dose-dependent manner, substantiating the relevance of this link between adaptive and innate immunity in SSc.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusion<\/jats:title>\n                <jats:p>This report describes for the first time the phenotypic recovery of innate Fc\u03b3-receptor-expressing cells in an SSc patient treated with CAR-T cells. Decreasing autoantibody levels associated with a reduced ability to form functional immune complexes, the latter appearing to contribute to pathology in SSc via activation of Fc\u03b3 receptor IIIA\u2009+\u2009cells such as NK cells.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Graphical Abstract<\/jats:title>\n                \n                <jats:p>Proposed mechanism of involvement of NK cells and soluble Immune Complexes (sICs) in disease progression during active autoimmunity in SSc (left) and resolution of fibrosis after deep B cell depletion by CD19.CAR-T cells and disappearance of autoantibodies (right).<\/jats:p>\n              <\/jats:sec>","DOI":"10.1186\/s13075-024-03451-1","type":"journal-article","created":{"date-parts":[[2024,12,13]],"date-time":"2024-12-13T09:33:20Z","timestamp":1734082400000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Immunological effects of CD19.CAR-T cell therapy in systemic sclerosis: an extended case study"],"prefix":"10.1186","volume":"26","author":[{"given":"Maren","family":"Claus","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Merle","family":"Freitag","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meike","family":"Ewald","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lea","family":"Rodon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Franca","family":"Deicher","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carsten","family":"Watzl","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philipp","family":"Kolb","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hanns-Martin","family":"Lorenz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Schmitt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wolfgang","family":"Merkt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,12,13]]},"reference":[{"issue":"4","key":"3451_CR1","doi-asserted-by":"publisher","first-page":"543","DOI":"10.1136\/ard-2023-225174","volume":"83","author":"W Merkt","year":"2024","unstructured":"Merkt W, Freitag M, Claus M, Kolb P, Falcone V, Rohrich M, et al. Third-generation CD19.CAR-T cell-containing combination therapy in Scl70\u2009+\u2009systemic sclerosis. Ann Rheum Dis. 2024;83(4):543\u20136.","journal-title":"Ann Rheum Dis"},{"issue":"9","key":"3451_CR2","doi-asserted-by":"publisher","first-page":"e18","DOI":"10.1164\/rccm.202202-0399ST","volume":"205","author":"G Raghu","year":"2022","unstructured":"Raghu G, Remy-Jardin M, Richeldi L, Thomson CC, Inoue Y, Johkoh T, et al. Idiopathic pulmonary fibrosis (an update) and progressive pulmonary fibrosis in adults: an Official ATS\/ERS\/JRS\/ALAT Clinical Practice Guideline. Am J Respir Crit Care Med. 2022;205(9):e18\u201347.","journal-title":"Am J Respir Crit Care Med"},{"issue":"10","key":"3451_CR3","doi-asserted-by":"publisher","first-page":"2124","DOI":"10.1038\/s41591-022-02017-5","volume":"28","author":"A Mackensen","year":"2022","unstructured":"Mackensen A, Muller F, Mougiakakos D, Boltz S, Wilhelm A, Aigner M, et al. Anti-CD19 CAR T cell therapy for refractory systemic lupus erythematosus. Nat Med. 2022;28(10):2124\u201332.","journal-title":"Nat Med"},{"issue":"5","key":"3451_CR4","doi-asserted-by":"publisher","first-page":"608","DOI":"10.1164\/rccm.202012-4418LE","volume":"204","author":"T Cruz","year":"2021","unstructured":"Cruz T, Jia M, Sembrat J, Tabib T, Agostino N, Bruno TC, et al. Reduced proportion and activity of natural killer cells in the lung of patients with idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2021;204(5):608\u201310.","journal-title":"Am J Respir Crit Care Med"},{"key":"3451_CR5","doi-asserted-by":"crossref","unstructured":"Padilla CM, Valenzi E, Tabib T, Nazari B, Sembrat J, Rojas M et al. Increased CD8\u2009+\u2009tissue resident memory T cells, regulatory T cells, and activated natural killer cells in systemic sclerosis lungs. 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The ethics committee of Heidelberg University, Germany, approved this study (S272\/2021).","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"The CAR-T cell patient, SSc patients, SLE patients and healthy donors gave their written informed consent to the therapeutic procedures, blood donations and publication.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"provided upon request.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"211"}}