{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T04:55:47Z","timestamp":1790744147261,"version":"4.1.0"},"reference-count":39,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,4,8]],"date-time":"2022-04-08T00:00:00Z","timestamp":1649376000000},"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. Immunol."],"abstract":"<jats:p>B cell abnormalities are common in systemic lupus erythematosus (SLE), and include expansion of double negative (DN) and age-associated-like B cells (ABC-like). We aimed to investigate rituximab (RTX) effects on DN and ABC-like B-cell subsets and, when possible, also secondary effects on T cells. Fifteen SLE patients, fulfilling the ACR 1982 criteria, starting RTX and followed longitudinally up to two years, were analyzed for B- and T- lymphocyte subsets using multicolor flow cytometry. DN were defined as IgD-CD27- and ABC-like as CD11c+CD21- within the DN gate. Additional phenotyping was performed adding CXCR5 in the B-cell panel. Cellular changes were further analyzed in the context of the generation of anti-drug antibodies (ADA) against RTX and clinical information. The SLE patients were mainly females (86.6%), of median age 36.7 (29.8-49.4) years and disease duration of 6.1 (1.6-11.8) years. Within the DN subset, ABC-like (IgD-CD27-CD11c+CD21-) B cell frequency reduced from baseline median level of 20.4% to 11.3% (p=0.03), at early follow-up. The DN B cells were further subdivided based on CXCR5 expression. Significant shifts were observed at the early follow-up in the DN2 sub-cluster (CD11c+CXCR5-), which reduced significantly (-15.4 percentage points, p=0.02) and in the recently described DN3 (CD11c-CXCR5-) which increased (+13 percentage points, p=0.03). SLE patients treated with RTX are at high risk of developing ADA. In our cohort, the presence of ADA at 6 months was associated with lower frequencies of DN cells and to a more pronounced expansion of plasmablasts at early follow-up. The frequency of follicular helper T cells (T<jats:sub>FH<\/jats:sub>, CD4+PD-1+CXCR5+) and of peripheral helper T cells (T<jats:sub>PH<\/jats:sub>, CD4+PD-1+CXCR5-) did not change after RTX. A sub-cluster of PD-1<jats:sup>high<\/jats:sup>CD4+ T cells showed a significant decrease at later follow-up compared to early follow-up (p=0.0039). It is well appreciated that RTX transiently influences B cells. Here, we extend these observations to cell phenotypes which are believed to directly contribute to autoimmunity in SLE. We show early transient effects of RTX on ABC-like memory B cells, later effects on PD-1<jats:sup>high<\/jats:sup> CD4+ cells, and possible implications for RTX immunogenicity. Further insight in such effects and their monitoring may be of clinical relevance.<\/jats:p>","DOI":"10.3389\/fimmu.2022.826152","type":"journal-article","created":{"date-parts":[[2022,4,8]],"date-time":"2022-04-08T12:51:39Z","timestamp":1649422299000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":40,"title":["Rituximab in Systemic Lupus Erythematosus: Transient Effects on Autoimmunity Associated Lymphocyte Phenotypes and Implications for Immunogenicity"],"prefix":"10.3389","volume":"13","author":[{"given":"Francesca","family":"Faustini","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natalie","family":"Sippl","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ragnhild","family":"St\u00e5lesen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karine","family":"Chemin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicky","family":"Dunn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Fogdell-Hahn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Iva","family":"Gunnarsson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vivianne","family":"Malmstr\u00f6m","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,4,8]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1038\/nrrheum.2016.186","article-title":"New Insights Into the Immunopathogenesis of Systemic Lupus Erythematosus","volume":"12","author":"Tsokos","year":"2016","journal-title":"Nat Rev Rheumatol"},{"key":"B2","doi-asserted-by":"publisher","first-page":"17","DOI":"10.1111\/j.1365-2249.2010.04309.x","article-title":"Quantitative and Functional Profiles of CD4+ Lymphocyte Subsets in Systemic Lupus Erythematosus Patients With Lymphopenia","volume":"164","author":"G\u00f3mez-Mart\u00edn","year":"2011","journal-title":"Clin Exp Immunol"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.165.10.5970","article-title":"Disturbed Peripheral B Lymphocyte Homeostasis in Systemic Lupus Erythematosus","volume":"165","author":"Odendahl","year":"2000","journal-title":"J Immunol (Baltimore Md: 1950)"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1002\/art.10949","article-title":"Correlation Between Circulating CD27high Plasma Cells and Disease Activity in Patients With Systemic Lupus Erythematosus","volume":"48","author":"Jacobi","year":"2003","journal-title":"Arthritis Rheum"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1002\/art.20592","article-title":"Rituximab Improves Peripheral B Cell Abnormalities in Human Systemic Lupus Erythematosus","volume":"50","author":"Anolik","year":"2004","journal-title":"Arthritis Rheum"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.178.10.6624","article-title":"A New Population of Cells Lacking Expression of CD27 Represents a Notable Component of the B Cell Memory Compartment in Systemic Lupus Erythematosus","volume":"178","author":"Wei","year":"2007","journal-title":"J Immunol (Baltimore Md: 1950)"},{"key":"B7","doi-asserted-by":"publisher","first-page":"e001258","DOI":"10.1136\/rmdopen-2020-001258","article-title":"Therapeutic Implications of the Anergic\/Postactivated Status of B Cells in Systemic Lupus Erythematosus","volume":"6","author":"D\u00f6rner","year":"2020","journal-title":"RMD Open"},{"key":"B8","doi-asserted-by":"publisher","first-page":"725","DOI":"10.1016\/j.immuni.2018.08.015","article-title":"Distinct Effector B Cells Induced by Unregulated Toll-Like Receptor 7 Contribute to Pathogenic Responses in Systemic Lupus Erythematosus","volume":"49","author":"Jenks","year":"2018","journal-title":"Immunity"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2011-01-331462","article-title":"Toll-Like Receptor 7 (TLR7)-Driven Accumulation of a Novel CD11c+; 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