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In addition to identifying unanticipated features of tissue-based B cell differentiation, we resolve two subsets of marginal zone B (MZB) cells differing in cell surface and transcriptomic profiles, clonal relationships to other subsets, enrichment of genes in the NOTCH pathway, distribution bias within splenic marginal zone microenvironment, and immunoglobulin repertoire diversity and hypermutation frequency. Each subset is present in spleen, gut-associated lymphoid tissue, mesenteric lymph nodes, and blood. MZB cells and the lineage from which they are derived are depleted in lupus nephritis. Here, we show that this depletion is of only one MZB subset. The other remains unchanged as a proportion of total B cells compared with health. Thus, it is important to factor MZB cell heterogeneity into studies of human B cell responses and pathology.<\/jats:p>","DOI":"10.1126\/sciimmunol.abm9060","type":"journal-article","created":{"date-parts":[[2022,3,18]],"date-time":"2022-03-18T13:58:20Z","timestamp":1647611900000},"source":"Crossref","is-referenced-by-count":72,"title":["Two subsets of human marginal zone B cells resolved by global analysis of lymphoid tissues and blood"],"prefix":"10.1126","volume":"7","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5181-407X","authenticated-orcid":true,"given":"Jacqueline H.Y.","family":"Siu","sequence":"first","affiliation":[{"name":"Department of Surgery, University of Cambridge and NIHR Cambridge Biomedical Research Centre, Cambridge CB2 0QQ, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1935-2968","authenticated-orcid":true,"given":"Michael J.","family":"Pitcher","sequence":"additional","affiliation":[{"name":"School of 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