{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T20:28:21Z","timestamp":1792787301664,"version":"4.5.0"},"reference-count":38,"publisher":"BMJ","issue":"2","license":[{"start":{"date-parts":[[2026,9,12]],"date-time":"2026-09-12T00:00:00Z","timestamp":1789171200000},"content-version":"unspecified","delay-in-days":73,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100012166","name":"National Key Research and Development Program of China","doi-asserted-by":"publisher","award":["2023YFC2706400"],"award-info":[{"award-number":["2023YFC2706400"]}],"id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Zhejiang Provincial Natural Science Foundation of China","award":["LMS26F020001"],"award-info":[{"award-number":["LMS26F020001"]}],"id":[{"id":"https:\/\/ror.org\/04aqat463","id-type":"ROR","asserted-by":"crossref"}]},{"name":"Medical Health Science and Technology Project of Zhejiang Provincial Health Commission","award":["2025KY938"],"award-info":[{"award-number":["2025KY938"]}],"id":[{"id":"https:\/\/ror.org\/00va36f15","id-type":"ROR","asserted-by":"crossref"}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["Lupus Sci Med"],"accepted":{"date-parts":[[2026,8,15]]},"published-print":{"date-parts":[[2026,7]]},"abstract":"<jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>Systemic lupus erythematosus (SLE) is a complex autoimmune disease characterised by substantial variability in clinical presentations and disease severity. This study aims to investigate the molecular and cellular mechanisms underlying distinct SLE Disease Activity Index (SLEDAI)-defined disease states of SLE and to identify potential prognostic biomarkers and therapeutic targets associated with heightened inflammatory activity.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We analysed bulk and single-cell RNA sequencing datasets from SLE patients. Patients were stratified into clinically distinct SLEDAI-defined disease states using established SLEDAI thresholds, which served as operational surrogates of inflammatory disease burden. Differentially expressed genes and gene co-expression networks were analysed to identify severity-associated hub genes. The immune microenvironment and intercellular communication were evaluated using CIBERSORTx and CellChat algorithms, respectively.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Differential expression and network analyses identified five key hub genes (KLRK1, IL2RB, RAG1, SH2D1B and NCR1) strongly correlated with SLE disease activity states, which were used to develop a five-gene SLE severity (SLEsev) score. The SLEsev score was significantly higher in high-activity\/severe SLE (sSLE) compared with low-activity\/mild SLE (mSLE) (p&lt;0.001), which showed a consistent trend in an independent validation cohort. Immune profiling revealed that mSLE was enriched in regulatory T cells (Tregs) and memory B cells, whereas sSLE exhibited elevated levels of CD8+T cells, natural killer cells and monocytes (p&lt;0.05). Single-cell analysis demonstrated that sSLE possessed a more complex cellular communication network (311 vs 283 inferred interactions) and greater overall interaction strength than mSLE, with prominent pro-inflammatory signalling pathways such as IFN-II, GAS and CCL playing a key role in sSLE.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>This study unveils the profound immunological and transcriptomic dysregulation underlying SLE severity. The identified five-gene SLEsev score serves as a potential biomarker for disease stratification, while the hyperactive intercellular signalling networks highlight specific molecular targets for modulating immune responses in severe SLE.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1136\/lupus-2026-002111","type":"journal-article","created":{"date-parts":[[2026,9,12]],"date-time":"2026-09-12T08:25:10Z","timestamp":1789201510000},"page":"e002111","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":0,"title":["Unveiling the molecular and immune heterogeneity across distinct disease activity states of systemic lupus erythematosus through integrative bulk and single-cell transcriptomics"],"prefix":"10.1136","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9187-9345","authenticated-orcid":false,"given":"Chen","family":"Shen","sequence":"first","affiliation":[{"name":"Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Children and Adolescents' Health and Diseases, Hangzhou, China"},{"name":"Sino-Finland Joint AI Laboratory for Child Health of Zhejiang Province, Hangzhou, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mingzhe","family":"Guo","sequence":"additional","affiliation":[{"name":"School of Public Health, Shandong Second Medical University, Weifang, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jian","family":"Huang","sequence":"additional","affiliation":[{"name":"Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Children and Adolescents' Health and Diseases, Hangzhou, China"},{"name":"Sino-Finland Joint AI Laboratory for Child Health of Zhejiang Province, Hangzhou, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5184-7226","authenticated-orcid":false,"given":"Huiwen","family":"Zheng","sequence":"additional","affiliation":[{"name":"Zhejiang University School of Medicine Sir Run Run Shaw Hospital, Hangzhou, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gang","family":"Yu","sequence":"additional","affiliation":[{"name":"Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Children and Adolescents' Health and Diseases, Hangzhou, China"},{"name":"Sino-Finland Joint AI Laboratory for Child Health of Zhejiang Province, Hangzhou, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"239","published-online":{"date-parts":[[2026,9,12]]},"reference":[{"key":"2026092908103106000_13.2.e002111.1","doi-asserted-by":"crossref","DOI":"10.3389\/fimmu.2022.1118180","article-title":"Editorial: Systemic lupus erythematosus - 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