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Compared with adult-onset SLE (aSLE), cSLE more frequently presents with strong type I interferon activity, BAFF-induced B-cell hyperactivation, and increased activity of T follicular helper cells that promote persistent generation of autoantibodies. These changes induce an IFN\u2013BAFF\u2013B-cell\u2013immune complex-complement axis positive feedback loop that can affect developmentally vulnerable organs, thus increasing the risk for early severe lupus nephritis, neuropsychiatric involvement, cytopenias, infection, and drug toxicities. We synthesize evidence for an immune ontogeny-based approach that considers altered molecular pathways, organ development, and responses to different therapeutics, and highlight that a higher genetic burden must be addressed for the effective stratification of patients. Finally, we propose a pragmatic approach to precision care based on developmental stage, immunophenotype, genetics, and long-term safety to enable the earlier onset of steroid-sparing therapy and long-term protection of patients.<\/jats:p>","DOI":"10.3389\/fimmu.2026.1885364","type":"journal-article","created":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T10:10:32Z","timestamp":1789121432000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Immune ontogeny in childhood-onset systemic lupus erythematosus: effect of immune maturity on disease phenotype and therapeutic responses"],"prefix":"10.3389","volume":"17","author":[{"given":"Wanfeng","family":"Xu","sequence":"first","affiliation":[{"name":"Department of Endocrinology, Shengjing Hospital of China Medical University","place":["Shenyang, 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