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Lupus nephritis (LN) is a major determinant of disease-related morbidity, disability, chronic kidney disease progression, kidney failure, and mortality in SLE, affecting approximately 30% of patients at diagnosis and up to 50\u201360% within the first decade. This review examines the disease\u2019s pathogenic mechanisms, emphasizing the innate immune system\u2019s role in the loss of self-tolerance and subsequent activation of the adaptive immune response. Mechanisms include dysregulated cell death pathways, impaired clearance of nucleic acid-containing debris and immune complexes, and involvement of antigen-presenting cells and other innate immune cells. These processes lead to the clonal expansion of autoreactive lymphocytes, generating effector T cells, memory B cells, and plasma cells that produce autoantibodies, resulting in renal injury. The review further explores the immunological processes driving kidney damage, beginning with autoantibody binding and immune complex deposition, followed by complement-mediated microvascular injury, kidney stromal cell activation, and leukocyte recruitment. Lastly, it discusses LN treatment strategies, from traditional to novel targeted therapies, with a focus on their systemic immunologic impacts and the protection of podocytes.<\/jats:p>","DOI":"10.3390\/diagnostics16142170","type":"journal-article","created":{"date-parts":[[2026,7,13]],"date-time":"2026-07-13T07:28:27Z","timestamp":1783927707000},"page":"2170","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Decoding Lupus Diagnosis, Pathogenesis and Therapy: From Systemic Autoimmunity to Renal Damage"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3495-2707","authenticated-orcid":false,"given":"Giuseppe Stefano","family":"Netti","sequence":"first","affiliation":[{"name":"Unit of Clinical Pathology, Department of Medical and Surgical Sciences, University of Foggia\u2014University Hospital \u201cPoliclinico Riuniti\u201d, Viale Luigi Pinto, 71122 Foggia, 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Italy"},{"name":"Center for Research and Innovation in Medicine (CREATE), Department of Medical and Surgical Sciences, University of Foggia\u2014University Hospital \u201cPoliclinico Riuniti\u201d, Viale Luigi Pinto, 71122 Foggia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giorgia","family":"Leccese","sequence":"additional","affiliation":[{"name":"Unit of Clinical Pathology, Department of Medical and Surgical Sciences, University of Foggia\u2014University Hospital \u201cPoliclinico Riuniti\u201d, Viale Luigi Pinto, 71122 Foggia, Italy"},{"name":"Center for Research and Innovation in Medicine (CREATE), Department of Medical and Surgical Sciences, University of Foggia\u2014University Hospital \u201cPoliclinico Riuniti\u201d, Viale Luigi Pinto, 71122 Foggia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Federica","family":"Galloso","sequence":"additional","affiliation":[{"name":"Unit of Clinical Pathology, Department of Medical and 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