{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,19]],"date-time":"2026-05-19T22:35:01Z","timestamp":1779230101874,"version":"3.51.4"},"reference-count":34,"publisher":"Wiley","issue":"11","license":[{"start":{"date-parts":[[2025,7,23]],"date-time":"2025-07-23T00:00:00Z","timestamp":1753228800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100005508","name":"Boettcher Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100005508","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100012051","name":"Lupus Research Alliance","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100012051","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["acrjournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Arthritis &amp; Rheumatology"],"published-print":{"date-parts":[[2025,11]]},"abstract":"<jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>The objective of this study was to investigate the mechanistic underpinnings and treatment response of lupus nephritis (LN) in activated phosphoinositide 3\u2010kinase \u03b4 syndrome type 1 (APDS1) using pathway\u2010specific therapy and advanced spatial proteomics.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We conducted mechanistic investigation of refractory class V LN in an 18\u2010year\u2010old female patient with genetically confirmed APDS1 (PIK3CD c.3061G&gt;A, p.E1021K mutation). Response to leniolisib, a selective phosphoinositide 3\u2010kinase \u03b4 (PI3K\u03b4) inhibitor, was evaluated through clinical parameters and flow cytometry of peripheral blood lymphocytes. Kidney tissue immune architecture was characterized using multiplexed ion beam imaging by time\u2010of\u2010flight (MIBI\u2010TOF) spectrometry, comparing the APDS1\u2010LN tissue signature with 12 patients with childhood\u2010onset LN and 5 healthy controls.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Following three years of unsuccessful treatment with conventional immunosuppressives, leniolisib treatment normalized hyperactive PI3K\u03b4 signaling, resulting in significant improvements in proteinuria, complement levels, and peripheral edema. Multiplexed Ion Beam Imaging (MIBI)\u2010Time\u2010of\u2010Flight (TOF) revealed a distinct tissue\u2010specific immunopathology with significantly increased proportions of CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cells (21.6% in APDS1 vs 12.0% in typical LN;\n                      <jats:italic>P<\/jats:italic>\n                      = 0.0410) and M1 macrophages (42.0% in APDS1 vs 9.0% in typical LN;\n                      <jats:italic>P<\/jats:italic>\n                      = 0.1445) clustering around glomeruli with immune complex deposition. This immune signature aligns with the constitutively active PI3K\u03b4 pathway's effect on lymphocyte exhaustion and inflammatory phenotype.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>This investigation advances rheumatology by demonstrating that APDS1\u2010associated LN displays a specific tissue immune signature and responds to targeted inhibition of the causative molecular pathway. Our findings provide mechanistic insights into genetic drivers of autoimmunity and support pathway\u2010specific therapeutic approaches for refractory autoimmune manifestations in primary immunodeficiencies.<\/jats:p>\n                    <jats:p>\n                      <jats:boxed-text content-type=\"graphic\" position=\"anchor\">\n                        <jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/art43254-toc-0001-m.png\">\n                          <jats:alt-text>image<\/jats:alt-text>\n                        <\/jats:graphic>\n                      <\/jats:boxed-text>\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/art.43254","type":"journal-article","created":{"date-parts":[[2025,5,19]],"date-time":"2025-05-19T06:53:11Z","timestamp":1747637591000},"page":"1596-1604","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Precision Medicine in Pediatric Autoimmunity: Leniolisib Treatment of Childhood\u2010Onset Lupus Nephritis Due to Activated Phosphoinositide 3\u2010Kinase \u03b4 Syndrome"],"prefix":"10.1002","volume":"77","author":[{"given":"Jonathan P.","family":"Lim","sequence":"first","affiliation":[{"name":"University of Colorado Anschutz Medical Campus and Children's Hospital of Colorado  Aurora"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mansooreh","family":"Ahmadian","sequence":"additional","affiliation":[{"name":"University of Colorado Anschutz Medical Campus  Aurora"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hongyu","family":"Du","sequence":"additional","affiliation":[{"name":"University of Colorado Anschutz Medical Campus  Aurora"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christian","family":"Rickert","sequence":"additional","affiliation":[{"name":"University of Colorado Anschutz Medical Campus  Aurora"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tusharkanti","family":"Ghosh","sequence":"additional","affiliation":[{"name":"University of Colorado Anschutz Medical Campus  Aurora"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fuyong","family":"Xing","sequence":"additional","affiliation":[{"name":"University of Colorado Anschutz Medical Campus  Aurora"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Angela","family":"Minic","sequence":"additional","affiliation":[{"name":"University of Colorado Anschutz Medical Campus  Aurora"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sara A.","family":"Johnson","sequence":"additional","affiliation":[{"name":"University of Colorado Anschutz Medical Campus and Children's Hospital of Colorado  Aurora"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jason P.","family":"Weinman","sequence":"additional","affiliation":[{"name":"University of Colorado Anschutz Medical Campus and Children's Hospital of Colorado  Aurora"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nicholas","family":"Willard","sequence":"additional","affiliation":[{"name":"University of Colorado Anschutz Medical Campus and Children's Hospital of Colorado  Aurora"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Clara","family":"Lin","sequence":"additional","affiliation":[{"name":"University of Colorado Anschutz Medical Campus and Children's Hospital of Colorado  Aurora"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jennifer C.","family":"Cooper","sequence":"additional","affiliation":[{"name":"University of Colorado Anschutz Medical Campus and Children's Hospital of Colorado  Aurora"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Melisha","family":"Hanna","sequence":"additional","affiliation":[{"name":"University of Colorado Anschutz Medical Campus and Children's Hospital of Colorado  Aurora"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vijaya","family":"Knight","sequence":"additional","affiliation":[{"name":"University of Colorado Anschutz Medical Campus and Children's Hospital of Colorado  Aurora"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Debashis","family":"Ghosh","sequence":"additional","affiliation":[{"name":"University of Colorado Anschutz Medical Campus  Aurora"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kimberly R.","family":"Jordan","sequence":"additional","affiliation":[{"name":"University of Colorado Anschutz Medical Campus  Aurora"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3969-6597","authenticated-orcid":false,"given":"Elena W. 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