{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T15:52:09Z","timestamp":1790092329985,"version":"4.0.1"},"reference-count":39,"publisher":"American Society of Hematology","issue":"11","content-domain":{"domain":["ashpublications.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2024,9,12]]},"abstract":"<jats:sec>\n                  <jats:title>Abstract<\/jats:title>\n                  <jats:p>Deficiency of X-linked inhibitor of apoptosis protein (XIAP) is a rare genetic condition that can present with recurrent episodes of hemophagocytic lymphohistiocytosis (HLH), though the exact mechanisms leading to this hyperinflammatory disorder are unclear. Understanding its biology is critical to developing targeted therapies for this potentially fatal disease. Here, we report on a novel multiexonic intragenic duplication leading to XIAP deficiency with recurrent HLH that demonstrated complete response to interleukin (IL)-1\u03b2 blockade. We further demonstrate using both primary patient cells and genetically modified THP-1 monocyte cell lines that, contrary to what has previously been shown in mouse cells, XIAP-deficient human macrophages do not produce excess IL-1\u03b2 when stimulated under standard conditions. Instead, nucleotide-binding oligomerization domain\u2013like receptor family pyrin domain containing 3 (NLRP3) inflammasome\u2013mediated hyperproduction of IL-1\u03b2 is observed only when the XIAP-deficient cells are stimulated under autophagy-promoting conditions and this correlates with defective autophagic flux as measured by decreased accumulation of the early autophagy marker LC3-II. This work, therefore, highlights IL-1\u03b2 blockade as a therapeutic option for patients with XIAP deficiency experiencing recurrent HLH and identifies a critical role for XIAP in promoting autophagy as a means of limiting IL-1\u03b2\u2013mediated hyperinflammation during periods of cellular stress.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1182\/blood.2023023707","type":"journal-article","created":{"date-parts":[[2024,5,31]],"date-time":"2024-05-31T20:56:47Z","timestamp":1717189007000},"page":"1183-1192","update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":12,"title":["Interleukin-1\u2013mediated hyperinflammation in XIAP deficiency is associated with defective autophagy"],"prefix":"10.1182","volume":"144","author":[{"given":"Dilan","family":"Dissanayake","sequence":"first","affiliation":[{"name":"1Cell Biology Program, SickKids Research Institute, Toronto, ON, Canada"},{"name":"2Division of Rheumatology, The Hospital for Sick Children, Toronto, ON, Canada"},{"name":"3Department of Paediatrics, University of Toronto, Toronto, ON, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ashkan","family":"Firouzabady","sequence":"additional","affiliation":[{"name":"1Cell Biology Program, SickKids Research Institute, Toronto, ON, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8291-9798","authenticated-orcid":false,"given":"Mohammad","family":"Massumi","sequence":"additional","affiliation":[{"name":"1Cell Biology Program, SickKids Research Institute, Toronto, ON, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guillermo A.","family":"de Paz Linares","sequence":"additional","affiliation":[{"name":"4Department of Biochemistry, University of Toronto, Toronto, ON, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"Marshall","sequence":"additional","affiliation":[{"name":"5Division of Genome Diagnostics, The Hospital for Sick Children, Toronto, ON, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Spencer A.","family":"Freeman","sequence":"additional","affiliation":[{"name":"1Cell Biology Program, SickKids Research Institute, Toronto, ON, Canada"},{"name":"4Department of Biochemistry, University of Toronto, Toronto, ON, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ronald M.","family":"Laxer","sequence":"additional","affiliation":[{"name":"2Division of Rheumatology, The Hospital for Sick Children, Toronto, ON, Canada"},{"name":"3Department of Paediatrics, University of Toronto, Toronto, ON, Canada"},{"name":"6Department of Medicine, University of Toronto, Toronto, ON, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2361-725X","authenticated-orcid":false,"given":"Rae S. 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