{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T04:46:38Z","timestamp":1785818798022,"version":"3.56.0"},"reference-count":51,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T00:00:00Z","timestamp":1785801600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>Biallelic mutations in ARPC1B gene are responsible for an inborn error of immunity (IEI) characterized by thrombocytopenia and combined immunodeficiency with heterogeneous immune-dysregulatory features. Sirolimus is a mammalian target of rapamycin (mTOR) inhibitor, which is successfully used in patients affected by primary or secondary autoimmune cytopenias. We report the case of a patient suffering from refractory\/relapsing thrombocytopenia secondary to a previously unreported homozygous variant on ARPC1B and successfully managed with sirolimus. Additional mild immune dysregulatory features, such as lymphoproliferation and autoantibodies, also resolved after sirolimus treatment. Protein\u2019s functional analysis showed an interaction between ARPC1B\u2019s role in actin cytoskeleton function and mTOR signaling pathway. However, the actin polymerization assay evaluation on samples collected before and after sirolimus treatment showed no significant differences. This result might suggest that the efficacy of sirolimus in controlling thrombocytopenia was mainly due to its immunomodulatory effect to reduce autoimmunity. The absence of a direct effect on actin cytoskeleton may also explain the lack of efficacy of sirolimus in previously reported ARPC1B-deficient patients affected by broader immune dysregulation features, including at least three or more systems involved. Although increased evidence is supporting early hematopoietic stem cell transplantation (HSCT) as an option for more severe broad-spectrum phenotypes, sirolimus could represent a therapeutic option in ARPC1B deficiency in case of a less severe immune-dysregulation phenotype or as a bridge therapy before transplant. Prospective observation can help in defining patients\u2019 evolution and prognosis with sirolimus monotherapy, and the risks and benefits of combination strategies with steroids or immune-modulating drugs should be compared with HSCT progress and results in transplant-related mortality.<\/jats:p>","DOI":"10.3389\/fimmu.2026.1845298","type":"journal-article","created":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T04:27:19Z","timestamp":1785817639000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Case Report: Sirolimus as management strategy for thrombocytopenia related to ARPC1B deficiency"],"prefix":"10.3389","volume":"17","author":[{"given":"Gianluca","family":"Dell\u2019Orso","sequence":"first","affiliation":[{"name":"Hematology Unit, IRCCS Istituto Giannina Gaslini","place":["Genoa, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martina","family":"Guardigni","sequence":"additional","affiliation":[{"name":"Hematology Unit, IRCCS Istituto Giannina Gaslini","place":["Genoa, Italy"]},{"name":"Department of Neurology, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DINOGMI), Universit\u00e0 degli Studi di Genova","place":["Genoa, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena","family":"Palmisani","sequence":"additional","affiliation":[{"name":"Hematology Unit, IRCCS Istituto Giannina Gaslini","place":["Genoa, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Enrico","family":"Drago","sequence":"additional","affiliation":[{"name":"Department of Neurology, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DINOGMI), Universit\u00e0 degli Studi di Genova","place":["Genoa, Italy"]},{"name":"Clinical and Experimental Immunology, IRCCS Istituto Giannina Gaslini","place":["Genoa, Italy"]},{"name":"Gene Therapy Program, Boston Children\u2019s Hospital, Harvard Medical School","place":["Boston, MA, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Federica","family":"Penco","sequence":"additional","affiliation":[{"name":"Rheumatology and Autoinflammatory Diseases Unit, IRCCS Istituto Giannina Gaslini","place":["Genoa, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ignazia","family":"Prigione","sequence":"additional","affiliation":[{"name":"Rheumatology and Autoinflammatory Diseases Unit, IRCCS Istituto Giannina Gaslini","place":["Genoa, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giuseppina","family":"Conteduca","sequence":"additional","affiliation":[{"name":"Laboratory of Human Genetics, IRCCS Istituto Giannina Gaslini","place":["Genoa, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lucia Augusta","family":"Baselli","sequence":"additional","affiliation":[{"name":"Pediatric Immunorheumatology Unit, Fondazione IRCCS Ca\u2019 Granda Ospedale Maggiore Policlinico","place":["Milan, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martina","family":"Rossano","sequence":"additional","affiliation":[{"name":"Pediatric Immunorheumatology Unit, Fondazione IRCCS Ca\u2019 Granda Ospedale Maggiore Policlinico","place":["Milan, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Damiano","family":"Lemmi","sequence":"additional","affiliation":[{"name":"Hematology Unit, IRCCS Istituto Giannina Gaslini","place":["Genoa, Italy"]},{"name":"Department of Neurology, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DINOGMI), Universit\u00e0 degli Studi di Genova","place":["Genoa, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Carla","family":"Giarratana","sequence":"additional","affiliation":[{"name":"Hematology Unit, IRCCS Istituto Giannina Gaslini","place":["Genoa, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eugenia","family":"Mariani","sequence":"additional","affiliation":[{"name":"Hematology Unit, IRCCS Istituto Giannina Gaslini","place":["Genoa, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luca","family":"Arcuri","sequence":"additional","affiliation":[{"name":"Hematology Unit, IRCCS Istituto Giannina Gaslini","place":["Genoa, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefano","family":"Volpi","sequence":"additional","affiliation":[{"name":"Clinical and Experimental Immunology, IRCCS Istituto Giannina Gaslini","place":["Genoa, Italy"]},{"name":"Pediatric Immunorheumatology Unit, Fondazione IRCCS Ca\u2019 Granda Ospedale Maggiore Policlinico","place":["Milan, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maurizio","family":"Miano","sequence":"additional","affiliation":[{"name":"Hematology Unit, IRCCS Istituto Giannina Gaslini","place":["Genoa, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,8,4]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1007\/s10875-022-01289-3","article-title":"Human inborn errors of immunity: 2022 update on the classification from the International Union of Immunological Societies Expert Committee","volume":"42","author":"Tangye","year":"2022","journal-title":"J ClinImmunol"},{"key":"B2","doi-asserted-by":"publisher","first-page":"26","DOI":"10.1111\/nyas.12049","article-title":"Wiskott-Aldrich syndrome: a comprehensive review","volume":"1285","author":"Massaad","year":"2013","journal-title":"Ann N Y Acad Sci"},{"key":"B3","doi-asserted-by":"publisher","first-page":"3308","DOI":"10.1038\/ncomms4308","article-title":"Structural analysis of the transitional state of Arp2\/3 complex activation by two actin-bound WCAs","volume":"5","author":"Boczkowska","year":"2014","journal-title":"Nat Commun"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1038\/nrm2026","article-title":"The ARP2\/3 complex: an actin nucleator comes of age","volume":"7","author":"Goley","year":"2006","journal-title":"Nat Rev Mol Cell Biol"},{"key":"B5","doi-asserted-by":"publisher","first-page":"7","DOI":"10.1038\/nrm3492","article-title":"New insights into the regulation and cellular functions of the ARP2\/3 complex","volume":"14","author":"Rotty","year":"2013","journal-title":"Nat Rev Mol Cell Biol"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.biophys.35.040405.101936","article-title":"Regulation of actin filament assembly by Arp2\/3 complex and formins","volume":"36","author":"Pollard","year":"2007","journal-title":"Annu Rev Biophys Biomol Struct"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms14816","article-title":"Loss of the Arp2\/3 complex component ARPC1B causes platelet abnormalities and predisposes to inflammatory disease","volume":"8","author":"Kahr","year":"2017","journal-title":"Nat Commun"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1002\/gcc.20643","article-title":"Characterization of the 7q21-q22 amplicon identifies ARPC1A, a subunit of the Arp2\/3 complex, as a regulator of cell migration and invasion in pancreatic cancer","volume":"48","author":"Laurila","year":"2009","journal-title":"Genes Chromosomes Cancer"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1700460","article-title":"Disruption of thrombocyte and T lymphocyte development by a mutation in ARPC1B","volume":"199","author":"Somech","year":"2017","journal-title":"J Immunol"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2018-07-863431","article-title":"T-cell defects in patients with ARPC1B germline mutations account for combined immunodeficiency","volume":"132","author":"Brigida","year":"2018","journal-title":"Blood"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2021.634313","article-title":"Case report: A novel synonymous ARPC1B gene mutation causes a syndrome of combined immunodeficiency, asthma, and allergy with significant intrafamilial clinical heterogeneity","volume":"12","author":"Papadatou","year":"2021","journal-title":"Front Immunol"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2019.02.003","article-title":"A combined immunodeficiency with severe infections, inflammation, and allergy caused by ARPC1B deficiency","volume":"143","author":"Volpi","year":"2019","journal-title":"J Allergy Clin Immunol"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2016.09.061","article-title":"Combined immunodeficiency with severe inflammation and allergy caused by ARPC1B deficiency","volume":"140","author":"Kuijpers","year":"2017","journal-title":"J Allergy Clin Immunol"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2019.01632","article-title":"Flow cytometric determination of actin polymerization in peripheral blood leukocytes effectively discriminate patients with homozygous mutation in ARPC1B from asymptomatic carriers and normal controls","volume":"10","author":"Kopitar","year":"2019","journal-title":"Front Immunol"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.919237","article-title":"Radiosensitivity in patients affected by ARPC1B deficiency: a new disease trait","volume":"13","author":"Chiriaco","year":"2022","journal-title":"Front Immunol"},{"key":"B16","doi-asserted-by":"publisher","first-page":"1261","DOI":"10.1016\/j.jaip.2022.12.045","article-title":"Is your kid actin out? A series of six patients with inherited actin-related protein 2\/3 complex subunit 1B deficiency and review of the literature","volume":"11","author":"V\u00e1squez-Echeverri","year":"2023","journal-title":"J Allergy Clin Immunology: In Pract"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1007\/s11684-024-1106-2","article-title":"Recurrent eosinophilia with a novel homozygous ARPC1B mutation","volume":"19","author":"Sonmez","year":"2025","journal-title":"Front Med"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.18502\/ijaai.v23i1.14960","article-title":"Description of a novel pathogenic variant in the ARPC1B and a severe allergy in two infants","volume":"23","author":"Mart\u00ednez","year":"2024","journal-title":"IJAAI"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1038\/s41435-025-00368-w","article-title":"Molecular analysis and immunological characterization of a founder mutation causing ARPC1B deficiency","volume":"27","author":"Dobrose","year":"2025","journal-title":"Genes Immun"},{"key":"B20","doi-asserted-by":"publisher","first-page":"64","DOI":"10.1007\/s12016-025-09070-1","article-title":"The c.64 + 2 T > A founder variant hits home: Report on 14 patients expands the phenotypic landscape of inherited ARPC1B deficiency \u2014 a comparative analysis","volume":"68","author":"Bhattarai","year":"2025","journal-title":"Clinic Rev Allerg Immunol"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1007\/s10875-021-01177-2","article-title":"The Immune Deficiency and Dysregulation Activity (IDDA2.1 \u2019Kaleidoscope\u2019) score and other clinical measures in inborn errors of immunity","volume":"42","author":"Seidel","year":"2022","journal-title":"J ClinImmunol"},{"key":"B22","unstructured":""},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1007\/s10875-022-01305-6","article-title":"Hematopoietic stem cell transplantation in ARPC1B deficiency","volume":"42","author":"Giardino","year":"2022","journal-title":"J ClinImmunol"},{"key":"B24","doi-asserted-by":"publisher","first-page":"33","DOI":"10.1007\/s10875-026-02002-4","article-title":"Characterisation of a leaky splice-site mutation associated with phenotypic diversity in two unrelated patients with ARPC1B deficiency","volume":"46","author":"Quach","year":"2026","journal-title":"J ClinImmunol"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2005-03-1219","article-title":"Deficiency in the Wiskott-Aldrich protein induces premature proplatelet formation and platelet production in the bone marrow compartment","volume":"108","author":"Sabri","year":"2006","journal-title":"Blood"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2012-07-443457","article-title":"Megakaryocytes assemble podosomes that degrade matrix and protrude through basement membrane","volume":"121","author":"Schachtner","year":"2013","journal-title":"Blood"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejcb.2022.151283","article-title":"Deciphering actin remodelling in immune cells through the prism of actin-related inborn errors of immunity","volume":"102","author":"Dupr\u00e9","year":"2023","journal-title":"Eur J Cell Biol"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1055\/s-2004-835674","article-title":"Molecular defects that affect platelet dense granules","volume":"30","author":"Gunay-Aygun","year":"2004","journal-title":"Semin Thromb Hemost"},{"key":"B29","doi-asserted-by":"publisher","first-page":"47","DOI":"10.1385\/1-59259-782-3:047","article-title":"Electron microscopy methods for studying platelet structure and function","volume":"272","author":"White","year":"2004","journal-title":"Methods Mol Biol"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V65.6.1439.bloodjournal6561439","article-title":"Platelet-associated immunoglobulin, platelet size, and the effect of splenectomy in the Wiskott-Aldrich syndrome","volume":"65","author":"Corash","year":"1985","journal-title":"Blood"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1182\/blood.v82.10.2961.bloodjournal82102961","article-title":"Splenectomy and\/or bone marrow transplantation in the management of the Wiskott-Aldrich syndrome: long-term follow-up of 62 cases","volume":"82","author":"Mullen","year":"1993","journal-title":"Blood"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1172\/JCI129388","article-title":"Loss of ARPC1B impairs cytotoxic T lymphocyte maintenance and cytolytic activity","volume":"129","author":"Randzavola","year":"2019","journal-title":"J Clin Invest"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.149376","article-title":"ARPC1B binds WASP to control actin polymerization and curtail tonic signaling in B cells","volume":"6","author":"Leung","year":"2021","journal-title":"JCI Insight"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2021.754029","article-title":"Case report: Deficiency of adenosine deaminase 2 presenting with overlapping features of autoimmune lymphoproliferative syndrome and bone marrow failure","volume":"12","author":"Dell\u2019Orso","year":"2021","journal-title":"Front Immunol"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.935321","article-title":"Gain-of-function defects in toll-like receptor 8 shed light on the interface between immune system and bone marrow failure disorders","volume":"13","author":"Bleesing","year":"2022","journal-title":"Front Immunol"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.3390\/ijms232314535","article-title":"Autoimmune neutropenia and immune-dysregulation in a patient carrying a TINF2 variant","volume":"23","author":"Chianucci","year":"2022","journal-title":"Int J Mol Sci"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2014.01.007","article-title":"ERCC6L2 mutations link a distinct bone-marrow-failure syndrome to DNA repair and mitochondrial function","volume":"94","author":"Tummala","year":"2014","journal-title":"Am J Hum Genet"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1002\/ajh.26242","article-title":"Genetic screening of children with marrow failure. The role of primary immunodeficiencies","volume":"96","author":"Miano","year":"2021","journal-title":"Am J Hematol"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1111\/bjh.13533","article-title":"Mycophenolate mofetil and sirolimus as second or further line treatment in children with chronic refractory primitive or secondary autoimmune cytopenias: a single centre experience","volume":"171","author":"Miano","year":"2015","journal-title":"Br J Haematol"},{"key":"B40","doi-asserted-by":"publisher","first-page":"17","DOI":"10.1182\/blood-2015-07-657981","article-title":"Sirolimus is effective in relapsed\/refractory autoimmune cytopenias: results of a prospective multi-institutional trial","volume":"127","author":"Bride","year":"2016","journal-title":"Blood"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1002\/ajh.25119","article-title":"Sirolimus as a rescue therapy in children with immune thrombocytopenia refractory to mycophenolate mofetil","volume":"93","author":"Miano","year":"2018","journal-title":"Am J Hematol"},{"key":"B42","doi-asserted-by":"publisher","first-page":"375","DOI":"10.1038\/s41392-023-01608-z","article-title":"Multifaceted role of mTOR (mammalian target of rapamycin) signaling pathway in human health and disease","volume":"8","author":"Panwar","year":"2023","journal-title":"Signal Transduct Target Ther"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1016\/j.heliyon.2024.e28005","article-title":"Pan-cancer identified ARPC1B as a promising target for tumor immunotherapy and prognostic biomarker, particularly in READ","volume":"10","author":"Zhang","year":"2024","journal-title":"Heliyon"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1007\/s00277-023-05348-6","article-title":"The mTORC1 pathway participate in hyper-function of B cells in immune thrombocytopenia","volume":"102","author":"Xiang","year":"2023","journal-title":"Ann Hematol"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.2478\/jtim-2024-0025","article-title":"Actin-related protein 2\/3 complex subunit 1B promotes ovarian cancer progression by regulating the AKT\/PI3K\/mTOR signaling pathway","volume":"12","author":"Ke","year":"2024","journal-title":"J Transl Int Med"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2024.1415389","article-title":"Infection risk in patients with autoimmune cytopenias and immune dysregulation treated with mycophenolate mofetil and sirolimus","volume":"15","author":"Comella","year":"2024","journal-title":"Front Immunol"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.70962\/CIS2025abstract.79","article-title":"Clinical outcome and quality of life in patients with ARPC1B deficiency managed conservatively or with allogeneic hematopoietic stem cell transplantation","volume":"1","author":"Drago","year":"2025","journal-title":"J Hum Immun"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1016\/j.gene.2022.146970","article-title":"Identification of alternative transcripts of NSD1 gene in Sotos Syndrome patients and healthy subjects","volume":"851","author":"Conteduca","year":"2023","journal-title":"Gene"},{"key":"B49","doi-asserted-by":"publisher","first-page":"199","DOI":"10.1111\/pai.13322","article-title":"A male infant with COVID\u201019 in the context of ARPC1B deficiency","volume":"32","author":"Castano\u2010Jaramillo","year":"2021","journal-title":"Pediatr Allergy Immunol"},{"key":"B50","doi-asserted-by":"publisher","first-page":"36","DOI":"10.1016\/j.clim.2005.06.004","article-title":"Increased chemoattractant induced neutrophil oxidative burst, accelerated apoptosis, and dysregulated tyrosine phosphorylation associated with lifelong bacterial infections","volume":"117","author":"Yan","year":"2005","journal-title":"Clin Immunol"},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.1097\/PG9.0000000000000095","article-title":"ARPC1B mutation manifesting as recurrent hematemesis with metaplasia","volume":"2","author":"Antala","year":"2021","journal-title":"JPGN Rep"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1845298\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T04:27:20Z","timestamp":1785817640000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1845298\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,4]]},"references-count":51,"alternative-id":["10.3389\/fimmu.2026.1845298"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2026.1845298","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,4]]},"article-number":"1845298"}}