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Immunol."],"abstract":"<jats:p>The C1858T variant of the protein tyrosine phosphatase N22 (<jats:italic>PTPN22<\/jats:italic>) gene is associated with pathophysiological phenotypes in several autoimmune conditions, namely, Type 1 diabetes and autoimmune thyroiditis. The R620W variant protein, encoded by C1858T, leads to a gain of function mutation with paradoxical reduced T cell activation. We previously exploited a novel personalized immunotherapeutic approach based on siRNA delivered by liposomes (lipoplexes, LiposiRNA) that selectively inhibit variant allele expression. In this manuscript, we functionalize lipoplexes carrying siRNA for variant C1858T with a high affinity ligand of Siglec-10 (Sig10L) coupled to lipids resulting in lipoplexes (LiposiRNA-Sig10L) that enhance delivery to Siglec-10 expressing immunocytes. LiposiRNA-Sig10L lipoplexes more efficiently downregulated variant C1858T <jats:italic>PTPN22<\/jats:italic> mRNA in PBMC of heterozygous patients than LiposiRNA without Sig10L. Following TCR engagement, LiposiRNA-Sig10L more significantly restored IL-2 secretion, known to be paradoxically reduced than in wild type patients, than unfunctionalized LiposiRNA in PBMC of heterozygous T1D patients.<\/jats:p>","DOI":"10.3389\/fimmu.2022.838331","type":"journal-article","created":{"date-parts":[[2022,3,9]],"date-time":"2022-03-09T10:42:20Z","timestamp":1646822540000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":12,"title":["Improvement of Lipoplexes With a Sialic Acid Mimetic to Target the C1858T PTPN22 Variant for Immunotherapy in Endocrine Autoimmunity"],"prefix":"10.3389","volume":"13","author":[{"given":"Andrea","family":"Arena","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eugenia","family":"Belcastro","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesca","family":"Ceccacci","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefania","family":"Petrini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Libenzio Adrian","family":"Conti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olivia","family":"Pagliarosi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ezio","family":"Giorda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simona","family":"Sennato","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Riccardo","family":"Schiaffini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peng","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James C.","family":"Paulson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giovanna","family":"Mancini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessandra","family":"Fierabracci","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,3,9]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1016\/j.beem.2019.101344","article-title":"Autoimmune Polyglandular Diseases","volume":"33","author":"Kahaly","year":"2019","journal-title":"Best Pract Res Clin Endocrinol Metab"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1089\/thy.2010.1639","article-title":"Genetics of the Autoimmune Polyglandular Syndrome Type 3 Variant","volume":"20","author":"Dittmar","year":"2010","journal-title":"Thyroid"},{"key":"B3","doi-asserted-by":"publisher","first-page":"47","DOI":"10.5114\/pedm.2020.103058","article-title":"\u03b2-Cell Self-Destruction and Extremely Complicated and Still Unknown Etiopathogenesis of Type 1 Diabetes","volume":"27","author":"Chwalba","year":"2021","journal-title":"Pediatr Endocrinol Diabetes Metab"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1016\/S2213-8587(19)30412-7","article-title":"Lars C Stene. 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