{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T16:28:19Z","timestamp":1789576099177,"version":"build-2803163510"},"reference-count":25,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,11,19]],"date-time":"2025-11-19T00:00:00Z","timestamp":1763510400000},"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":"\n Objective<\/jats:title>\n \n As a critical immune checkpoint, cytotoxic T-lymphocyte-associated protein 4(\n CTLA-4<\/jats:italic>\n )deficiency is a well-established cause of inborn errors of immunity. This study characterizes a novel\n CTLA-4<\/jats:italic>\n deletion variant identified in a pediatric case of refractory autoimmune hemolytic anemia (AIHA), with the aim of delineating the clinical profile and elucidating the underlying pathogenic mechanism.\n <\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n \n Trio-based whole-exome sequencing (WES) was performed on peripheral blood samples from a 6-year-old female with refractory AIHA and her parents. Candidate variants were validated by Sanger sequencing. Structural modeling of mutant\n CTLA-4<\/jats:italic>\n was conducted, followed by\n in vitro<\/jats:italic>\n functional assays in 293T cells to assess mRNA transcription (qPCR) and protein expression (Western blot).\n <\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n A\n CTLA-4<\/jats:italic>\n (c.362_391del) variant was identified within the immunoglobulin V-set domain of the\n CTLA-4<\/jats:italic>\n protein.\n In vitro<\/jats:italic>\n experiments demonstrated significant reductions in both mRNA and protein expression levels caused by this variant.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusion<\/jats:title>\n \n The\n CTLA-4<\/jats:italic>\n (c.362_391del) variant may contribute to refractory AIHA in children. This case highlights the potential necessity of including\n CTLA-4<\/jats:italic>\n variants in the differential diagnosis of pediatric AIHA, particularly when conventional therapies prove ineffective, and warrants further validation in larger cohorts.\n <\/jats:p>\n <\/jats:sec>","DOI":"10.3389\/fimmu.2025.1665184","type":"journal-article","created":{"date-parts":[[2025,11,19]],"date-time":"2025-11-19T06:37:52Z","timestamp":1763534272000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["A novel CTLA-4 deletion variant in a child with refractory autoimmune hemolytic anemia: molecular and functional 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