{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,27]],"date-time":"2026-07-27T06:01:18Z","timestamp":1785132078392,"version":"3.55.0"},"reference-count":56,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,7,27]],"date-time":"2026-07-27T00:00:00Z","timestamp":1785110400000},"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:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      Cytotoxic T-Lymphocyte-Associated Protein 4 (CTLA4) haploinsufficiency is a rare monogenic immunodysregulatory disorder that can affect multiple organ systems, leading to a combination of autoimmunity, immunodeficiency, and lymphoproliferation. It is caused by heterozygous germline mutations of\n                      <jats:italic>CTLA4<\/jats:italic>\n                      , yet the structure-function relationships underlying individual pathogenic variants remain incompletely understood.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We performed whole-exome sequencing on a patient with adolescent-onset autoimmune enteropathy, early-onset gastric malignancy and multisystem comorbidities, who was initially misdiagnosed with Crohn\u2019s disease and refractory to multiple biologics. Functional assays assessed CTLA4 dimerization and CD80\/CD86 binding capacity. Peripheral blood immunophenotyping was conducted using CyTOF and flow cytometry. Intestinal histopathology was evaluated by immunohistochemistry. The patient subsequently received targeted therapy with abatacept.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      A novel heterozygous missense variant in\n                      <jats:italic>CTLA4<\/jats:italic>\n                      (c.167T&amp;gt;G, p.Phe56Cys) was identified. Functional assays demonstrated that this variant impairs CTLA4 protein dimerization and its binding capacity to CD80\/CD86, establishing loss-of-function as the molecular basis of pathogenicity. Comprehensive peripheral blood immunophenotyping by CyTOF revealed a broad adaptive immune dysregulation landscape, characterized by depletion of regulatory T cells (Tregs), \u03b3\u03b4 T cells, and CD161+ cytotoxic-like CD8+ T cells. Flow cytometry confirmed reduction in CD4+CD25+Foxp3+ Treg cells along with decreased CTLA4 expression. Intestinal histopathology showed crypt apoptosis with T cell-predominant infiltration, distinct from classic inflammatory bowel disease. Notably, targeted therapy with abatacept partially restored Treg frequency and alleviated clinical symptoms.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>These findings identify p.Phe56Cys as a novel loss-of-function CTLA4 variant that disrupts protein dimerization and ligand binding, expanding the mechanistic understanding of CTLA4 haploinsufficiency and supporting genetic screening in patients with refractory autoimmune enteropathy and early-onset gastric malignancy.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1855020","type":"journal-article","created":{"date-parts":[[2026,7,27]],"date-time":"2026-07-27T05:38:13Z","timestamp":1785130693000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Novel pathogenic CTLA4 missense variant associated with autoimmune enteropathy and systemic immune dysregulation"],"prefix":"10.3389","volume":"17","author":[{"given":"Danping","family":"Zheng","sequence":"first","affiliation":[{"name":"Department of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University","place":["Guangzhou, China"]},{"name":"Department of Gastroenterology, Huiya Hospital of The First Affiliated Hospital, Sun Yat-Sen University","place":["Huizhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chunyang","family":"Tian","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University","place":["Guangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoqi","family":"Ye","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University","place":["Guangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ziyin","family":"Ye","sequence":"additional","affiliation":[{"name":"Department of Pathology, The First Affiliated Hospital, Sun Yat-sen University","place":["Guangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gayatree","family":"Mohapatra","sequence":"additional","affiliation":[{"name":"Division of Microbiome and Cancer, German Cancer Research Center (DKFZ)","place":["Heidelberg, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haiyuan","family":"Ma","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University","place":["Guangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Baili","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University","place":["Guangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhirong","family":"Zeng","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University","place":["Guangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shenghong","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University","place":["Guangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Taofeng","family":"Jiang","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Meizhou People\u2019s Hospital, Meizhou Academy of Medical Sciences","place":["Meizhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yao","family":"He","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen 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