{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,15]],"date-time":"2026-08-15T02:27:52Z","timestamp":1786760872941,"version":"build-2736575974"},"reference-count":28,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,8,14]],"date-time":"2026-08-14T00:00:00Z","timestamp":1786665600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,8,14]],"date-time":"2026-08-14T00:00:00Z","timestamp":1786665600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100004410","name":"T\u00fcrkiye Bilimsel ve Teknolojik Ara\u015ft\u0131rma Kurumu","doi-asserted-by":"publisher","award":["Project Number: 315S125"],"award-info":[{"award-number":["Project Number: 315S125"]}],"id":[{"id":"10.13039\/501100004410","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Immunology"],"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Transmembrane activator and calcium\u2010modulator and cyclophilin\u2010ligand interactor (TACI), encoded by TNFRSF13B, plays a central role in B cell maturation and antibody responses through its interactions with BAFF and APRIL, with variants being linked to common variable immunodeficiency (CVID) and selective IgA deficiency. To characterise the clinical, immunological and genetic spectrum of these individuals, we recruited 30 participants (21 patients and nine family members) and classified patients into Group 1 (\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u200916), carrying only TACI variants and Group 2 (\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u20095), carrying both an IEI\u2010related variant and an additional TACI variant. With a male\/female ratio of 12\/9, the median age was 2\u2009years at symptom onset and 14\u2009years at genetic diagnosis. Common clinical manifestations included recurrent infections (90%), autoimmune\/inflammatory features (62%) and lymphoproliferation (57%). Twelve distinct TNFRSF13B mutations were identified, predominantly clustering in the cysteine\u2010rich domain 2 (CRD2), with Cys104Arg being the most frequent (57%) variant. Immunophenotyping revealed decreased switched\u2010memory and marginal zone B cells, reduced na\u00efve CD4\n                    <jats:sup>+<\/jats:sup>\n                    T cells and increased effector memory subsets. Notably, clinical and laboratory features overlapped between Groups 1 and 2, as well as between monoallelic and biallelic TNFRSF13B variant carriers. Patients with TNFRSF13B variants display broad phenotypic heterogeneity ranging from asymptomatic carriage to CVID and combined immunodeficiency phenotypes. Given the high polymorphism ratio and incomplete penetrance observed, TACI acts as both a genetic modifier and a monogenic disease\u2010causing gene in this cohort, suggesting that coexisting genetic variants and exposomal factors likely determine the clinical expression and disease severity.\n                  <\/jats:p>","DOI":"10.1111\/imm.70192","type":"journal-article","created":{"date-parts":[[2026,8,15]],"date-time":"2026-08-15T01:55:51Z","timestamp":1786758951000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Clinical Heterogeneity of\n                    <scp>TNFRSF13B<\/scp>\n                    Variants: A Monogenic Cause or a Genetic Modifier?"],"prefix":"10.1111","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9053-2785","authenticated-orcid":false,"given":"Begum","family":"Cicek","sequence":"first","affiliation":[{"name":"Division of Immunology, Department of Pediatric Basic Sciences Institute of Child Health, Hacettepe University  Ankara Turkey"},{"name":"Ihsan Dogramaci Children's Hospital, Hacettepe University Faculty of Medicine  Ankara Turkey"},{"name":"Pediatric Immunology Laboratory, Faculty of Medicine Hacettepe University  Ankara Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0823-1327","authenticated-orcid":false,"given":"Deniz Ilgun","family":"Gurel","sequence":"additional","affiliation":[{"name":"Ihsan Dogramaci Children's Hospital, Hacettepe University Faculty of Medicine  Ankara Turkey"},{"name":"Division of Immunology, Department of Pediatrics Hacettepe University Faculty of Medicine  Ankara Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5278-7456","authenticated-orcid":false,"given":"Ismail","family":"Yaz","sequence":"additional","affiliation":[{"name":"Division of Immunology, Department of Pediatric Basic Sciences Institute of Child Health, Hacettepe University  Ankara Turkey"},{"name":"Ihsan Dogramaci Children's Hospital, Hacettepe University Faculty of Medicine  Ankara Turkey"},{"name":"Pediatric Immunology Laboratory, Faculty of Medicine Hacettepe University  Ankara Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5689-8014","authenticated-orcid":false,"given":"Sevda Tuten","family":"Dal","sequence":"additional","affiliation":[{"name":"Ihsan Dogramaci Children's Hospital, Hacettepe University Faculty of Medicine  Ankara Turkey"},{"name":"Division of Immunology, Department of Pediatrics Hacettepe University Faculty of Medicine  Ankara Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2801-8494","authenticated-orcid":false,"given":"Hacer Neslihan","family":"Bildik","sequence":"additional","affiliation":[{"name":"Division of Immunology, Department of Pediatric Basic Sciences Institute of Child Health, Hacettepe University  Ankara Turkey"},{"name":"Pediatric Immunology Laboratory, Faculty of Medicine Hacettepe University  Ankara Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9398-8465","authenticated-orcid":false,"given":"Baran","family":"Erman","sequence":"additional","affiliation":[{"name":"Division of Immunology, Department of Pediatric Basic Sciences Institute of Child Health, Hacettepe University  Ankara Turkey"},{"name":"Can Sucak Research Laboratory for Translational Immunology Hacettepe University  Ankara Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0726-5004","authenticated-orcid":false,"given":"Canberk","family":"Ipsir","sequence":"additional","affiliation":[{"name":"Division of Immunology, Department of Pediatric Basic Sciences Institute of Child Health, Hacettepe University  Ankara Turkey"},{"name":"Pediatric Immunology Laboratory, Faculty of Medicine Hacettepe University  Ankara Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2329-7543","authenticated-orcid":false,"given":"Elif Soyak","family":"Aytekin","sequence":"additional","affiliation":[{"name":"Ihsan Dogramaci Children's Hospital, Hacettepe University Faculty of Medicine  Ankara Turkey"},{"name":"Division of Immunology, Department of Pediatrics Hacettepe University Faculty of Medicine  Ankara Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0562-9863","authenticated-orcid":false,"given":"Saliha","family":"Esenboga","sequence":"additional","affiliation":[{"name":"Ihsan Dogramaci Children's Hospital, Hacettepe University Faculty of Medicine  Ankara Turkey"},{"name":"Division of Immunology, Department of Pediatrics Hacettepe University Faculty of Medicine  Ankara Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ilhan","family":"Tezcan","sequence":"additional","affiliation":[{"name":"Division of Immunology, Department of Pediatric Basic Sciences Institute of Child Health, Hacettepe University  Ankara Turkey"},{"name":"Ihsan Dogramaci Children's Hospital, Hacettepe University Faculty of Medicine  Ankara Turkey"},{"name":"Pediatric Immunology Laboratory, Faculty of Medicine Hacettepe University  Ankara Turkey"},{"name":"Division of Immunology, Department of Pediatrics Hacettepe University Faculty of Medicine  Ankara Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2213-4627","authenticated-orcid":false,"given":"Deniz","family":"Cagdas","sequence":"additional","affiliation":[{"name":"Division of Immunology, Department of Pediatric Basic Sciences Institute of Child Health, Hacettepe University  Ankara Turkey"},{"name":"Ihsan Dogramaci Children's Hospital, Hacettepe University Faculty of Medicine  Ankara Turkey"},{"name":"Pediatric Immunology Laboratory, Faculty of Medicine Hacettepe University  Ankara Turkey"},{"name":"Division of Immunology, Department of Pediatrics Hacettepe University Faculty of Medicine  Ankara Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,8,14]]},"reference":[{"key":"e_1_2_12_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.coi.2021.06.004"},{"issue":"7","key":"e_1_2_12_3_1","doi-asserted-by":"crossref","first-page":"491","DOI":"10.1038\/nri2572","article-title":"Cracking the BAFF Code","volume":"9","author":"MacKay F.","year":"2009","journal-title":"Nature Reviews. Immunology"},{"issue":"8","key":"e_1_2_12_4_1","doi-asserted-by":"crossref","first-page":"829","DOI":"10.1038\/ng1601","article-title":"TACI Is Mutant in Common Variable Immunodeficiency and IgA Deficiency","volume":"37","author":"Castigli E.","year":"2005","journal-title":"Nature Genetics"},{"issue":"1","key":"e_1_2_12_5_1","first-page":"1","article-title":"The 2024 Update of IUIS Phenotypic Classification of Human Inborn Errors of Immunity","volume":"1","author":"Bousfiha A. A.","year":"2025","journal-title":"Journal of Human Immunology"},{"issue":"9","key":"e_1_2_12_6_1","doi-asserted-by":"crossref","first-page":"1967","DOI":"10.1182\/blood-2008-02-141937","article-title":"Relevance of Biallelic Versus Monoallelic TNFRSF13B Mutations in Distinguishing Disease\u2010Causing From Risk\u2010Increasing TNFRSF13B Variants in Antibody Deficiency Syndromes","volume":"113","author":"Salzer U.","year":"2009","journal-title":"Blood"},{"issue":"1","key":"e_1_2_12_7_1","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1111\/cei.13645","article-title":"Clinical and Laboratory Findings in Patients With Leukocyte Adhesion Deficiency Type I: A Multicenter Study in Turkey","volume":"206","author":"Yaz I.","year":"2021","journal-title":"Clinical and Experimental Immunology"},{"issue":"1","key":"e_1_2_12_8_1","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1007\/s10875-025-01934-7","article-title":"Beyond the Classical Triad: Atypical Presentations and Regulatory T Cell Phenotyping in a Cohort of IPEX Patients","volume":"45","author":"Yaz I.","year":"2025","journal-title":"Journal of Clinical Immunology"},{"issue":"4","key":"e_1_2_12_9_1","doi-asserted-by":"crossref","first-page":"436","DOI":"10.1111\/j.1365-3083.2012.02671.x","article-title":"Paediatric Reference Values for the Peripheral T Cell Compartment","volume":"75","author":"Schatorj\u00e9 E. J. H.","year":"2012","journal-title":"Scandinavian Journal of Immunology"},{"issue":"6","key":"e_1_2_12_10_1","doi-asserted-by":"crossref","first-page":"372","DOI":"10.1002\/cyto.b.20536","article-title":"B Cell Subsets in Healthy Children: Reference Values for Evaluation of B Cell Maturation Process in Peripheral Blood","volume":"78","author":"Pia\u0327tosa B.","year":"2010","journal-title":"Cytometry Part B, Clinical Cytometry"},{"issue":"3","key":"e_1_2_12_11_1","first-page":"117","article-title":"Immunophenotype, Clinical Effect, and Comparison of TNFRSF13B\/TACI Mutations: A Single\u2010Center Retrospective Cohort Study of 34 Patients","volume":"11","author":"Cepniler E.","year":"2023","journal-title":"Turkish Journal of Immunology"},{"issue":"8","key":"e_1_2_12_12_1","first-page":"1","article-title":"Taci Mutations in Primary Antibody Deficiencies: A Nationwide Study in Greece","volume":"57","author":"Kakkas I.","year":"2021","journal-title":"Medicus"},{"issue":"2","key":"e_1_2_12_13_1","doi-asserted-by":"crossref","first-page":"468","DOI":"10.1016\/j.jaci.2012.10.029","article-title":"TACI Mutations and Impaired B\u2010Cell Function in Subjects With CVID and Healthy Heterozygotes","volume":"131","author":"Martinez\u2010Gallo M.","year":"2013","journal-title":"Journal of Allergy and Clinical Immunology"},{"issue":"2","key":"e_1_2_12_14_1","doi-asserted-by":"crossref","first-page":"407","DOI":"10.1177\/039463201202500210","article-title":"The Impact of Taci Mutations: From Hypogammaglobulinemia in Infancy to Autoimmunity in Adulthood","volume":"25","author":"Barroeta Seijas A. B.","year":"2012","journal-title":"International Journal of Immunopathology and Pharmacology"},{"key":"e_1_2_12_15_1","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1155\/2016\/8390356","article-title":"Clinical Associations of Biallelic and Monoallelic TNFRSF13B Variants in Italian Primary Antibody Deficiency Syndromes","volume":"2016","author":"Pulvirenti F.","year":"2016","journal-title":"Journal of Immunology Research"},{"issue":"10","key":"e_1_2_12_16_1","doi-asserted-by":"crossref","first-page":"4283","DOI":"10.1172\/JCI69854","article-title":"CVID\u2010Associated TACI Mutations Affect Autoreactive B Cell Selection and Activation","volume":"123","author":"Romberg N.","year":"2013","journal-title":"Journal of Clinical Investigation"},{"key":"e_1_2_12_17_1","doi-asserted-by":"crossref","first-page":"1","DOI":"10.3389\/fimmu.2017.01965","article-title":"Clinical Implications of Digenic Inheritance and Epistasis in Primary Immunodeficiency Disorders","volume":"8","author":"Ameratunga R.","year":"2018","journal-title":"Frontiers in Immunology"},{"key":"e_1_2_12_18_1","doi-asserted-by":"crossref","first-page":"1","DOI":"10.3389\/fimmu.2021.634544","article-title":"TNFRSF13B Diversification Fueled by B Cell Responses to Environmental Challenges\u2014A Hypothesis","volume":"12","author":"Cascalho M.","year":"2021","journal-title":"Frontiers in Immunology"},{"key":"e_1_2_12_19_1","doi-asserted-by":"publisher","DOI":"10.70962\/jhi.20250016"},{"key":"e_1_2_12_20_1","doi-asserted-by":"publisher","DOI":"10.1111\/jth.13806"},{"key":"e_1_2_12_21_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood\u20102014\u201005\u2010575845"},{"issue":"6","key":"e_1_2_12_22_1","doi-asserted-by":"crossref","first-page":"1550","DOI":"10.1172\/JCI31023","article-title":"Dominant\u2010Negative Effect of the Heterozygous C104R TACI Mutation in Common Variable Immunodeficiency (CVID)","volume":"117","author":"Garibyan L.","year":"2007","journal-title":"Journal of Clinical Investigation"},{"key":"e_1_2_12_23_1","doi-asserted-by":"publisher","DOI":"10.1097\/00000441\u2010200101000\u201000007"},{"issue":"1","key":"e_1_2_12_24_1","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s12865-025-00752-1","article-title":"Autoimmune Cytopenias in Inborn Errors of Immunity: Associations With Monogenic Mutations and Immunologic Parameters","volume":"26","author":"Sa\u011fun F.","year":"2025","journal-title":"BMC Immunology"},{"issue":"5","key":"e_1_2_12_25_1","doi-asserted-by":"crossref","first-page":"753","DOI":"10.2169\/internalmedicine.4057-24","article-title":"Pathogenic TNFRSF13B Variant in an Adult Japanese Patient With Common Variable Immunodeficiency","volume":"64","author":"Nakamura N.","year":"2025","journal-title":"Internal Medicine"},{"issue":"1","key":"e_1_2_12_26_1","doi-asserted-by":"crossref","first-page":"14","DOI":"10.18176\/jiaci.0388","article-title":"Common Variable Immunodeficiency: Epidemiology, Pathogenesis, Clinical Manifestations, Diagnosis, Classification, and Management","volume":"30","author":"Yazdani R.","year":"2020","journal-title":"Journal of Investigational Allergology & Clinical Immunology"},{"key":"e_1_2_12_27_1","doi-asserted-by":"crossref","first-page":"1","DOI":"10.3389\/fimmu.2022.911385","article-title":"Targeted Treatment of Autoimmune Cytopenias in Primary Immunodeficiencies","volume":"13","author":"Pacillo L.","year":"2022","journal-title":"Frontiers in Immunology"},{"key":"e_1_2_12_28_1","doi-asserted-by":"crossref","first-page":"1","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 M.","year":"2024","journal-title":"Frontiers in Immunology"},{"issue":"1","key":"e_1_2_12_29_1","first-page":"1","article-title":"Common Variable Immunodeficiency Unmasked by Treatment of Immune Thrombocytopenic Purpura With Rituximab","volume":"13","author":"Mogensen T. H.","year":"2013","journal-title":"BMC Hematology"}],"container-title":["Immunology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/imm.70192","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1111\/imm.70192","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/imm.70192","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,15]],"date-time":"2026-08-15T01:55:55Z","timestamp":1786758955000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/imm.70192"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,14]]},"references-count":28,"alternative-id":["10.1111\/imm.70192"],"URL":"https:\/\/doi.org\/10.1111\/imm.70192","archive":["Portico"],"relation":{},"ISSN":["0019-2805","1365-2567"],"issn-type":[{"value":"0019-2805","type":"print"},{"value":"1365-2567","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,14]]},"assertion":[{"value":"2026-03-17","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-08-07","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-08-14","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"imm.70192"}}