{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,31]],"date-time":"2026-10-31T07:55:27Z","timestamp":1793433327668,"version":"4.5.0"},"reference-count":69,"publisher":"Springer Science and Business Media LLC","issue":"3","license":[{"start":{"date-parts":[[2024,2,16]],"date-time":"2024-02-16T00:00:00Z","timestamp":1708041600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2024,2,16]],"date-time":"2024-02-16T00:00:00Z","timestamp":1708041600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100000925","name":"National Health and Medical Research Council","doi-asserted-by":"publisher","award":["1042925"],"award-info":[{"award-number":["1042925"]}],"id":[{"id":"10.13039\/501100000925","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000925","name":"National Health and Medical Research Council","doi-asserted-by":"crossref","award":["2017463"],"award-info":[{"award-number":["2017463"]}],"id":[{"id":"10.13039\/501100000925","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100000925","name":"National Health and Medical Research Council","doi-asserted-by":"crossref","award":["1113904"],"award-info":[{"award-number":["1113904"]}],"id":[{"id":"10.13039\/501100000925","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001773","name":"University of New South Wales","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100001773","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["J Clin Immunol"],"published-print":{"date-parts":[[2024,4]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>B cells and their secreted antibodies are fundamental for host-defense against pathogens. The generation of high-affinity class switched antibodies results from both somatic hypermutation (SHM) of the immunoglobulin (Ig) variable region genes of the B-cell receptor and class switch recombination (CSR) which alters the Ig heavy chain constant region. Both of these processes are initiated by the enzyme activation-induced cytidine deaminase (AID), encoded by <jats:italic>AICDA<\/jats:italic>. Deleterious variants in <jats:italic>AICDA<\/jats:italic> are causal of hyper-IgM syndrome type 2 (HIGM2), a B-cell intrinsic primary immunodeficiency characterised by recurrent infections and low serum IgG and IgA levels. Biallelic variants affecting exons 2, 3 or 4 of <jats:italic>AICDA<\/jats:italic> have been identified that impair both CSR and SHM in patients with autosomal recessive HIGM2. Interestingly, B cells from patients with autosomal dominant HIGM2, caused by heterozygous variants (V186X, R190X) located in <jats:italic>AICDA<\/jats:italic> exon 5 encoding the nuclear export signal (NES) domain, show abolished CSR but variable SHM. We herein report the immunological and functional phenotype of two related patients presenting with common variable immunodeficiency who were found to have a novel heterozygous variant in <jats:italic>AICDA<\/jats:italic> (L189X)<jats:italic>.<\/jats:italic> This variant led to a truncated AID protein lacking the last 10 amino acids of the NES at the C-terminal domain. Interestingly, patients\u2019 B cells carrying the L189X variant exhibited not only greatly impaired CSR but also SHM in vivo, as well as CSR and production of IgG and IgA in vitro. Our findings demonstrate that the NES domain of AID can be essential for SHM, as well as for CSR, thereby refining the correlation between <jats:italic>AICDA<\/jats:italic> genotype and SHM phenotype as well as broadening our understanding of the pathophysiology of HIGM disorders.<\/jats:p>","DOI":"10.1007\/s10875-024-01665-1","type":"journal-article","created":{"date-parts":[[2024,2,16]],"date-time":"2024-02-16T11:02:39Z","timestamp":1708081359000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["A Novel Heterozygous Variant in AICDA Impairs Ig Class Switching and Somatic Hypermutation in Human B Cells and is Associated with Autosomal Dominant HIGM2 Syndrome"],"prefix":"10.1007","volume":"44","author":[{"given":"Erika","family":"Della Mina","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katherine J. L.","family":"Jackson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander J. I.","family":"Crawford","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Megan L.","family":"Faulks","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karrnan","family":"Pathmanandavel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicolino","family":"Acquarola","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"O\u2019Sullivan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tessa","family":"Kerre","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leslie","family":"Naesens","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karlien","family":"Claes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher C.","family":"Goodnow","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Filomeen","family":"Haerynck","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sven","family":"Kracker","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isabelle","family":"Meyts","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lloyd J.","family":"D\u2019Orsogna","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cindy S.","family":"Ma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5360-5180","authenticated-orcid":false,"given":"Stuart G.","family":"Tangye","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,2,16]]},"reference":[{"issue":"5","key":"1665_CR1","doi-asserted-by":"crossref","first-page":"1570","DOI":"10.1182\/blood-2008-02-078071","volume":"112","author":"TW LeBien","year":"2008","unstructured":"LeBien TW, Tedder TF. B lymphocytes: how they develop and function. Blood. 2008;112(5):1570\u201380.","journal-title":"Blood"},{"key":"1665_CR2","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1016\/S0065-2776(08)60876-7","volume":"52","author":"J Banchereau","year":"1992","unstructured":"Banchereau J, Rousset F. Human B lymphocytes: phenotype, proliferation, and differentiation. Adv Immunol. 1992;52:125\u2013262.","journal-title":"Adv Immunol"},{"issue":"2","key":"1665_CR3","doi-asserted-by":"crossref","first-page":"256","DOI":"10.1016\/S0952-7915(97)80145-8","volume":"9","author":"YJ Liu","year":"1997","unstructured":"Liu YJ, de Bouteiller O, Fugier-Vivier I. Mechanisms of selection and differentiation in germinal centers. Curr Opin Immunol. 1997;9(2):256\u201362.","journal-title":"Curr Opin Immunol"},{"issue":"8","key":"1665_CR4","doi-asserted-by":"crossref","first-page":"681","DOI":"10.1038\/ni.1900","volume":"11","author":"CC Goodnow","year":"2010","unstructured":"Goodnow CC, Vinuesa CG, Randall KL, Mackay F, Brink R. Control systems and decision making for antibody production. Nat Immunol. 2010;11(8):681\u20138.","journal-title":"Nat Immunol"},{"key":"1665_CR5","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1146\/annurev.immunol.26.021607.090248","volume":"26","author":"J Stavnezer","year":"2008","unstructured":"Stavnezer J, Guikema JE, Schrader CE. Mechanism and regulation of class switch recombination. Annu Rev Immunol. 2008;26:261\u201392.","journal-title":"Annu Rev Immunol"},{"issue":"8","key":"1665_CR6","doi-asserted-by":"crossref","first-page":"3716","DOI":"10.4049\/jimmunol.1500753","volume":"195","author":"D Bagnara","year":"2015","unstructured":"Bagnara D, Squillario M, Kipling D, Mora T, Walczak AM, Da Silva L, et al. A reassessment of IgM memory subsets in humans. J Immunol. 2015;195(8):3716\u201324.","journal-title":"J Immunol"},{"key":"1665_CR7","doi-asserted-by":"crossref","unstructured":"Weill JC, Weller S, Reynaud CA. B cell diversification in gut-associated lymphoid tissues: from birds to humans. J Exp Med. 2023;220(11):e20231501.","DOI":"10.1084\/jem.20231501"},{"issue":"7","key":"1665_CR8","doi-asserted-by":"crossref","first-page":"1508","DOI":"10.1007\/s10875-022-01352-z","volume":"42","author":"A Bousfiha","year":"2022","unstructured":"Bousfiha A, Moundir A, Tangye SG, Picard C, Jeddane L, Al-Herz W, et al. The 2022 Update of IUIS Phenotypical Classification for Human Inborn Errors of Immunity. J Clin Immunol. 2022;42(7):1508\u201320.","journal-title":"J Clin Immunol"},{"key":"1665_CR9","doi-asserted-by":"crossref","unstructured":"Tangye SG, Nguyen T, Deenick EK, Bryant VL, Ma CS. Inborn errors of human B cell development, differentiation, and function. J Exp Med. 2023;220(7):e20221105.","DOI":"10.1084\/jem.20221105"},{"issue":"4","key":"1665_CR10","doi-asserted-by":"crossref","first-page":"389","DOI":"10.1002\/stem.3327","volume":"39","author":"E Della Mina","year":"2021","unstructured":"Della Mina E, Gu\u00e9rin A, Tangye SG. Molecular requirements for human lymphopoiesis as defined by inborn errors of immunity. Stem Cells. 2021;39(4):389\u2013402.","journal-title":"Stem Cells"},{"issue":"4","key":"1665_CR11","doi-asserted-by":"crossref","first-page":"218","DOI":"10.1186\/ar3904","volume":"14","author":"A Durandy","year":"2012","unstructured":"Durandy A, Kracker S. Immunoglobulin class-switch recombination deficiencies. Arthritis Res Ther. 2012;14(4):218.","journal-title":"Arthritis Res Ther"},{"key":"1665_CR12","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1016\/S0065-2776(06)94009-7","volume":"94","author":"A Durandy","year":"2007","unstructured":"Durandy A, Taubenheim N, Peron S, Fischer A. Pathophysiology of B-cell intrinsic immunoglobulin class switch recombination deficiencies. Adv Immunol. 2007;94:275\u2013306.","journal-title":"Adv Immunol"},{"key":"1665_CR13","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1016\/j.clim.2018.11.007","volume":"198","author":"R Yazdani","year":"2019","unstructured":"Yazdani R, Fekrvand S, Shahkarami S, Azizi G, Moazzami B, Abolhassani H, et al. The hyper IgM syndromes: epidemiology, pathogenesis, clinical manifestations, diagnosis and management. Clin Immunol. 2019;198:19\u201330.","journal-title":"Clin Immunol"},{"key":"1665_CR14","doi-asserted-by":"crossref","first-page":"1336","DOI":"10.1056\/NEJM196312192692502","volume":"269","author":"FS Rosen","year":"1963","unstructured":"Rosen FS, Bougas JA. Acquired dysgammaglobulinemia: elevation of the 19s gamma globulin and deficiency of the 7s gamma globulin in a woman with chronic progressive bronchiectasis. N Engl J Med. 1963;269:1336\u201340.","journal-title":"N Engl J Med"},{"issue":"2","key":"1665_CR15","first-page":"101","volume":"3","author":"LD Notarangelo","year":"1992","unstructured":"Notarangelo LD, Duse M, Ugazio AG. Immunodeficiency with hyper-IgM (HIM). Immunodefic Rev. 1992;3(2):101\u201321.","journal-title":"Immunodefic Rev"},{"issue":"9","key":"1665_CR16","doi-asserted-by":"crossref","first-page":"843","DOI":"10.1038\/ni964","volume":"4","author":"VT Ta","year":"2003","unstructured":"Ta VT, Nagaoka H, Catalan N, Durandy A, Fischer A, Imai K, et al. AID mutant analyses indicate requirement for class-switch-specific cofactors. Nat Immunol. 2003;4(9):843\u20138.","journal-title":"Nat Immunol"},{"issue":"7","key":"1665_CR17","doi-asserted-by":"crossref","first-page":"586","DOI":"10.1016\/j.it.2020.04.009","volume":"41","author":"Y Feng","year":"2020","unstructured":"Feng Y, Seija N, Di Noia JM, Martin A. AID in antibody diversification: there and back again. Trends Immunol. 2020;41(7):586\u2013600.","journal-title":"Trends Immunol"},{"issue":"10","key":"1665_CR18","doi-asserted-by":"crossref","first-page":"1291","DOI":"10.1084\/jem.20030481","volume":"197","author":"SK Dickerson","year":"2003","unstructured":"Dickerson SK, Market E, Besmer E, Papavasiliou FN. AID mediates hypermutation by deaminating single stranded DNA. J Exp Med. 2003;197(10):1291\u20136.","journal-title":"J Exp Med"},{"issue":"11","key":"1665_CR19","doi-asserted-by":"crossref","first-page":"E1545","DOI":"10.1073\/pnas.1601678113","volume":"113","author":"S Mondal","year":"2016","unstructured":"Mondal S, Begum NA, Hu W, Honjo T. Functional requirements of AID\u2019s higher order structures and their interaction with RNA-binding proteins. Proc Natl Acad Sci U S A. 2016;113(11):E1545\u201354.","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"11","key":"1665_CR20","doi-asserted-by":"crossref","first-page":"525","DOI":"10.1093\/intimm\/dxx061","volume":"29","author":"A Al Ismail","year":"2017","unstructured":"Al Ismail A, Husain A, Kobayashi M, Honjo T, Begum NA. Depletion of recombination-specific cofactors by the C-terminal mutant of the activation-induced cytidine deaminase causes the dominant negative effect on class switch recombination. Int Immunol. 2017;29(11):525\u201337.","journal-title":"Int Immunol"},{"issue":"5","key":"1665_CR21","doi-asserted-by":"crossref","first-page":"553","DOI":"10.1016\/S0092-8674(00)00078-7","volume":"102","author":"M Muramatsu","year":"2000","unstructured":"Muramatsu M, Kinoshita K, Fagarasan S, Yamada S, Shinkai Y, Honjo T. Class switch recombination and hypermutation require activation-induced cytidine deaminase (AID), a potential RNA editing enzyme. Cell. 2000;102(5):553\u201363.","journal-title":"Cell"},{"issue":"6","key":"1665_CR22","doi-asserted-by":"crossref","first-page":"3382","DOI":"10.4049\/jimmunol.172.6.3382","volume":"172","author":"IB Rogozin","year":"2004","unstructured":"Rogozin IB, Diaz M. Cutting edge: DGYW\/WRCH is a better predictor of mutability at G: C bases in Ig hypermutation than the widely accepted RGYW\/WRCY motif and probably reflects a two-step activation-induced cytidine deaminase-triggered process. J Immunol. 2004;172(6):3382\u20134.","journal-title":"J Immunol"},{"issue":"5","key":"1665_CR23","doi-asserted-by":"crossref","first-page":"565","DOI":"10.1016\/S0092-8674(00)00079-9","volume":"102","author":"P Revy","year":"2000","unstructured":"Revy P, Muto T, Levy Y, Geissmann F, Plebani A, Sanal O, et al. Activation-induced cytidine deaminase (AID) deficiency causes the autosomal recessive form of the Hyper-IgM syndrome (HIGM2). Cell. 2000;102(5):565\u201375.","journal-title":"Cell"},{"issue":"3","key":"1665_CR24","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1006\/clim.2000.4956","volume":"97","author":"Y Minegishi","year":"2000","unstructured":"Minegishi Y, Lavoie A, Cunningham-Rundles C, Bedard PM, Hebert J, Cote L, et al. Mutations in activation-induced cytidine deaminase in patients with hyper IgM syndrome. Clin Immunol. 2000;97(3):203\u201310.","journal-title":"Clin Immunol"},{"key":"1665_CR25","doi-asserted-by":"publisher","unstructured":"Dirks J, Haase G, Cantaert T, Frey L, Klaas M, Rickert CH, et al. A novel AICDA splice-site mutation in two siblings with HIGM2 permits somatic hypermutation but abrogates mutational targeting. J Clin Immunol. 2022;42(4):771\u201382. https:\/\/doi.org\/10.1007\/s10875-022-01233-5","DOI":"10.1007\/s10875-022-01233-5"},{"issue":"3","key":"1665_CR26","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1111\/sji.12523","volume":"85","author":"B Erman","year":"2017","unstructured":"Erman B, Bilic I, Hirschmugl T, Salzer E, Boztug H, Sanal \u00d6, et al. Investigation of genetic defects in severe combined immunodeficiency patients from Turkey by targeted sequencing. Scand J Immunol. 2017;85(3):227\u201334.","journal-title":"Scand J Immunol"},{"issue":"11","key":"1665_CR27","doi-asserted-by":"crossref","first-page":"4289","DOI":"10.1172\/JCI84645","volume":"126","author":"T Cantaert","year":"2016","unstructured":"Cantaert T, Schickel JN, Bannock JM, Ng YS, Massad C, Delmotte FR, et al. Decreased somatic hypermutation induces an impaired peripheral B cell tolerance checkpoint. J Clin Invest. 2016;126(11):4289\u2013302.","journal-title":"J Clin Invest"},{"issue":"2","key":"1665_CR28","doi-asserted-by":"crossref","first-page":"148","DOI":"10.3109\/08916934.2012.750299","volume":"46","author":"A Durandy","year":"2013","unstructured":"Durandy A, Cantaert T, Kracker S, Meffre E. Potential roles of activation-induced cytidine deaminase in promotion or prevention of autoimmunity in humans. Autoimmunity. 2013;46(2):148\u201356.","journal-title":"Autoimmunity"},{"issue":"4","key":"1665_CR29","doi-asserted-by":"crossref","first-page":"755","DOI":"10.1016\/S0091-6749(03)01860-8","volume":"112","author":"Y Kasahara","year":"2003","unstructured":"Kasahara Y, Kaneko H, Fukao T, Terada T, Asano T, Kasahara K, et al. Hyper-IgM syndrome with putative dominant negative mutation in activation-induced cytidine deaminase. J Allergy Clin Immunol. 2003;112(4):755\u201360.","journal-title":"J Allergy Clin Immunol"},{"issue":"3","key":"1665_CR30","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1016\/j.clim.2005.02.003","volume":"115","author":"K Imai","year":"2005","unstructured":"Imai K, Zhu Y, Revy P, Morio T, Mizutani S, Fischer A, et al. Analysis of class switch recombination and somatic hypermutation in patients affected with autosomal dominant hyper-IgM syndrome type 2. Clin Immunol. 2005;115(3):277\u201385.","journal-title":"Clin Immunol"},{"issue":"207\u201311","key":"1665_CR31","volume":"223","author":"J Fadlallah","year":"2020","unstructured":"Fadlallah J, Chentout L, Boisson B, Pouliet A, Masson C, Morin F, et al. From dysgammaglobulinemia to autosomal-dominant activation-induced cytidine deaminase deficiency: unraveling an inherited immunodeficiency after 50 Years. J Pediatr. 2020;223(207\u201311): e1.","journal-title":"J Pediatr"},{"issue":"11","key":"1665_CR32","doi-asserted-by":"crossref","first-page":"E988","DOI":"10.1073\/pnas.1320486111","volume":"111","author":"A Zahn","year":"2014","unstructured":"Zahn A, Eranki AK, Patenaude AM, Methot SP, Fifield H, Cortizas EM, et al. Activation induced deaminase C-terminal domain links DNA breaks to end protection and repair during class switch recombination. Proc Natl Acad Sci U S A. 2014;111(11):E988\u201397.","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"12","key":"1665_CR33","doi-asserted-by":"crossref","first-page":"1185","DOI":"10.1002\/humu.20414","volume":"27","author":"A Durandy","year":"2006","unstructured":"Durandy A, Peron S, Taubenheim N, Fischer A. Activation-induced cytidine deaminase: structure-function relationship as based on the study of mutants. Hum Mutat. 2006;27(12):1185\u201391.","journal-title":"Hum Mutat"},{"issue":"8","key":"1665_CR34","doi-asserted-by":"crossref","first-page":"777","DOI":"10.1002\/cyto.a.24018","volume":"97","author":"K Payne","year":"2020","unstructured":"Payne K, Li W, Salomon R, Ma CS. OMIP-063: 28-color flow cytometry panel for broad human immunophenotyping. Cytometry A. 2020;97(8):777\u201381.","journal-title":"Cytometry A"},{"issue":"1","key":"1665_CR35","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1084\/jem.20091706","volume":"207","author":"DT Avery","year":"2010","unstructured":"Avery DT, Deenick EK, Ma CS, Suryani S, Simpson N, Chew GY, et al. B cell-intrinsic signaling through IL-21 receptor and STAT3 is required for establishing long-lived antibody responses in humans. J Exp Med. 2010;207(1):155\u201371.","journal-title":"J Exp Med"},{"issue":"1","key":"1665_CR36","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1084\/jem.184.1.277","volume":"184","author":"PD Hodgkin","year":"1996","unstructured":"Hodgkin PD, Lee JH, Lyons AB. B cell differentiation and isotype switching is related to division cycle number. J Exp Med. 1996;184(1):277\u201381.","journal-title":"J Exp Med"},{"issue":"7","key":"1665_CR37","doi-asserted-by":"crossref","first-page":"4034","DOI":"10.4049\/jimmunol.174.7.4034","volume":"174","author":"DT Avery","year":"2005","unstructured":"Avery DT, Ellyard JI, Mackay F, Corcoran LM, Hodgkin PD, Tangye SG. Increased expression of CD27 on activated human memory B cells correlates with their commitment to the plasma cell lineage. J Immunol. 2005;174(7):4034\u201342.","journal-title":"J Immunol"},{"key":"1665_CR38","doi-asserted-by":"crossref","unstructured":"Zhang Z, Mateus J, Coelho CH, Dan JM, Moderbacher CR, Galvez RI, et al. Humoral and cellular immune memory to four COVID-19 vaccines. Cell. 2022;185(14):2434\u201351 e17.","DOI":"10.1016\/j.cell.2022.05.022"},{"issue":"5","key":"1665_CR39","doi-asserted-by":"crossref","first-page":"878","DOI":"10.1016\/j.cell.2020.01.029","volume":"180","author":"M Singh","year":"2020","unstructured":"Singh M, Jackson KJL, Wang JJ, Schofield P, Field MA, Koppstein D, et al. Lymphoma driver mutations in the pathogenic evolution of an iconic human autoantibody. Cell. 2020;180(5):878-94.e19.","journal-title":"Cell"},{"issue":"21","key":"1665_CR40","doi-asserted-by":"crossref","first-page":"2957","DOI":"10.1093\/bioinformatics\/btr507","volume":"27","author":"T Mago\u010d","year":"2011","unstructured":"Mago\u010d T, Salzberg SL. FLASH: fast length adjustment of short reads to improve genome assemblies. Bioinformatics. 2011;27(21):2957\u201363.","journal-title":"Bioinformatics"},{"issue":"13","key":"1665_CR41","doi-asserted-by":"crossref","first-page":"1930","DOI":"10.1093\/bioinformatics\/btu138","volume":"30","author":"JA Vander Heiden","year":"2014","unstructured":"Vander Heiden JA, Yaari G, Uduman M, Stern JNH, O\u2019Connor KC, Hafler DA, et al. pRESTO: a toolkit for processing high-throughput sequencing raw reads of lymphocyte receptor repertoires. Bioinformatics. 2014;30(13):1930\u20132.","journal-title":"Bioinformatics"},{"key":"1665_CR42","unstructured":"Lefranc M-P, Lefranc G. The immunoglobulin factsbook. San Diego: Academic Press; 2001. xiv, pp. 457."},{"issue":"W1","key":"1665_CR43","doi-asserted-by":"crossref","first-page":"W34","DOI":"10.1093\/nar\/gkt382","volume":"41","author":"J Ye","year":"2013","unstructured":"Ye J, Ma N, Madden TL, Ostell JM. IgBLAST: an immunoglobulin variable domain sequence analysis tool. Nucleic Acids Res. 2013;41(W1):W34\u201340.","journal-title":"Nucleic Acids Res"},{"issue":"23","key":"1665_CR44","doi-asserted-by":"crossref","first-page":"3150","DOI":"10.1093\/bioinformatics\/bts565","volume":"28","author":"L Fu","year":"2012","unstructured":"Fu L, Niu B, Zhu Z, Wu S, Li W. CD-HIT: accelerated for clustering the next-generation sequencing data. Bioinformatics. 2012;28(23):3150\u20132.","journal-title":"Bioinformatics"},{"key":"1665_CR45","unstructured":"Team RC. R: a language and environment for statistical computing. Vienna: R Foundation for Statistical Computing; 2023."},{"key":"1665_CR46","unstructured":"team P. RStudio: integrated development environment for R. Boston: Posit Software, PBC; 2023."},{"key":"1665_CR47","doi-asserted-by":"crossref","first-page":"1686","DOI":"10.21105\/joss.01686","volume":"4","author":"HAM Wickham","year":"2019","unstructured":"Wickham HAM, Bryan J, Chang W, McGowan LD, Fran\u00e7ois R, Grolemund G, Hayes A, Henry L, Hester J, Kuhn M, Pedersen TL, Miller E, Bache SM, M\u00fcller K, Ooms J, Robinson D, Seidel DP, Spinu V, Takahashi K, Vaughan D, Wilke C, Woo K, Yutani H. Welcome to the tidyverse. J Open Source Soft. 2019;4:1686.","journal-title":"J Open Source Soft"},{"key":"1665_CR48","unstructured":"A K. _rstatix: Pipe-friendly framework for basic statistical tests_. . R package version 072. 2023. https:\/\/rpkgs.datanovia.com\/rstatix\/"},{"issue":"10","key":"1665_CR49","doi-asserted-by":"crossref","first-page":"981","DOI":"10.1038\/s41422-018-0076-9","volume":"28","author":"J Chen","year":"2018","unstructured":"Chen J, Cai Z, Bai M, Yu X, Zhang C, Cao C, et al. The RNA-binding protein ROD1\/PTBP3 cotranscriptionally defines AID-loading sites to mediate antibody class switch in mammalian genomes. Cell Res. 2018;28(10):981\u201395.","journal-title":"Cell Res"},{"issue":"33","key":"1665_CR50","doi-asserted-by":"crossref","first-page":"28007","DOI":"10.1074\/jbc.M112.370189","volume":"287","author":"Y Mu","year":"2012","unstructured":"Mu Y, Prochnow C, Pham P, Chen XS, Goodman MF. A structural basis for the biochemical behavior of activation-induced deoxycytidine deaminase class-switch recombination-defective hyper-IgM-2 mutants. J Biol Chem. 2012;287(33):28007\u201316.","journal-title":"J Biol Chem"},{"issue":"6","key":"1665_CR51","doi-asserted-by":"crossref","first-page":"586","DOI":"10.1016\/j.jmoldx.2022.02.007","volume":"24","author":"W Kermode","year":"2022","unstructured":"Kermode W, De Santis D, Truong L, Della Mina E, Salman S, Thompson G, et al. A novel targeted amplicon next-generation sequencing gene panel for the diagnosis of common variable immunodeficiency has a high diagnostic yield: results from the Perth CVID cohort study. J Mol Diagn. 2022;24(6):586\u201399.","journal-title":"J Mol Diagn"},{"key":"1665_CR52","doi-asserted-by":"crossref","unstructured":"Aan de Kerk DJ, Jansen MH, Jolles S, Warnatz K, Seneviratne SL, Ten Berge IJ, et al. Phenotypic and functional comparison of class switch recombination deficiencies with a subgroup of common variable immunodeficiencies. J Clin Immunol. 2016;36(7):656\u201366.","DOI":"10.1007\/s10875-016-0321-2"},{"issue":"5","key":"1665_CR53","doi-asserted-by":"crossref","first-page":"1881","DOI":"10.1182\/blood-2003-12-4420","volume":"105","author":"WI Lee","year":"2005","unstructured":"Lee WI, Torgerson TR, Schumacher MJ, Yel L, Zhu Q, Ochs HD. Molecular analysis of a large cohort of patients with the hyper immunoglobulin M (IgM) syndrome. Blood. 2005;105(5):1881\u201390.","journal-title":"Blood"},{"issue":"4","key":"1665_CR54","doi-asserted-by":"crossref","first-page":"325","DOI":"10.4161\/nucl.1.4.12107","volume":"1","author":"AM Patenaude","year":"2010","unstructured":"Patenaude AM, Di Noia JM. The mechanisms regulating the subcellular localization of AID. Nucleus. 2010;1(4):325\u201331.","journal-title":"Nucleus"},{"issue":"10","key":"1665_CR55","doi-asserted-by":"crossref","first-page":"3318","DOI":"10.1182\/blood-2004-04-1558","volume":"104","author":"L Pasqualucci","year":"2004","unstructured":"Pasqualucci L, Guglielmino R, Houldsworth J, Mohr J, Aoufouchi S, Polakiewicz R, et al. Expression of the AID protein in normal and neoplastic B cells. Blood. 2004;104(10):3318\u201325.","journal-title":"Blood"},{"issue":"7","key":"1665_CR56","doi-asserted-by":"crossref","first-page":"1975","DOI":"10.1073\/pnas.0307335101","volume":"101","author":"S Ito","year":"2004","unstructured":"Ito S, Nagaoka H, Shinkura R, Begum N, Muramatsu M, Nakata M, et al. Activation-induced cytidine deaminase shuttles between nucleus and cytoplasm like apolipoprotein B mRNA editing catalytic polypeptide 1. Proc Natl Acad Sci U S A. 2004;101(7):1975\u201380.","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"26","key":"1665_CR57","doi-asserted-by":"crossref","first-page":"18470","DOI":"10.1074\/jbc.274.26.18470","volume":"274","author":"M Muramatsu","year":"1999","unstructured":"Muramatsu M, Sankaranand VS, Anant S, Sugai M, Kinoshita K, Davidson NO, et al. Specific expression of activation-induced cytidine deaminase (AID), a novel member of the RNA-editing deaminase family in germinal center B cells. J Biol Chem. 1999;274(26):18470\u20136.","journal-title":"J Biol Chem"},{"issue":"9","key":"1665_CR58","doi-asserted-by":"crossref","first-page":"1691","DOI":"10.1084\/jem.188.9.1691","volume":"188","author":"SG Tangye","year":"1998","unstructured":"Tangye SG, Liu YJ, Aversa G, Phillips JH, de Vries JE. Identification of functional human splenic memory B cells by expression of CD148 and CD27. J Exp Med. 1998;188(9):1691\u2013703.","journal-title":"J Exp Med"},{"issue":"2","key":"1665_CR59","doi-asserted-by":"crossref","first-page":"322","DOI":"10.1172\/JCI25720","volume":"116","author":"CS Ma","year":"2006","unstructured":"Ma CS, Pittaluga S, Avery DT, Hare NJ, Maric I, Klion AD, et al. Selective generation of functional somatically mutated IgM+CD27+, but not Ig isotype-switched, memory B cells in X-linked lymphoproliferative disease. J Clin Investig. 2006;116(2):322\u201333.","journal-title":"J Clin Investig"},{"issue":"12","key":"1665_CR60","doi-asserted-by":"crossref","first-page":"2739","DOI":"10.1084\/jem.20130323","volume":"210","author":"EK Deenick","year":"2013","unstructured":"Deenick EK, Avery DT, Chan A, Berglund LJ, Ives ML, Moens L, et al. Naive and memory human B cells have distinct requirements for STAT3 activation to differentiate into antibody-secreting plasma cells. J Exp Med. 2013;210(12):2739\u201353.","journal-title":"J Exp Med"},{"key":"1665_CR61","doi-asserted-by":"crossref","first-page":"65","DOI":"10.3389\/fimmu.2014.00065","volume":"5","author":"L Moens","year":"2014","unstructured":"Moens L, Tangye SG. Cytokine-mediated regulation of plasma cell generation: IL-21 takes center stage. Front Immunol. 2014;5:65.","journal-title":"Front Immunol"},{"issue":"3","key":"1665_CR62","doi-asserted-by":"crossref","first-page":"1767","DOI":"10.4049\/jimmunol.181.3.1767","volume":"181","author":"DT Avery","year":"2008","unstructured":"Avery DT, Bryant VL, Ma CS, de Waal MR, Tangye SG. IL-21-induced isotype switching to IgG and IgA by human naive B cells is differentially regulated by IL-4. J Immunol. 2008;181(3):1767\u201379.","journal-title":"J Immunol"},{"key":"1665_CR63","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1146\/annurev.immunol.20.090501.112049","volume":"20","author":"T Honjo","year":"2002","unstructured":"Honjo T, Kinoshita K, Muramatsu M. Molecular mechanism of class switch recombination: linkage with somatic hypermutation. Annu Rev Immunol. 2002;20:165\u201396.","journal-title":"Annu Rev Immunol"},{"issue":"2","key":"1665_CR64","doi-asserted-by":"crossref","first-page":"335","DOI":"10.1006\/jmbi.2001.4937","volume":"312","author":"T Matsuda","year":"2001","unstructured":"Matsuda T, Bebenek K, Masutani C, Rogozin IB, Hanaoka F, Kunkel TA. Error rate and specificity of human and murine DNA polymerase eta. J Mol Biol. 2001;312(2):335\u201346.","journal-title":"J Mol Biol"},{"issue":"6","key":"1665_CR65","doi-asserted-by":"crossref","first-page":"1121","DOI":"10.1016\/0092-8674(91)90289-B","volume":"67","author":"C Berek","year":"1991","unstructured":"Berek C, Berger A, Apel M. Maturation of the immune response in germinal centers. Cell. 1991;67(6):1121\u20139.","journal-title":"Cell"},{"issue":"12","key":"1665_CR66","doi-asserted-by":"crossref","first-page":"2070","DOI":"10.1016\/j.ebiom.2015.11.034","volume":"2","author":"JD Galson","year":"2015","unstructured":"Galson JD, Truck J, Fowler A, Clutterbuck EA, Munz M, Cerundolo V, et al. Analysis of B cell repertoire dynamics following hepatitis B vaccination in humans, and enrichment of vaccine-specific antibody sequences. EBioMedicine. 2015;2(12):2070\u20139.","journal-title":"EBioMedicine"},{"issue":"10","key":"1665_CR67","doi-asserted-by":"crossref","first-page":"3967","DOI":"10.1182\/blood-2005-10-4170","volume":"107","author":"G Cattoretti","year":"2006","unstructured":"Cattoretti G, B\u00fcttner M, Shaknovich R, Kremmer E, Alobeid B, Niedobitek G. Nuclear and cytoplasmic AID in extrafollicular and germinal center B cells. Blood. 2006;107(10):3967\u201375.","journal-title":"Blood"},{"issue":"6","key":"1665_CR68","doi-asserted-by":"crossref","first-page":"879","DOI":"10.1172\/JCI13051","volume":"108","author":"E Meffre","year":"2001","unstructured":"Meffre E, Milili M, Blanco-Betancourt C, Antunes H, Nussenzweig MC, Schiff C. Immunoglobulin heavy chain expression shapes the B cell receptor repertoire in human B cell development. J Clin Invest. 2001;108(6):879\u201386.","journal-title":"J Clin Invest"},{"issue":"28","key":"1665_CR69","doi-asserted-by":"crossref","first-page":"11554","DOI":"10.1073\/pnas.1102600108","volume":"108","author":"G Meyers","year":"2011","unstructured":"Meyers G, Ng YS, Bannock JM, Lavoie A, Walter JE, Notarangelo LD, et al. Activation-induced cytidine deaminase (AID) is required for B-cell tolerance in humans. Proc Natl Acad Sci U S A. 2011;108(28):11554\u20139.","journal-title":"Proc Natl Acad Sci U S A"}],"container-title":["Journal of Clinical Immunology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s10875-024-01665-1.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s10875-024-01665-1\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s10875-024-01665-1.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,7,1]],"date-time":"2024-07-01T23:32:03Z","timestamp":1719876723000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s10875-024-01665-1"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,2,16]]},"references-count":69,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2024,4]]}},"alternative-id":["1665"],"URL":"https:\/\/doi.org\/10.1007\/s10875-024-01665-1","relation":{},"ISSN":["0271-9142","1573-2592"],"issn-type":[{"value":"0271-9142","type":"print"},{"value":"1573-2592","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,2,16]]},"assertion":[{"value":"24 September 2023","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"21 January 2024","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"16 February 2024","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"1 July 2024","order":4,"name":"change_date","label":"Change Date","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"Update","order":5,"name":"change_type","label":"Change Type","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The original version of this paper was updated to present the family name of Erika Della Mina.","order":6,"name":"change_details","label":"Change Details","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"This study was approved by the Sydney Local Health District RPAH Zone Human Research Ethics Committee and Research Governance Office, Royal Prince Alfred Hospital, Camperdown, NSW, Australia (Protocol X16-0210\/LNR\/16\/RPAH\/257); and the West Australian South Metropolitan Health Service (SMHS) Human Research Ethics Committee (RGS 0665). Written informed consent was obtained from participants or their guardians. Experiments using samples from human subjects were conducted in accordance with local regulations and with the approval of the IRBs of corresponding institutions.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics Approval"}},{"value":"Written informed consent was obtained from participants or their guardians.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent to Participate"}},{"value":"Patients signed informed consent regarding publishing their data.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent to Publish"}},{"value":"All authors have no conflicts of interest to declare.","order":5,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of Interest"}}],"article-number":"66"}}