{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T11:00:46Z","timestamp":1785841246064,"version":"3.56.0"},"reference-count":40,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2023,8,2]],"date-time":"2023-08-02T00:00:00Z","timestamp":1690934400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000362","name":"Asthma and Lung UK","doi-asserted-by":"publisher","award":["AUK\u2010CDA\u20102019\u2010412"],"award-info":[{"award-number":["AUK\u2010CDA\u20102019\u2010412"]}],"id":[{"id":"10.13039\/501100000362","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000265","name":"Medical Research Council","doi-asserted-by":"publisher","award":["MR\/M022943\/1"],"award-info":[{"award-number":["MR\/M022943\/1"]}],"id":[{"id":"10.13039\/501100000265","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["pericles.pericles-gcp.literatumonline.com"],"crossmark-restriction":true},"short-container-title":["Immunology"],"published-print":{"date-parts":[[2023,12]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Phosphoinositide 3\u2010kinase (PI3K) p110\u03b4 signalling negatively regulates the production of mouse IgE. However, there are disparities between the mouse and human IgE biology, and the role of PI3K p110\u03b4 in the production of human IgE is yet to be determined. To investigate the effect of PI3K p110\u03b4 inhibition in the production of human IgE we isolated human B cells from tonsil tissue and stimulated them with IL\u20104 and anti\u2010CD40 antibody\u00a0to induce class switching to IgE and IgG1 in the presence or absence of IC87114, a small molecule inhibitor of PI3K p110\u03b4. Using FACS, RT\u2010PCR and ELISA we examined the effect of PI3K p110\u03b4 inhibition on IgE production and determined the mechanisms involved. Unlike in mice, we observed that PI3K p110\u03b4 inhibition significantly reduces the number of IgE\n                    <jats:sup>+<\/jats:sup>\n                    switched cells and the amounts of secreted IgE in IL4 and anti\u2010CD40 cultures. However, the number of IgG1\n                    <jats:sup>+<\/jats:sup>\n                    cells and secreted IgG1 were largely unaffected by PI3K p110\u03b4 inhibition. The expression levels of AID, \u03b5 and \u03b31 germinal transcripts or other factors involved in the regulation of CSR to IgE and IgG1 were also unaffected by IC87114. However, we found that IC87114 significantly decreases the proliferation of tonsil B cells stimulated with IL\u20104 and anti\u2010CD40, specifically reducing the frequency of cells that had undergone 4 divisions or more. In addition, PI3K p110\u03b4 inhibition reduced the levels of IRF4 expression in IgE\n                    <jats:sup>+<\/jats:sup>\n                    germinal centre\u2010like B cells leading to a block in plasma cell differentiation. In conclusion, PI3K p110\u03b4 signalling is required for the production of human IgE, which makes it a pharmacological target for the treatment of allergic disease.\n                  <\/jats:p>","DOI":"10.1111\/imm.13684","type":"journal-article","created":{"date-parts":[[2023,8,2]],"date-time":"2023-08-02T07:35:30Z","timestamp":1690961730000},"page":"483-494","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Inhibition of\n                    <scp>PI3K<\/scp>\n                    p110\u03b4 activity reduces\n                    <scp>IgE<\/scp>\n                    production in\n                    <scp>IL<\/scp>\n                    \u20104 and\n                    <scp>anti\u2010CD40<\/scp>\n                    stimulated human B cell cultures"],"prefix":"10.1111","volume":"170","author":[{"given":"Anna","family":"Cutrina\u2010Pons","sequence":"first","affiliation":[{"name":"Randall Centre for Cell &amp; Molecular Biophysics King's College London  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7714-8906","authenticated-orcid":false,"given":"Aloka","family":"De Sa","sequence":"additional","affiliation":[{"name":"Randall Centre for Cell &amp; Molecular Biophysics King's College London  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David J.","family":"Fear","sequence":"additional","affiliation":[{"name":"Division of Asthma, Allergy and Lung Biology King's College London  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hannah J.","family":"Gould","sequence":"additional","affiliation":[{"name":"Randall Centre for Cell &amp; Molecular Biophysics King's College London  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8228-4868","authenticated-orcid":false,"given":"Faruk","family":"Ramadani","sequence":"additional","affiliation":[{"name":"Randall Centre for Cell &amp; Molecular Biophysics King's College London  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2023,8,2]]},"reference":[{"key":"e_1_2_12_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/nri2273"},{"key":"e_1_2_12_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2011.10.029"},{"key":"e_1_2_12_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2021.11.006"},{"key":"e_1_2_12_5_1","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.21238"},{"key":"e_1_2_12_6_1","doi-asserted-by":"publisher","DOI":"10.1038\/ni.3508"},{"issue":"12","key":"e_1_2_12_7_1","first-page":"2755","article-title":"The distinctive germinal center phase of IgE+ B lymphocytes limits their contribution to the classical memory response","volume":"210","author":"He JS","year":"2013","journal-title":"."},{"key":"e_1_2_12_8_1","first-page":"40","volume-title":"Trends Immunol","author":"Gould HJ","year":"2015"},{"issue":"1","key":"e_1_2_12_9_1","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1111\/all.12911","article-title":"Ontogeny of human IgE\u2010expressing B cells and plasma cells","volume":"72","author":"Ramadani F","journal-title":"Allergy"},{"key":"e_1_2_12_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2012.02.009"},{"key":"e_1_2_12_11_1","doi-asserted-by":"publisher","DOI":"10.1038\/nri1181"},{"issue":"1","key":"e_1_2_12_12_1","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1084\/jem.181.1.181","article-title":"Characterization of an Interleukln 4 (IL\u20104) Responsive Region in the Immunoglobulln Heavy Chain Germ!Ine E Promoter: Regulation by NF\u2010IL\u20104, a C\/EBP Family Member and NF\u2010KB\/p50","volume":"181","author":"Delphin S","year":"1995","journal-title":"J Exp Med"},{"key":"e_1_2_12_13_1","doi-asserted-by":"publisher","DOI":"10.1038\/380627a0"},{"issue":"3","key":"e_1_2_12_14_1","doi-asserted-by":"crossref","first-page":"395","DOI":"10.1093\/intimm\/dxh042","article-title":"Induction of activation\u2010induced cytidine deaminase gene expression by IL\u20104 and CD40 ligation is dependent on STAT6 and NF\u03baB","volume":"16","author":"Dedeoglu F","year":"2004","journal-title":"Int Immunol"},{"key":"e_1_2_12_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopha.2006.10.001"},{"issue":"4","key":"e_1_2_12_16_1","doi-asserted-by":"crossref","first-page":"811","DOI":"10.1016\/j.jaci.2008.08.008","article-title":"Genetic or pharmaceutical blockade of p110\u03b4 phosphoinositide 3\u2010kinase enhances IgE production","volume":"122","author":"Ting ZT","year":"2008","journal-title":"J Allergy Clin Immunol"},{"issue":"8","key":"e_1_2_12_17_1","doi-asserted-by":"crossref","first-page":"3700","DOI":"10.4049\/jimmunol.1103302","article-title":"p110\u03b4 phosphoinositide 3\u2010kinase represses IgE switch by potentiating BCL6 expression","volume":"188","author":"Ting ting Z","year":"2012","journal-title":"J Immunol"},{"key":"e_1_2_12_18_1","doi-asserted-by":"publisher","DOI":"10.1093\/intimm\/dxn009"},{"key":"e_1_2_12_19_1","doi-asserted-by":"publisher","DOI":"10.1038\/nri1056"},{"key":"e_1_2_12_20_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2009-07-232330"},{"key":"e_1_2_12_21_1","doi-asserted-by":"publisher","DOI":"10.1002\/eji.200636401"},{"key":"e_1_2_12_22_1","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.19.10.7264"},{"key":"e_1_2_12_23_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41573-021-00209-1"},{"key":"e_1_2_12_24_1","doi-asserted-by":"crossref","DOI":"10.3389\/fimmu.2017.00747","article-title":"The selective phosphoinoside\u20103\u2010kinase p110\u03b4 inhibitor IPI\u20103063 potently suppresses b cell survival, proliferation, and differentiation","volume":"8","author":"Chiu H","year":"2017","journal-title":"Front Immunol"},{"issue":"10","key":"e_1_2_12_25_1","doi-asserted-by":"crossref","first-page":"1269","DOI":"10.1111\/all.12679","article-title":"Intrinsic properties of germinal center\u2010derived B cells promote their enhanced class switching to IgE","volume":"70","author":"Ramadani F","year":"2015","journal-title":"J Allergy Clin Immunol"},{"key":"e_1_2_12_26_1","doi-asserted-by":"publisher","DOI":"10.1080\/10409238.2016.1215288"},{"key":"e_1_2_12_27_1","doi-asserted-by":"crossref","unstructured":"BilancioA OkkenhaugK CampsM EmeryJL RuckleT RommelC et al.Key role of the p110 isoform of PI3K in B\u2010cell antigen and IL\u20104 receptor signaling: comparative analysis of genetic and pharmacologic interference with p110 function in B cells. Blood.2006;107(2):642\u2013650.","DOI":"10.1182\/blood-2005-07-3041"},{"key":"e_1_2_12_28_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0167-4781(99)00131-1"},{"key":"e_1_2_12_29_1","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1521-4141(199803)28:03<1040::AID-IMMU1040>3.0.CO;2-9"},{"key":"e_1_2_12_30_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2019.00402"},{"key":"e_1_2_12_31_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature02991"},{"key":"e_1_2_12_32_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.180.4.2538"},{"key":"e_1_2_12_33_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-020-64594-0"},{"key":"e_1_2_12_34_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1440-1843.2008.01369.x"},{"key":"e_1_2_12_35_1","doi-asserted-by":"publisher","DOI":"10.1096\/fj.05-5045com"},{"key":"e_1_2_12_36_1","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1007\/978-0-387-79311-5_5","article-title":"The role of PI3K signalling in the b cell response to antigen","volume":"633","author":"Turner M","year":"2009","journal-title":"Adv Exp Med Biol."},{"key":"e_1_2_12_37_1","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20020805"},{"key":"e_1_2_12_38_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1073560"},{"key":"e_1_2_12_39_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2006.08.015"},{"key":"e_1_2_12_40_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1001730"},{"key":"e_1_2_12_41_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2020.107982"}],"container-title":["Immunology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/imm.13684","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,11,29]],"date-time":"2023-11-29T06:27:55Z","timestamp":1701239275000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/imm.13684"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,8,2]]},"references-count":40,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2023,12]]}},"alternative-id":["10.1111\/imm.13684"],"URL":"https:\/\/doi.org\/10.1111\/imm.13684","archive":["Portico"],"relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2022.08.09.503316","asserted-by":"object"}]},"ISSN":["0019-2805","1365-2567"],"issn-type":[{"value":"0019-2805","type":"print"},{"value":"1365-2567","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,8,2]]},"assertion":[{"value":"2022-12-08","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-07-20","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-08-02","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}