{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,9]],"date-time":"2026-04-09T11:48:31Z","timestamp":1775735311354,"version":"3.50.1"},"reference-count":27,"publisher":"Wiley","issue":"12","license":[{"start":{"date-parts":[[2025,12,29]],"date-time":"2025-12-29T00:00:00Z","timestamp":1766966400000},"content-version":"vor","delay-in-days":28,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2025,12,1]],"date-time":"2025-12-01T00:00:00Z","timestamp":1764547200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Immunity Inflam &amp;amp; Disease"],"published-print":{"date-parts":[[2025,12]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Objectives<\/jats:title>\n                    <jats:p>\n                      Pathogenic variants in\n                      <jats:italic>IL2RG<\/jats:italic>\n                      , encoding the common \u03b3 chain (\u03b3\n                      <jats:sub>c<\/jats:sub>\n                      \/CD132), usually lead to T\u2009\u2212\u2009B\u2009+\u2009NK\u2010 X\u2010SCID but can, occasionally, generate a T\u2009\u2212\u2009B\u2009+\u2009NK+ phenotype. We wanted to delineate potential mechanisms for this discrepancy.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>The immunological work\u2010up of our patient comprised: whole genome sequencing and subsequent bioinformatics, flow\u2010cytometry (lymphocyte surface receptor expression, STAT5 phosphorylation, NK cell proliferation and degranulation), lymphocyte stimulation (IL\u20102, IL\u20104 and IL\u201015) as well as restriction enzyme digestion and fragment size separation (evaluation of relative WT\/variant expression).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Findings<\/jats:title>\n                    <jats:p>\n                      Our patient, hemizygous for a maternally derived, c.677\u2009G\u2009&gt;\u2009A\n                      <jats:italic>IL2RG<\/jats:italic>\n                      missense variant displayed a T\u2009\u2212\u2009B\u2009+\u2009NK+ phenotype, no dysmorphic features and no thymus. The \u03b3\n                      <jats:sub>c<\/jats:sub>\n                      was surface expressed. In contrast to B cells from cord\u2010blood and adults (including maternal B cells), only pre\u2010gene therapy (patient) B cells did not decrease IL\u20104R\u03b1 surface expression upon IL\u20104 stimulation, consistent with compromised IL\u20104R (and \u03b3\n                      <jats:sub>c<\/jats:sub>\n                      ) function. After gene therapy, patient B cells decreased IL\u20104R\u03b1 upon Il\u20104 stimulation. Pre\u2010gene therapy NK cells displayed normal, K562 cell, induced degranulation and, in response to IL\u20102 and IL\u201015 and exhibited normal initial pSTAT5 kinetics but clearly attenuated activation and proliferation day six. By restriction enzyme digestion and fragment size separation, selected T and B cells from the healthy mother exhibited skewed expression (92% and 84%, respectively) of the WT\n                      <jats:italic>IL2RG<\/jats:italic>\n                      allele.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      The selective WT\n                      <jats:italic>IL2RG<\/jats:italic>\n                      expression in maternal B cells was consistent with the compromised IL\u20104R signaling (and compromised IL\u201021R signaling) in her offspring (the patient), as both IL\u20104 and IL\u201021 are critical for normal human B cell germinal center reactions but not for peripheral B cell homeostasis. The c.677\u2009G\u2009&gt;\u2009A\n                      <jats:italic>IL2RG<\/jats:italic>\n                      variant permitted normal NK cell degranulation and initial STAT5 phosphorylation but was incapable of sustaining normal NK cell activation and proliferation in vitro. As IL\u20102 and IL\u201015 induced in\u2010vitro NK cell proliferation is primarily mediated through the low affinity \u03b2\u03b3\n                      <jats:sub>c<\/jats:sub>\n                      (CD122\u2010CD132) complex, our data indicate the importance of high affinity IL\u201015R\u03b1 and IL\u20102 R\u03b1 mediated signaling in\u2010vivo for sustaining NK cell numbers in X\u2010linked SCID. Consequently, we further hypothesize that in cases of X\u2010linked SCID, where even initial IL\u201015 and IL\u20102 STAT5 phosphorylation is compromised, in\u2010vivo trans\u2010presentation of IL\u201015 (and IL\u20102), via the high affinity IL\u201015R\u03b1 and IL\u20102R\u03b1 receptor subunits, will not be able to sustain normal peripheral NK cell numbers\u201d.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/iid3.70307","type":"journal-article","created":{"date-parts":[[2025,12,30]],"date-time":"2025-12-30T05:51:17Z","timestamp":1767073877000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Functional Characterization of an\n                    <i>IL2RG<\/i>\n                    Variant, a Case Report of X\u2010Linked T\u2010 B\u2009+\u2009NK\u2009+\u2009SCID"],"prefix":"10.1002","volume":"13","author":[{"given":"Kristian","family":"Assing","sequence":"first","affiliation":[{"name":"Department of Clinical Immunology Odense University Hospital (OUH) Odense Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0470-0210","authenticated-orcid":false,"given":"Emil Birch","family":"Christensen","sequence":"additional","affiliation":[{"name":"Department of Clinical Immunology Odense University Hospital (OUH) Odense Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christoffer","family":"Dellgren","sequence":"additional","affiliation":[{"name":"Department of Clinical Immunology Odense University Hospital (OUH) Odense Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2129-2466","authenticated-orcid":false,"given":"Kerstin 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