{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,28]],"date-time":"2026-04-28T22:16:41Z","timestamp":1777414601890,"version":"3.51.4"},"reference-count":34,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,1,5]],"date-time":"2026-01-05T00:00:00Z","timestamp":1767571200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100011103","name":"Rann\u00eds","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100011103","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>Selective IgA deficiency (sIgAD) is the most common primary antibody deficiency in Western populations and is associated with increased risks of respiratory infections, atopy, and autoimmunity. However, the serologic and B-cell\u2013intrinsic pathways underlying this immune dysregulation remain poorly defined. We sought to characterize a population-based adult sIgAD cohort clinically and immunologically and to identify soluble and transcriptional signatures that link cytokine milieu to B-cell dysfunction.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We studied 61 adults with sIgAD and 73 age- and sex-matched healthy controls from the Icelandic sIgAD cohort. Participants completed standardized questionnaires on infections, atopy, and autoimmune disease. Serum immunoglobulins and autoantibodies (ANA, ENA, RF, CCP) were quantified, and a 65-plex Luminex cytokine\/chemokine panel was measured in a subset of sIgAD individuals without active inflammatory disease and healthy controls. Purified CD19\u207a B cells from adults with sIgAD and controls were profiled by bulk RNA-seq at baseline and after 48 h TLR9 stimulation with CpG ODN 2006. Unsupervised analyses, differential expression, and correlation networks integrated clinical, serologic, and transcriptional data.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Clinically, adults with sIgAD had an airway-predominant infectious burden (notably increased sinusitis and pneumonia), a skin-skewed atopic pattern (eczema and urticaria), and frequent ANA\/ENA positivity despite normal IgG and IgM. Immunoglobulin measurements showed very low IgA, increased total IgG and IgG1, and selectively reduced IgG4. Serum profiling revealed a coherent five-analyte signature, IL-18, sCD40L, TSLP, CCL3, and TWEAK, elevated in sIgAD and associated with higher IgG, lower residual IgA, and ANA\/ENA positivity. This pattern was not reproduced in CpG-stimulated B-cell supernatants, indicating a non\u2013B-cell origin. RNA-seq of purified B cells demonstrated diagnosis-dependent transcriptional programs at baseline and after CpG, with prominently reduced expression of IL-18 receptor components in sIgAD B cells.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>Adult sIgAD is characterized by a blood-measurable endotype in which a systemic IL-18\u2013centered soluble signature coexists with reduced IL-18 receptor expression and altered signaling programs in B cells. This IL-18-IL-18R axis aligns with ANA\/ENA-associated immune dysregulation and an IgG-skewed class-switch profile, nominating IL-18\u2013related mediators and B-cell IL-18R expression as candidate biomarkers and mechanistic targets in a subset of adults with sIgAD.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2025.1687720","type":"journal-article","created":{"date-parts":[[2026,1,5]],"date-time":"2026-01-05T05:31:02Z","timestamp":1767591062000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Serologic IL-18 increase with B-cell IL-18R loss characterizes selective IgA deficiency"],"prefix":"10.3389","volume":"16","author":[{"given":"Andri L.","family":"Lemarquis","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hildur","family":"Sigurgrimsdottir","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fannar P.","family":"Theodors","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ida","family":"Karnsund","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Helga 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