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However, it remains unclear whether this phenomenon also occurs in other antigen-defined antibody populations. Here, we investigated synergistic polyreactivity in isohemagglutinins (naturally occurring antibodies against ABO blood group antigens) and its potential role in antimicrobial defense. Isohemagglutinins were affinity-purified from pooled plasma from groups of healthy donors sharing the same ABO blood group, then characterized by solid-phase immunoassays, SDS-PAGE, and Western blotting. Binding to formaldehyde-fixed\n                    <jats:italic>Streptococcus pneumoniae<\/jats:italic>\n                    representing 30 serotypes was assessed by flow cytometry. Specificity was further examined using inhibition assays with soluble pneumococcal polysaccharides. To evaluate clinical relevance, ABO blood group types (used as proxies for isohemagglutinin profiles) were linked to serotype-specific invasive pneumococcal disease (IPD) events using Danish nationwide registry data. The purified isohemagglutinins retained specificity for their cognate ABO antigens. Notably, they bound all tested pneumococcal strains, primarily through reactivity with the common cell wall polysaccharide. Adsorption studies further revealed serotype-specific capsule binding mediated by distinct isohemagglutinin clones, demonstrating synergistic polyreactivity. Despite this, population-level analyses showed only modest protection: most notably, individuals with blood types B or O (producers of anti-A and anti-A,B isohemagglutinins, respectively) had a 19% lower prevalence of serotype 9V IPD than blood type A or AB individuals. Although the overall protective effect of isohemagglutinins against IPD seems limited, the observed synergistic polyreactivity supports the concept that this is a general feature of antigen-defined antibodies, extending beyond anti-\u03b1Gal antibodies.\n                  <\/jats:p>","DOI":"10.1007\/s00430-025-00862-y","type":"journal-article","created":{"date-parts":[[2026,1,9]],"date-time":"2026-01-09T10:43:14Z","timestamp":1767955394000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Isohemagglutinins exhibit synergistic polyreactivity toward Streptococcus pneumoniae surface antigens: implications for broad-spectrum reactivity of human antibodies"],"prefix":"10.1007","volume":"215","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5004-7822","authenticated-orcid":false,"given":"Jens Magnus","family":"Bernth Jensen","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9107-2023","authenticated-orcid":false,"given":"Ole Schmeltz","family":"S\u00f8gaard","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-6317-553X","authenticated-orcid":false,"given":"Mikkel Steen","family":"Petersen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steen","family":"Hoffmann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2808-4755","authenticated-orcid":false,"given":"Bjarne Kuno","family":"M\u00f8ller","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annette Gudmann","family":"Hansen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6777-054X","authenticated-orcid":false,"given":"Uffe B. 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