{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T05:44:50Z","timestamp":1791438290078,"version":"4.3.3"},"reference-count":99,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,2,18]],"date-time":"2026-02-18T00:00:00Z","timestamp":1771372800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>Cold agglutinin disease is an autoimmune condition characterised by expression of self-reactive antibodies to I\/i carbohydrate blood group antigens (polymers of N-acetyllactosamine or \u2018LacNAc\u2019 units) resulting in anaemia through the agglutination and complement-mediated destruction of red blood cells. This antibody response is dominated by antibodies of the human IGHV4\u201334 germline, which display a unique hydrophobic patch formed by germline-encoded tryptophan and tyrosine residues at positions 7 and 25 within framework 1 (FR1). Although the requirement for conservation of this FR1 patch for binding to the I\/i carbohydrate antigen has been well established, structural insights regarding the mechanistic role of the FR1 patch have remained elusive. Intriguingly, recent papers describing IGHV4\u201334 antibodies bound to the glycan-adorned surface of the HIV envelope glycoprotein shed light on the utility of this FR1 surface. Rather than indirectly shaping the conformation of the conventional antigen binding site as previously proposed, the structures reveal direct interfaces between the hydrophobic FR1 patch and high mannose glycans projected by HIV. Given the stereochemical similarities between these glycans and LacNAc, these structures suggest how I\/i self-antigen glycans might be similarly engaged by IGHV4\u201334 antibodies in a framework-centric non-CDR mode and provide a rationale for the preservation of this otherwise self-reactive antibody germline.<\/jats:p>","DOI":"10.3389\/fimmu.2026.1767837","type":"journal-article","created":{"date-parts":[[2026,2,18]],"date-time":"2026-02-18T06:53:42Z","timestamp":1771397622000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["Framework-mediated binding of foreign and self-glycans by IGHV4\u201334 antibodies"],"prefix":"10.3389","volume":"17","author":[{"given":"David B.","family":"Langley","sequence":"first","affiliation":[{"name":"Immune Biotherapies Program, Garvan Institute of Medical Research","place":["Darlinghurst, NSW, Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher J.","family":"Jara","sequence":"additional","affiliation":[{"name":"Immune Biotherapies Program, Garvan Institute of Medical Research","place":["Darlinghurst, NSW, Australia"]},{"name":"St. Vincent\u2019s Clinical School, Faculty of Medicine, University of New South Wales Sydney","place":["Sydney, NSW, Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jake Y.","family":"Henry","sequence":"additional","affiliation":[{"name":"Immune Biotherapies Program, Garvan Institute of Medical Research","place":["Darlinghurst, NSW, Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joanne H.","family":"Reed","sequence":"additional","affiliation":[{"name":"The Westmead Institute for Medical Research, The University of Sydney","place":["Westmead, NSW, Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher C.","family":"Goodnow","sequence":"additional","affiliation":[{"name":"Immune Biotherapies Program, Garvan Institute of Medical Research","place":["Darlinghurst, NSW, Australia"]},{"name":"St. Vincent\u2019s Clinical School, Faculty of Medicine, University of New South Wales Sydney","place":["Sydney, NSW, Australia"]},{"name":"Cellular Genomics Futures Institute, University of New South Wales Sydney","place":["Sydney, NSW, Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Christ","sequence":"additional","affiliation":[{"name":"Immune Biotherapies Program, Garvan Institute of Medical Research","place":["Darlinghurst, NSW, Australia"]},{"name":"St. Vincent\u2019s Clinical School, Faculty of Medicine, University of New South Wales Sydney","place":["Sydney, NSW, Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,2,18]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"107","DOI":"10.1001\/archinte.1937.00170170113007","article-title":"Reversible autohemagglutination with peripheral vascular symptoms","volume":"59","author":"McCombs","year":"1937","journal-title":"Arch Intern Med"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI101624","article-title":"COLD Agglutinins. 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