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How some lymphocytes escape these constraints to cause autoimmune disease remains poorly understood. A long-standing hypothesis posits that somatic mutations in immune\u00a0regulatory genes may enable self-reactive lymphocytes to bypass tolerance checkpoints\n                    <jats:sup>1\u20133<\/jats:sup>\n                    , but testing this has been challenging owing to technical limitations. Here we used whole-exome and targeted NanoSeq\n                    <jats:sup>4,5<\/jats:sup>\n                    , an accurate single-molecule DNA sequencing protocol, to comprehensively search for driver mutations in autoimmune thyroid disease. This showed many B cell clones convergently acquiring loss-of-function mutations in the key immune checkpoint genes\n                    <jats:italic>TNFRSF14<\/jats:italic>\n                    (also known as\u00a0\n                    <jats:italic>HVEM<\/jats:italic>\n                    ) and\n                    <jats:italic>CD274<\/jats:italic>\n                    (which encodes\u00a0PD-L1), as well as less frequent mutations in other immune genes. In highly inflamed biopsies, we detected tens to hundreds of independent immune checkpoint mutant clones. Laser microdissection, methylation sequencing, spatial transcriptomics, immunostaining, single-nucleus DNA sequencing and antibody synthesis localized these mutations to B cells, confirmed some to be self-reactive and identified clones carrying multiple hits. We found widespread\n                    <jats:italic>TNFRSF14<\/jats:italic>\n                    biallelic loss, and clones with as many as 4\u20136 driver mutations. While each clone accounts for a small fraction of cells (typically less than 1%), the myriad mutant clones in each donor amounted to a substantial fraction of B cells harbouring driver mutations. Our results support the hypothesis that somatic mutations in autoimmune lymphocytes may allow them to escape tolerance constraints through a polyclonal cascade of somatic evolution, providing insights into the molecular basis of autoimmune disease.\n                  <\/jats:p>","DOI":"10.1038\/s41586-026-10493-9","type":"journal-article","created":{"date-parts":[[2026,4,14]],"date-time":"2026-04-14T15:02:09Z","timestamp":1776178929000},"page":"131-141","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Polyclonal selection of immune checkpoint mutations in thyroid autoimmunity"],"prefix":"10.1038","volume":"654","author":[{"given":"Pantelis A.","family":"Nicola","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3592-1005","authenticated-orcid":false,"given":"Andrew R. 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