{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T21:36:54Z","timestamp":1768513014821,"version":"3.49.0"},"posted":{"date-parts":[[2024,6,2]]},"group-title":"Immunology","reference-count":85,"publisher":"openRxiv","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2024,6,2]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>Complement-mediated hemolytic uremic syndrome (CM-HUS) is a thrombotic microangiopathy characterized by germline variants or acquired antibodies to complement proteins and regulators. Building upon our prior experience with the modified Ham (mHam) assay for ex vivo diagnosis of complementopathies, we have developed an array of cell-based complement \u201cbiosensors\u2019\u2019 by selective removal of complement regulatory proteins (CD55 and CD59, CD46, or a combination thereof) in an autonomously bioluminescent HEK293 cell line. These biosensors can be used as a sensitive method for diagnosing CM-HUS and monitoring therapeutic complement blockade. Using specific complement pathway inhibitors, this model identifies IgM-driven classical pathway stimulus during both acute disease and in many patients during clinical remission. This provides a potential explanation for ~50% of CM-HUS patients who lack an alternative pathway \u201cdriving\u201d variant and suggests at least a subset of CM-HUS is characterized by a breakdown of IgM immunologic tolerance.<\/jats:p>\n                <jats:sec>\n                  <jats:title>Key Points<\/jats:title>\n                  <jats:list list-type=\"order\">\n                    <jats:list-item>\n                      <jats:p>CM-HUS has a CP stimulus driven by polyreactive IgM, addressing the mystery of why 40% of CM-HUS lack complement specific variants<\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>Complement biosensors and the bioluminescent mHam can be used to aid in diagnosis of CM-HUS and monitor complement inhibitor therapy<\/jats:p>\n                    <\/jats:list-item>\n                  <\/jats:list>\n                <\/jats:sec>","DOI":"10.1101\/2024.05.29.596475","type":"posted-content","created":{"date-parts":[[2024,6,2]],"date-time":"2024-06-02T19:25:24Z","timestamp":1717356324000},"source":"Crossref","is-referenced-by-count":0,"title":["Complement Biosensors Identify a Classical Pathway Stimulus in Complement-Mediated Hemolytic Uremic Syndrome"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0617-7256","authenticated-orcid":false,"given":"Michael A.","family":"Cole","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nikhil","family":"Ranjan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gloria F.","family":"Gerber","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiang-Zuo","family":"Pan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daniel","family":"Flores-Guerrero","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shruti","family":"Chaturvedi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"C. John","family":"Sperati","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Keith R.","family":"McCrae","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Robert A.","family":"Brodsky","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2024060604300972000_2024.05.29.596475v1.1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1208981"},{"key":"2024060604300972000_2024.05.29.596475v1.2","doi-asserted-by":"publisher","DOI":"10.1002\/humu.21256"},{"key":"2024060604300972000_2024.05.29.596475v1.3","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1701695"},{"key":"2024060604300972000_2024.05.29.596475v1.4","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2011-10-383281"},{"issue":"22","key":"2024060604300972000_2024.05.29.596475v1.5","doi-asserted-by":"crossref","first-page":"2185","DOI":"10.1182\/blood.2021012037","article-title":"Functional characterization of 105 factor H variants associated with aHUS: lessons for variant classification","volume":"138","year":"2021","journal-title":"Blood"},{"key":"2024060604300972000_2024.05.29.596475v1.6","doi-asserted-by":"publisher","DOI":"10.1016\/j.molimm.2006.08.024"},{"issue":"6","key":"2024060604300972000_2024.05.29.596475v1.7","doi-asserted-by":"crossref","first-page":"1614","DOI":"10.1016\/j.ekir.2021.03.885","article-title":"Risk of Atypical HUS Among Family Members of Patients Carrying Complement Regulatory Gene Abnormality","volume":"6","year":"2021","journal-title":"Kidney Int Rep"},{"key":"2024060604300972000_2024.05.29.596475v1.8","doi-asserted-by":"publisher","DOI":"10.1016\/j.semnephrol.2013.08.003"},{"key":"2024060604300972000_2024.05.29.596475v1.9","doi-asserted-by":"crossref","first-page":"108616","DOI":"10.1016\/j.clim.2020.108616","article-title":"Ex vivo assays to detect complement activation in complementopathies","volume":"221","year":"2020","journal-title":"Clin. 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