{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,7,30]],"date-time":"2025-07-30T15:58:15Z","timestamp":1753891095513,"version":"3.41.2"},"reference-count":34,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,1,21]],"date-time":"2022-01-21T00:00:00Z","timestamp":1642723200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100017415","name":"Peking University First Hospital","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100017415","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>Atypical hemolytic uremic syndrome (aHUS) is a rare but severe type of thrombotic microangiopathy that is triggered by the abnormal activation of the alternative complement pathway. Previous studies have reported that three completely linked coding variants of<jats:italic>CFHR1<\/jats:italic>form two haplotypes, namely,<jats:italic>CFHR1<\/jats:italic>*A (c.469C, c.475C, c.523G) and<jats:italic>CFHR1<\/jats:italic>*B (c.469T, c.475G, c.523C).<jats:italic>CFHR1<\/jats:italic>*B is associated with susceptibility to aHUS. To explore the genetic mechanism by which<jats:italic>CFHR1<\/jats:italic>isoforms contribute to aHUS, we compared the structures of FHR1*A and FHR1*B by homology modeling and found differences in the angles between SCR3 and SCR4-SCR5, as FHR1*B had a larger angle than FHR1*A. Then, we expressed FHR1*A and FHR1*B recombinant proteins and compared their functions in complement system regulation and inflammation. We found that FHR1*B presented a significantly higher capacity for binding C3b and necrotic cells than FHR1*A. In a cofactor assay, the FHR-1*B showed stronger influence on FH mediated cofactor function than the FHR-1*A, resulted in fewer C3b cleavage products. In the C3 convertase assays, FHR1*B showed more powerful effect compared with FHR1*A regarding to de-regulate FH function of inhibition the assembling of C3bBb. Additionally, we also found that FHR1*B triggered monocytes to secrete higher levels of IL-1\u03b2 and IL-6 than FHR1*A. In the present study, we showed that variants of<jats:italic>CFHR1<\/jats:italic>might differently affect complement activation and sterile inflammation. Our findings provide a possible mechanism underlying the predisposition to aHUS caused by<jats:italic>CFHR1<\/jats:italic>isoform<jats:italic>CFHR1<\/jats:italic>*B.<\/jats:p>","DOI":"10.3389\/fimmu.2022.755694","type":"journal-article","created":{"date-parts":[[2022,1,21]],"date-time":"2022-01-21T06:03:49Z","timestamp":1642745029000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":3,"title":["Atypical Hemolytic Uremic Syndrome-Associated FHR1 Isoform FHR1*B Enhances Complement Activation and Inflammation"],"prefix":"10.3389","volume":"13","author":[{"given":"Boyang","family":"Xu","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuqi","family":"Kang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yujing","family":"Du","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Weiyi","family":"Guo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Li","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hong","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2022,1,21]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"e431","DOI":"10.1371\/journal.pmed.0030431","article-title":"Atypical 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