{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,23]],"date-time":"2026-07-23T01:39:15Z","timestamp":1784770755684,"version":"3.55.0"},"reference-count":47,"publisher":"Oxford University Press (OUP)","issue":"2","license":[{"start":{"date-parts":[[2016,1,1]],"date-time":"2016-01-01T00:00:00Z","timestamp":1451606400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2016,1,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>The serum proteins factor H (FH), consisting of 20 complement control protein modules (CCPs), and its splice product FH-like protein 1 (FHL-1; consisting of CCPs 1\u20137) are major regulators of the alternative pathway (AP) of complement activation. The engineered version of FH, miniFH, contains only the N- and C-terminal portions of FH linked by an optimized peptide and shows \u223c10-fold higher ex vivo potency. We explored the hypothesis that regulatory potency is enhanced by unmasking of a ligand-binding site in the C-terminal CCPs 19\u201320 that is cryptic in full-length native FH. Therefore, we produced an FH variant lacking the central domains 10\u201315 (FH\u039410\u201315). To explore how avidity affects regulatory strength, we generated a duplicated version of miniFH, termed midiFH. We compared activities of FH\u039410\u201315 and midiFH to miniFH, FH, and FHL-1. Relative to FH, FH\u039410\u201315 exhibited an altered binding profile toward C3 activation products and a 5-fold-enhanced complement regulation on a paroxysmal nocturnal hemoglobinuria patient\u2019s erythrocytes. Contrary to dogma, FHL-1 and FH exhibited equal regulatory activity, suggesting that the role of FHL-1 in AP regulation has been underestimated. Unexpectedly, a substantially increased avidity for complement opsonins, as seen in midiFH, did not potentiate the inhibitory potential on host cells. In conclusion, comparisons of engineered and native FH-based regulators have identified features that determine high AP regulatory activity on host cells. Unrestricted availability of FH CCPs 19\u201320 and an optimal spatial orientation between the N- and C-terminal FH regions are key.<\/jats:p>","DOI":"10.4049\/jimmunol.1501919","type":"journal-article","created":{"date-parts":[[2015,12,8]],"date-time":"2015-12-08T14:29:59Z","timestamp":1449584999000},"page":"866-876","source":"Crossref","is-referenced-by-count":35,"title":["Comparative Analysis of Novel Complement-Targeted Inhibitors, MiniFH, and the Natural Regulators Factor H and Factor H\u2013like Protein 1 Reveal Functional Determinants of Complement Regulation"],"prefix":"10.1093","volume":"196","author":[{"given":"Markus J","family":"Harder","sequence":"first","affiliation":[{"name":"Institute of Pharmacology of Natural Products and Clinical Pharmacology, Ulm University , 89081 Ulm ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Markus","family":"Anliker","sequence":"additional","affiliation":[{"name":"Institute of Transfusion Medicine, University of Ulm , 89081 Ulm ,","place":["Germany"]},{"name":"Institute of Clinical Transfusion Medicine and Immunogenetics, German Red Cross Blood Service Baden-W\u00fcrttemberg \u2013 Hessen and University Hospital Ulm , 89081 Ulm ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Britta","family":"H\u00f6chsmann","sequence":"additional","affiliation":[{"name":"Institute of Transfusion Medicine, University of Ulm , 89081 Ulm ,","place":["Germany"]},{"name":"Institute of Clinical Transfusion Medicine and Immunogenetics, German Red Cross Blood Service Baden-W\u00fcrttemberg \u2013 Hessen and University Hospital Ulm , 89081 Ulm ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Simmet","sequence":"additional","affiliation":[{"name":"Institute of Pharmacology of Natural Products and Clinical Pharmacology, Ulm University , 89081 Ulm ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Markus","family":"Huber-Lang","sequence":"additional","affiliation":[{"name":"Department of Traumatology, Center of Surgery, University of Ulm , 89081 Ulm ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hubert","family":"Schrezenmeier","sequence":"additional","affiliation":[{"name":"Institute of Transfusion Medicine, University of Ulm , 89081 Ulm ,","place":["Germany"]},{"name":"Institute of Clinical Transfusion Medicine and Immunogenetics, German Red Cross Blood Service Baden-W\u00fcrttemberg \u2013 Hessen and University Hospital Ulm , 89081 Ulm ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6140-0233","authenticated-orcid":false,"given":"Daniel","family":"Ricklin","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, University of Pennsylvania , Philadelphia, PA 19102"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John D","family":"Lambris","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, University of Pennsylvania , Philadelphia, PA 19102"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul N","family":"Barlow","sequence":"additional","affiliation":[{"name":"School of Chemistry, University of Edinburgh , Edinburgh EH9 3JJ ,","place":["United Kingdom"]},{"name":"School of Biological Sciences, University of Edinburgh , Edinburgh EH9 3JJ ,","place":["United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christoph Q","family":"Schmidt","sequence":"additional","affiliation":[{"name":"Institute of Pharmacology of Natural Products and Clinical Pharmacology, Ulm University , 89081 Ulm ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2016,1,15]]},"reference":[{"key":"2025030702114193600_r1","doi-asserted-by":"crossref","first-page":"785","DOI":"10.1038\/ni.1923","article-title":"Complement: a key system for immune surveillance and homeostasis","volume":"11","author":"Ricklin","year":"2010","journal-title":"Nat. Immunol."},{"key":"2025030702114193600_r2","doi-asserted-by":"crossref","first-page":"2600","DOI":"10.4049\/jimmunol.179.4.2600","article-title":"Properdin can initiate complement activation by binding specific target surfaces and providing a platform for de novo convertase assembly","volume":"179","author":"Spitzer","year":"2007","journal-title":"J. Immunol."},{"key":"2025030702114193600_r3","doi-asserted-by":"crossref","first-page":"5301","DOI":"10.1073\/pnas.1401011111","article-title":"Low-dose recombinant properdin provides substantial protection against Streptococcus pneumoniae and Neisseria meningitidis infection","volume":"111","author":"Ali","year":"2014","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2025030702114193600_r4","first-page":"412","article-title":"Local release of properdin in the cellular microenvironment: role in pattern recognition and amplification of the alternative pathway of complement","volume":"3","author":"Cortes","year":"2012","journal-title":"Front. Immunol."},{"key":"2025030702114193600_r5","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1016\/j.molimm.2015.03.006","article-title":"More than just immune evasion: hijacking complement by Plasmodium falciparum","volume":"67","author":"Schmidt","year":"2015","journal-title":"Mol. Immunol."},{"key":"2025030702114193600_r6","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1016\/j.jim.2013.01.009","article-title":"Distribution and determinants of circulating complement factor H concentration determined by a high-throughput immunonephelometric assay","volume":"390","author":"Sofat","year":"2013","journal-title":"J. Immunol. 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