{"doi":"10.3389/fimmu.2021.676662","title":"Selective Binding of Heparin/Heparan Sulfate Oligosaccharides to Factor H and Factor H-Related Proteins: Therapeutic Potential for C3 Glomerulopathies","abstract":"Complement dysregulation is characteristic of the renal diseases atypical hemolytic uremic syndrome (aHUS) and complement component 3 glomerulopathy (C3G). Complement regulatory protein Factor H (FH) inhibits complement activity, whereas FH-related proteins (FHRs) lack a complement regulatory domain. FH and FHRs compete for binding to host cell glycans, in particular heparan sulfates (HS). HS is a glycosaminoglycan with an immense structural variability, where distinct sulfation patterns mediate specific binding of proteins. Mutations in FH, FHRs, or an altered glomerular HS structure may disturb the FH : FHRs balance on glomerular endothelial cells, thereby leading to complement activation and the subsequent development of aHUS/C3G. In this study, we aimed to identify specific HS structures that could specifically compete off FHRs from HS glycocalyx (HS Glx ), without interfering with FH binding. FH/FHR binding to human conditionally immortalized glomerular endothelial cells (ciGEnCs) and HS Glx purified from ciGEnC glycocalyx was assessed. HS modifications important for FH/FHR binding to HS Glx were analyzed using selectively desulfated heparins in competition with purified HS Glx . We further assessed effects of heparinoids on FHR1- and FHR5-mediated C3b deposition on ciGEnCs. In the presence of C3b, binding of FH, FHR1 and FHR5 to ciGEnCs was significantly increased, whereas binding of FHR2 was minimal. FHR1 and 5 competitively inhibited FH binding to HS Glx , leading to alternative pathway dysregulation. FHR1 and FHR5 binding was primarily mediated by N-sulfation while FH binding depended on N-, 2-O- and 6-O-sulfation. Addition of 2-O-desulfated heparin significantly reduced FHR1- and FHR5-mediated C3b deposition on ciGEnCs. We identify 2-O-desulfated heparin derivatives as potential therapeutics for C3G and other diseases with dysregulated complement.","journal":"Frontiers in Immunology","year":2021,"id":176675,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":21,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9556,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":719416,"name":"Marissa L. Maciej-Hulme","orcid":"0000-0001-5615-4197","position":1,"is_corresponding":false},{"id":719417,"name":"Cansu Yanginlar","orcid":"0000-0002-0282-1078","position":2,"is_corresponding":false},{"id":720053,"name":"Melanie C. Hubers","orcid":null,"position":3,"is_corresponding":false},{"id":719418,"name":"Edwin Kellenbach","orcid":"0000-0002-6762-1050","position":4,"is_corresponding":false},{"id":719419,"name":"Mark de Graaf","orcid":"0000-0001-6381-7892","position":5,"is_corresponding":false},{"id":568723,"name":"Toin H. Van Kuppevelt","orcid":"0000-0002-7028-6783","position":6,"is_corresponding":false},{"id":232681,"name":"Jack F.M. Wetzels","orcid":"0000-0002-0650-6921","position":7,"is_corresponding":false},{"id":719420,"name":"Ton J. Rabelink","orcid":"0000-0001-6780-5186","position":8,"is_corresponding":false},{"id":291758,"name":"Richard J. Smith","orcid":"0000-0003-1201-6731","position":9,"is_corresponding":false},{"id":719421,"name":"Johan van der Vlag","orcid":"0000-0001-7843-5918","position":10,"is_corresponding":false},{"id":720052,"name":"Markus A. Loeven","orcid":null,"position":0,"is_corresponding":true}],"reference_count":45,"raw_metadata":null,"created_at":"2026-07-18T23:47:23.605867Z","pmid":"34489931","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}