ORIGINAL RESEARCH article
Front. Immunol.
Sec. Molecular Innate Immunity
Volume 16 - 2025 | doi: 10.3389/fimmu.2025.1645196
Glycoproteomics analysis of Complement Factor H and its effect on complement regulatory function during Streptococcus pneumoniaeassociated hemolytic uremic syndrome
Provisionally accepted- 1Department of Pediatric Nephrology, Amalia Children's Hospital, Radboud University Medical Centre, Nijmegen, Netherlands
- 2Department of Human Genetics, Radboud University Medical Centre, Nijmegen, Netherlands
- 3Department of Pediatric Nephrology, Radboud University Medical Centre, Nijmegen, Netherlands
- 4Department of Pediatric Nephrology, Emma Children's Hospital, Amsterdam UMC Locatie AMC, Amsterdam, Netherlands
- 5Department of Human Genetics, Radboud Medical Centre, Nijmegen, Netherlands
- 6Laboratory of Medical Immunology, Department of Laboratory Medicine, Radboud University Medical Centre, Nijmegen, Netherlands
- 7Department of Neurology, Radboud Universiteit Donders Institute for Brain Cognition and Behaviour, Nijmegen, Netherlands
- 8Department of Pediatrics/Pediatric Nephrology, UZ Leuven, Leuven, Belgium
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Hemolytic uremic syndrome caused by an invasive Streptococcus pneumoniae infection (SP-HUS) is a rare and severe disease that primarily affects children under two years of age. The pathophysiology of SP-HUS remains poorly understood, and treatment is largely supportive. Complement factor H (FH) is a key regulator of the alternative pathway of the complement system. It has been hypothesized that loss of sialic acids from FH's N-glycans may impair its regulatory functions, thereby potentially leading to complement-mediated endothelial cell damage in SP-HUS. In this study, we investigated the N-glycosylation patterns of FH across three N-glycosylation sites for four SP-HUS patients and compared it to healthy controls using LC-MS/MS-based glycopeptide profiling.We identified significant changes in FH glycosylation during the acute phase of SP-HUS, including an increased presence of N-glycans lacking sialic acids, galactose and N-acetylglucosamine (GlcNAc) relative to the controls. This abnormal glycosylation was most prominent during the acute phase in all patients and showed partial or complete normalization during remission. Interestingly, despite these major glycosylation changes, functional assays revealed no significant impairment in the complement regulatory activity of FH, as measured by its ability to facilitate C3b degradation and to prevent complement-mediated hemolysis of sheep erythrocytes. In conclusion, our findings show that FH's N-glycosylation is severely altered in the acute phase in SP-HUS patients, comprising more than just the loss of sialic acids. However, these changes do not directly affect FH's complement regulatory function. These results highlight the complex yet poorly understood role of Nglycosylation during infection, and the contribution of FH's N-glycans to complement (dys)regulation and disease pathogenesis.
Keywords: Complement Factor H, Streptococcus pneumoniae, Hemolytic uremic syndrome, Glycosylation, Glycoproteomics, Functional assays
Received: 11 Jun 2025; Accepted: 01 Aug 2025.
Copyright: © 2025 Baas, Wijnsma, Zijlstra, van de Kar, Ter Steeg, Bouts, Michels, Langereis, Lefeber, Wessels and Van Den Heuvel. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Lambertus Petrus Van Den Heuvel, Department of Pediatric Nephrology, Amalia Children's Hospital, Radboud University Medical Centre, Nijmegen, Netherlands
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