FHR-1 Binds to C-Reactive Protein and Enhances Rather than Inhibits Complement Activation

Csincsi, Ádám I.; Szabó, Zsóka; Bánlaki, Zsófia; Uzonyi, Barbara; Cserhalmi, Marcell; Kárpáti, Éva; Tortajada, Agustín; Caesar, Joseph; Prohászka, Zoltán; Jokiranta, T. Sakari; Lea, Susan M.; Córdoba, Santiago Rodrı́guez de; Józsi, Mihály

doi:10.4049/jimmunol.1600483

Cited by 45 publications

(95 citation statements)

References 66 publications

(109 reference statements)

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“…Our data underline the concept emerged from recent research that FHRs-in contrast to FH-rather promote complement activation (13,14,(20)(21)(22)(23)(24). The FHRs may be involved in the finetuning of complement activation on ligands and surfaces exposed on altered self and during inflammation and complement attack, such as deposited C3b, the pentraxins PTX3 and CRP, ECM components, and dying cells.…”

Section: Discussionsupporting

confidence: 69%

“…At the same time, FHRs can compete with FH for self-ligands such as pentraxins, too [ Figure 5A and (23, 24)]. In addition, similar to what was described for the well-known positive complement regulator properdin (43,44), FHRs serve as a platform for alternative pathway convertase formation and are able to promote complement activation on host ligands and surfaces where they are bound (23,24). Such an activity is shared by FHR-B; it can activate mouse complement and can also promote complement activation and C3 fragment deposition on mouse PTX3, CRP, and Matrigel (Figures 4 and 5).…”

Section: Discussionmentioning

confidence: 81%

“…Although there are some controversies regarding the roles of human FHR proteins, a main function identified by recent studies is that they compete with FH for certain self and non-self ligands, such as C3b deposited on surfaces, pentraxins, ECM and, in the case of FHR-3, the FH-binding protein of N. meningitidis (20)(21)(22)(23)(24)(25). In addition to this indirect role in the enhancement of complement activation, some FHRs may directly activate complement by serving as a platform for alternative pathway convertase formation and are able to promote complement activation on host ligands and surfaces (23,24,26).…”

Section: Discussionmentioning

confidence: 99%

“…Most, particularly early, studies assessed the direct complement regulatory roles of FHRs, and some activities in the regulation of C3 or C5 convertases (15)(16)(17)(18), inhibition of the terminal pathway by FHR-1 (19), and synergistic enhancement of the cofactor activity of FH by FHR-3 and FHR-4 (15) were reported. Recent studies, however, highlight a paradigm change, and described deregulation, i.e., competitive inhibition of FH, as a major function of FHR-1, FHR-2, and FHR-5 (20)(21)(22)(23)(24). FHR-3 was described to compete off FH from binding to fHbp of Neisseria meningitidis (25).…”

Section: Figure 1 | Expression and Purification Of Factor H-related (mentioning

confidence: 99%

“…***p < 0.001, one-way ANOVA. active C3bBb convertase (23,24,26). We therefore tested whether FHR-B was also able to support convertase formation.…”

Section: Fhr-b Binds To Human C3b and Competes With Fhmentioning

confidence: 99%

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The murine factor H-related protein FHR-B promotes complement activation

Cserhalmi

Csincsi

Mezei

et al. 2017

Molecular Immunology

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Section: Discussionsupporting

confidence: 69%

Section: Discussionmentioning

confidence: 81%

Section: Discussionmentioning

confidence: 99%

Section: Figure 1 | Expression and Purification Of Factor H-related (mentioning

confidence: 99%

“…***p < 0.001, one-way ANOVA. active C3bBb convertase (23,24,26). We therefore tested whether FHR-B was also able to support convertase formation.…”

Section: Fhr-b Binds To Human C3b and Competes With Fhmentioning

confidence: 99%

See 3 more Smart Citations

The murine factor H-related protein FHR-B promotes complement activation

Cserhalmi

Csincsi

Mezei

et al. 2017

Molecular Immunology

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C3 glomerulopathy: Understanding an ultra‐rare complement‐mediated renal disease

Heiderscheit

Hauer

Smith

2022

American J of Med Genetics Pt C

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C3 glomerulopathy (C3G) describes a pathologic pattern of injury diagnosed by renal biopsy. It is characterized by the dominant deposition of the third component of complement (C3) in the renal glomerulus as resolved by immunofluorescence microscopy. The underlying pathophysiology is driven by dysregulation of the alternative pathway of complement in the fluid-phase and in the glomerular microenvironment.Characterization of clinical features and a _targeted evaluation for indices and drivers of complement dysregulation are necessary for optimal patient care. Autoantibodies to the C3 and C5 convertases of complement are the most commonly detected drivers of complement dysregulation, although genetic mutations in complement genes can also be found. Approximately half of patients progress to end-stage renal disease within 10 years of diagnosis, and, while transplantation is a viable option, there is high risk for disease recurrence and allograft failure. This poor outcome reflects the lack of disease-specific therapy for C3G, relegating patients to symptomatic treatment to minimize proteinuria and suppress renal inflammation. Fortunately, the future is bright as several anti-complement drugs are currently in clinical trials.

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