A Family Affair: Addressing the Challenges of Factor H and the Related Proteins

Poppelaars, Felix; Jorge, Elena Goicoechea de; Jongerius, Ilse; Baeumner, Antje J.; Steiner, Mark‐Steven; Józsi, Mihály; Toonen, Erik J. M.; Pauly, Diana

doi:10.3389/fimmu.2021.660194

Cited by 27 publications

(44 citation statements)

References 156 publications

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“…The FH protein family is implicated in the regulation and modulation of complement activation, and members of this protein family were linked to various inflammatory and infectious diseases ( 46 ). Whereas the exact functions of the FHR proteins are still to be determined and currently in part controversial, a number of FHR ligands have already been identified.…”

Section: Discussionmentioning

confidence: 99%

Complement Factor H-Related Proteins FHR1 and FHR5 Interact With Extracellular Matrix Ligands, Reduce Factor H Regulatory Activity and Enhance Complement Activation

Papp

Uzonyi

et al. 2022

Front. Immunol.

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Components of the extracellular matrix (ECM), when exposed to body fluids may promote local complement activation and inflammation. Pathologic complement activation at the glomerular basement membrane and at the Bruch’s membrane is implicated in renal and eye diseases, respectively. Binding of soluble complement inhibitors to the ECM, including factor H (FH), is important to prevent excessive complement activation. Since the FH-related (FHR) proteins FHR1 and FHR5 are also implicated in these diseases, our aim was to study whether these FHRs can also bind to ECM components and affect local FH activity and complement activation. Both FH and the FHRs showed variable binding to ECM components. We identified laminin, fibromodulin, osteoadherin and PRELP as ligands of FHR1 and FHR5, and found that FHR1 bound to these ECM components through its C-terminal complement control protein (CCP) domains 4-5, whereas FHR5 bound via its middle region, CCPs 3-7. Aggrecan, biglycan and decorin did not bind FH, FHR1 and FHR5. FHR5 also bound to immobilized C3b, a model of surface-deposited C3b, via CCPs 3-7. By contrast, soluble C3, C3(H2O), and the C3 fragments C3b, iC3b and C3d bound to CCPs 8-9 of FHR5. Properdin, which was previously described to bind via CCPs 1-2 to FHR5, did not bind in its physiologically occurring serum forms in our assays. FHR1 and FHR5 inhibited the binding of FH to the identified ECM proteins in a dose-dependent manner, which resulted in reduced FH cofactor activity. Moreover, both FHR1 and FHR5 enhanced alternative complement pathway activation on immobilized ECM proteins when exposed to human serum, resulting in the increased deposition of C3-fragments, factor B and C5b-9. Thus, our results identify novel ECM ligands of FH family proteins and indicate that FHR1 and FHR5 are competitive inhibitors of FH on ECM and, when bound to these ligands, they may enhance local complement activation and promote inflammation under pathological conditions.

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Section: Discussionmentioning

confidence: 99%

Complement Factor H-Related Proteins FHR1 and FHR5 Interact With Extracellular Matrix Ligands, Reduce Factor H Regulatory Activity and Enhance Complement Activation

Papp

Uzonyi

et al. 2022

Front. Immunol.

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“…For example, mutations that cause a complete Factor H deficiency lead to uncontrolled complement activation in the fluid phase and are linked to C3 glomerulopathy (C3G), a heterogeneous histopathological entity characterized by glomerular C3 deposition [ 36 ]. Heterozygous mutations in Factor H only lead to partial deficiencies, and these are associated with C3G but also with other diseases such as age-related macular degeneration (AMD), atypical hemolytic uremic syndrome (aHUS), and IgAN [ 37 ]. Alternatively, mutations or autoantibodies that affect the binding sites of Factor H give rise to aHUS because they impair the ability of Factor H to control complement activation on surfaces without modifying complement regulation in the fluid phase [ 38 , 39 , 40 , 41 ].…”

Section: Novel Insights Into An Old Defense Systemmentioning

confidence: 99%

“…Thus, FHRs act as de-regulators of the complement system by competing with Factor H for binding to surfaces that require protection. Notably, clear differences exist among the different FHRs [ 37 ]. For instance, FHR-1, FHR-2, and FHR-5 can dimerize to form homodimers.…”

Section: Novel Insights Into An Old Defense Systemmentioning

confidence: 99%

“…Surprisingly, urinary levels of Factor H were positively associated with markers of IgAN severity and disease progression. It is noteworthy to mention that because of the structural homology between Factor H and FHRs, it is very well possible that these Factor H assays also detected the FHRs and thereby confound the results [ 37 ]. Proteomic analysis of micro-dissected glomeruli in IgAN biopsies have verified the presence of Factor H, FHR-1, FHR-2, FHR-3, and FHR-5 [ 96 ].…”

Section: The Complement System In Iga Nephropathymentioning

confidence: 99%

“…These data indicate that FHR-5 might be a key contributor to complement dysregulation in IgAN ( Table 1 ). It is important to mention that FHR-5 detection by immunohistochemistry in the study by Medjeral-Thomas et al and by Guo et al was achieved by using rabbit polyclonal antibodies against FHR-5 [ 88 , 98 ], creating the possibility of cross-reactivity with other FHRs [ 37 ].…”

Section: The Complement System In Iga Nephropathymentioning

confidence: 99%

See 2 more Smart Citations

The Contribution of Complement to the Pathogenesis of IgA Nephropathy: Are Complement-Targeted Therapies Moving from Rare Disorders to More Common Diseases?

Poppelaars

Faria

Schwaeble

et al. 2021

JCM

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Primary IgA nephropathy (IgAN) is a leading cause of chronic kidney disease and kidney failure for which there is no disease-specific treatment. However, this could change, since novel therapeutic approaches are currently being assessed in clinical trials, including complement-targeting therapies. An improved understanding of the role of the lectin and the alternative pathway of complement in the pathophysiology of IgAN has led to the development of these treatment strategies. Recently, in a phase 2 trial, treatment with a blocking antibody against mannose-binding protein-associated serine protease 2 (MASP-2, a crucial enzyme of the lectin pathway) was suggested to have a potential benefit for IgAN. Now in a phase 3 study, this MASP-2 inhibitor for the treatment of IgAN could mark the start of a new era of complement therapeutics where common diseases can be treated with these drugs. The clinical development of complement inhibitors requires a better understanding by physicians of the biology of complement, the pathogenic role of complement in IgAN, and complement-targeted therapies. The purpose of this review is to provide an overview of the role of complement in IgAN, including the recent discovery of new mechanisms of complement activation and opportunities for complement inhibitors as the treatment of IgAN.

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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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A Family Affair: Addressing the Challenges of Factor H and the Related Proteins

Cited by 27 publications

References 156 publications

Complement Factor H-Related Proteins FHR1 and FHR5 Interact With Extracellular Matrix Ligands, Reduce Factor H Regulatory Activity and Enhance Complement Activation

Complement Factor H-Related Proteins FHR1 and FHR5 Interact With Extracellular Matrix Ligands, Reduce Factor H Regulatory Activity and Enhance Complement Activation

The Contribution of Complement to the Pathogenesis of IgA Nephropathy: Are Complement-Targeted Therapies Moving from Rare Disorders to More Common Diseases?

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

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