Common haplotypes at the CFH locus and low-frequency variants in CFHR2 and CFHR5 associate with systemic FHR concentrations and age-related macular degeneration

Lorés‐Motta, Laura; Beek, Anna E. van; Willems, Esther; Zandstra, Judith; Mierlo, Gerard van; Einhaus, Alfred; Mary, Jean-Luc; Stucki, Corinne; Bakker, Björn; Hoyng, Carel B.; Fauser, Sascha; Clark, Simon J.; Jonge, Marien I. de; Nogoceke, Everson; Koertvely, Elod; Jongerius, Ilse; Kuijpers, Taco W.; Hollander, Anneke I. den

doi:10.1016/j.ajhg.2021.06.002

Cited by 44 publications

(76 citation statements)

References 58 publications

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“…Most reports to date have been inconsistent when measuring systemic FH levels in AMD. For instance, Silva et al [48] and Sharma et al [49] reported reduced levels of FH in AMD cases versus controls, whereas more recent reports with larger patient cohorts failed to detect alternations in systemic FH levels by ELISA due to AMD status [50,51], and no difference in FH levels was found by targeted mass spectrometry [52]. Furthermore, no significant differences have been reported between sera from CFH Y402H genotypes [48].…”

Section: Discussionmentioning

confidence: 99%

Local factor H production by human choroidal endothelial cells mitigates complement deposition: implications for macular degeneration

Mulfaul

Mullin

Giacalone

et al. 2022

The Journal of Pathology

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Activation of the alternative complement pathway is an initiating event in the pathology of age‐related macular degeneration (AMD). Unchecked complement activation leads to the formation of a pro‐lytic pore, the membrane attack complex (MAC). MAC deposition is observed on the choriocapillaris of AMD patients and likely causes lysis of choroidal endothelial cells (CECs). Complement factor H (FH, encoded by the gene CFH) is an inhibitor of complement. Both loss of function of FH and reduced choroidal levels of FH have been reported in AMD. It is plausible that reduced local FH availability promotes MAC deposition on CECs. FH is produced primarily in the liver; however, cells including the retinal pigment epithelium can produce FH locally. We hypothesized that CECs produce FH locally to protect against MAC deposition. We aimed to investigate the effect of reduced FH levels in the choroid to determine whether increasing local FH could protect CECs from MAC deposition. We demonstrated that siRNA knockdown of FH (CFH) in human immortalized CECs results in increased MAC deposition. We generated AMD iPSC‐derived CECs and found that overexpression of FH protects against MAC deposition. These results suggest that local CEC‐produced FH protects against MAC deposition, and that increasing local FH protein may be beneficial in limiting MAC deposition in AMD. © 2022 The Pathological Society of Great Britain and Ireland.

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Section: Discussionmentioning

confidence: 99%

Local factor H production by human choroidal endothelial cells mitigates complement deposition: implications for macular degeneration

Mulfaul

Mullin

Giacalone

et al. 2022

The Journal of Pathology

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“…FHR1 and FHR5 were found in immune deposits in several kidney and eye diseases where excessive complement activation is implicated, indicating that FHRs play an important role in these pathological processes ( 3 , 25 , 26 , 28 , 47 ). Under these conditions, components of the ECM are exposed and available to interact with complement proteins ( 31 – 34 ).…”

Section: Discussionmentioning

confidence: 99%

“…Under these conditions, components of the ECM are exposed and available to interact with complement proteins ( 31 – 34 ). Previously, it was reported that FHR5 binds to MaxGel, an ECM extract ( 7 ) and to human laminin ( 18 ), an important component of the GBM, and FHR5 was also detected in the ECM of the eye ( 47 ); moreover, FHR5 promoted complement activation when bound to MaxGel ( 7 ).…”

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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“…The relation to a key regulator of complement activation sparked great interest in FHRs and rendered them the subject of extensive research over the recent years. Since their discovery, the clinical relevance of the FHRs has been well established, with numerous reports of aberrant FHRs associating with ‘typical’ complement-related diseases, including meningococcal disease [ 28 ], aHUS and other nephropathies [ 29 – 31 ], and AMD [ 32 ], among others. It is still unclear, though, whether the reported disease-associated mechanisms of FHRs reflect their normal function within the complement system.…”

Section: Complement: a Fresh Look At An Old Systemmentioning

confidence: 99%

Tipping the balance: intricate roles of the complement system in disease and therapy

Pouw

Ricklin

2021

Semin Immunopathol

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The ability of the complement system to rapidly and broadly react to microbial intruders, apoptotic cells and other threats by inducing forceful elimination responses is indispensable for its role as host defense and surveillance system. However, the danger sensing versatility of complement may come at a steep price for patients suffering from various immune, inflammatory, age-related, or biomaterial-induced conditions. Misguided recognition of cell debris or transplants, excessive activation by microbial or damaged host cells, autoimmune events, and dysregulation of the complement response may all induce effector functions that damage rather than protect host tissue. Although complement has long been associated with disease, the prevalence, impact and complexity of complement’s involvement in pathological processes is only now becoming fully recognized. While complement rarely constitutes the sole driver of disease, it acts as initiator, contributor, and/or exacerbator in numerous disorders. Identifying the factors that tip complement’s balance from protective to damaging effects in a particular disease continues to prove challenging. Fortunately, however, molecular insight into complement functions, improved disease models, and growing clinical experience has led to a greatly improved understanding of complement’s pathological side. The identification of novel complement-mediated indications and the clinical availability of the first therapeutic complement inhibitors has also sparked a renewed interest in developing complement-targeted drugs, which meanwhile led to new approvals and promising candidates in late-stage evaluation. More than a century after its description, complement now has truly reached the clinic and the recent developments hold great promise for diagnosis and therapy alike.

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Common haplotypes at the CFH locus and low-frequency variants in CFHR2 and CFHR5 associate with systemic FHR concentrations and age-related macular degeneration

Cited by 44 publications

References 58 publications

Local factor H production by human choroidal endothelial cells mitigates complement deposition: implications for macular degeneration

Local factor H production by human choroidal endothelial cells mitigates complement deposition: implications for macular degeneration

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

Tipping the balance: intricate roles of the complement system in disease and therapy

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