Complement Factor H: Using Atomic Resolution Structure to Illuminate Disease Mechanisms

Barlow, Paul N.; Hageman, Gregory S.; Lea, Susan M.

doi:10.1007/978-0-387-78952-1_10

Cited by 5 publications

(5 citation statements)

References 128 publications

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“…Factor H, factor I, and properdin are unique to the alternative pathway. Factor H is both a soluble and cell-surface membrane regulator ( 124 ) which accelerates the decay of the C3 convertase (C3bBb) to reduce complement deposition ( 125 ), and it functions as a Factor I cofactor to cleave C3b and C4b components ( 111 ). Properdin is a positive regulator of the alternative pathway which stabilizes the C3 convertase (C3bBb) and promotes its association with further C3b molecules ( 129 ).…”

Section: Introductionmentioning

confidence: 99%

Viral Evasion of the Complement System and Its Importance for Vaccines and Therapeutics

et al. 2020

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The complement system is a key component of innate immunity which readily responds to invading microorganisms. Activation of the complement system typically occurs via three main pathways and can induce various antimicrobial effects, including: neutralization of pathogens, regulation of inflammatory responses, promotion of chemotaxis, and enhancement of the adaptive immune response. These can be vital host responses to protect against acute, chronic, and recurrent viral infections. Consequently, many viruses (including dengue virus, West Nile virus and Nipah virus) have evolved mechanisms for evasion or dysregulation of the complement system to enhance viral infectivity and even exacerbate disease symptoms. The complement system has multifaceted roles in both innate and adaptive immunity, with both intracellular and extracellular functions, that can be relevant to all stages of viral infection. A better understanding of this virus-host interplay and its contribution to pathogenesis has previously led to: the identification of genetic factors which influence viral infection and disease outcome, the development of novel antivirals, and the production of safer, more effective vaccines. This review will discuss the antiviral effects of the complement system against numerous viruses, the mechanisms employed by these viruses to then evade or manipulate this system, and how these interactions have informed vaccine/therapeutic development. Where relevant, conflicting findings and current research gaps are highlighted to aid future developments in virology and immunology, with potential applications to the current COVID-19 pandemic.

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Section: Introductionmentioning

confidence: 99%

Viral Evasion of the Complement System and Its Importance for Vaccines and Therapeutics

et al. 2020

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“…The apparently contradictory finding that the CCP19-20 region is likely to represent the major binding site for the interaction of CFH in other tissues (e.g. kidney) (see [18]) can be explained by the tissue-specific biosynthesis of GAGs [49,52], i.e. with distinct compositions/sequences differentially recognized by the two CFH heparin/HS-binding sites [35].…”

Section: Cfh-binding Sites In Human Eye Tissuementioning

confidence: 95%

“…Although other risk and protective polymorphisms have been identified in CFH (see [18]) and in other complement components (e.g. in factor B [19]), the Y402H polymorphism is currently considered to represent the major genetic risk factor for AMD [20]; some of these influence the activation of complement in blood, but the effects of the Y402H polymorphism appear to be mediated locally in tissues [20].…”

Section: Cfh and Its Association With Amdmentioning

confidence: 98%

Complement factor H and age-related macular degeneration: the role of glycosaminoglycan recognition in disease pathology

Clark

Bishop

Day

2010

Biochemical Society Transactions

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AMD (age-related macular degeneration) is the major cause of blindness in the western world, associated with the formation of extracellular deposits called drusen in the macula, i.e. the central region of the retina. These drusen contain cellular debris and proteins, including components of the complement system such as the regulator CFH (complement factor H); dysregulation of complement is thought to play a major role in the development of AMD. CFH acts through its capacity to recognize polyanionic structures [e.g. sulfated GAGs (glycosaminoglycans)] found on host tissues, and thereby inactivates any C3b that becomes deposited. Importantly, a common polymorphism in CFH (Y402H) has been strongly associated with an increased risk of AMD. This polymorphism, which causes a tyrosine to histidine coding change, has been shown to alter the binding of CFH to sulfated GAGs, as well as to other ligands including C-reactive protein, necrotic cells and bacterial coat proteins. Of these, the change in the GAG-recognition properties of CFH is likely to be of most significance to AMD. Recent research has revealed that the disease-associated 402H allotype interacts less well (compared with 402Y) with binding sites within the macula (e.g. Bruch's membrane), where the GAGs heparan sulfate and dermatan sulfate play a major role in mediating the interaction with CFH. Reduced binding of the 402H allotype could result in impaired regulation of complement leading to chronic local inflammation that may contribute to the accumulation of drusen and thus the initiation, development and progression of AMD.

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“…CCPs 1-4 of FH bind C3b and display decay-accelerating activity by dissociating Bb from C3 convertases. In addition, FH possess cofactor activity (Figs 1B and 3B) probably by inducing a substrate conformation of C3b susceptible to FImediated degradation (Gordon et al, 1995;Kuhn & Zipfel, 1996;Barlow et al, 2008) and by providing a binding platform for FI (Roversi et al, 2011). The C3b:FH CCP1-4 crystal structure provides insight into the molecular basis of these FH functions (Wu et al, 2009).…”

Section: Regulators Of Complement Activationmentioning

confidence: 99%

Complement activation, regulation, and molecular basis for complement‐related diseases

et al. 2015

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The complement system is an essential element of the innate immune response that becomes activated upon recognition of molecular patterns associated with microorganisms, abnormal host cells, and modified molecules in the extracellular environment. The resulting proteolytic cascade tags the complement activator for elimination and elicits a pro-inflammatory response leading to recruitment and activation of immune cells from both the innate and adaptive branches of the immune system. Through these activities, complement functions in the first line of defense against pathogens but also contributes significantly to the maintenance of homeostasis and prevention of autoimmunity. Activation of complement and the subsequent biological responses occur primarily in the extracellular environment. However, recent studies have demonstrated autocrine signaling by complement activation in intracellular vesicles, while the presence of a cytoplasmic receptor serves to detect complement-opsonized intracellular pathogens. Furthermore, breakthroughs in both functional and structural studies now make it possible to describe many of the intricate molecular mechanisms underlying complement activation and the subsequent downstream events, as well as its cross talk with, for example, signaling pathways, the coagulation system, and adaptive immunity. We present an integrated and updated view of complement based on structural and functional data and describe the new roles attributed to complement. Finally, we discuss how the structural and mechanistic understanding of the complement system rationalizes the genetic defects conferring uncontrolled activation or other undesirable effects of complement.

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Complement Factor H: Using Atomic Resolution Structure to Illuminate Disease Mechanisms

Cited by 5 publications

References 128 publications

Viral Evasion of the Complement System and Its Importance for Vaccines and Therapeutics

Viral Evasion of the Complement System and Its Importance for Vaccines and Therapeutics

Complement factor H and age-related macular degeneration: the role of glycosaminoglycan recognition in disease pathology

Complement activation, regulation, and molecular basis for complement‐related diseases

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