Complementing the Sugar Code: Role of GAGs and Sialic Acid in Complement Regulation

Langford-Smith, Alex; Day, Anthony J.; Bishop, Paul N.; Clark, Simon J.

doi:10.3389/fimmu.2015.00025

Cited by 71 publications

(70 citation statements)

References 86 publications

(122 reference statements)

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“…In this regard, sialic acid-capped glycans and the GAG chains of proteoglycans are abundant on the cell surface and in the extracellular matrix of host tissues, where these structures function as markers of self [14, 31]. By interacting with these surface patterns, it is thought that FH can prevent excessive or inappropriate AP activation/amplification on host tissues; e.g., the interaction with sialic acid increases the affinity of FH for C3b on the mammalian plasma membrane, which enhances the cofactor and decay accelerating activities of FH [13, 47].…”

Section: Interaction Of Factor H With Glycans—discriminating Self Fromentioning

confidence: 99%

“…FH is the major regulator of the AP in solution phase, but also has a critical role in the inhibition of complement amplification on cells and in the extracellular matrix of host tissues due to its ability to recognize (and associate with) self surfaces (i.e., via glycan markers) to ensure that these are non-activating (see [13, 14]). In this regard, FH is amongst the most abundant complement components in human blood (with plasma concentrations ranging from 200 to 800 μg/ml; see [15]), where the liver is the major source of FH protein in vivo.…”

Section: Introductionmentioning

confidence: 99%

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Complement factor H in host defense and immune evasion

Parente

Clark

Inforzato

et al. 2016

Cell. Mol. Life Sci.

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155

147

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Complement is the major humoral component of the innate immune system. It recognizes pathogen- and damage-associated molecular patterns, and initiates the immune response in coordination with innate and adaptive immunity. When activated, the complement system unleashes powerful cytotoxic and inflammatory mechanisms, and thus its tight control is crucial to prevent damage to host tissues and allow restoration of immune homeostasis. Factor H is the major soluble inhibitor of complement, where its binding to self markers (i.e., particular glycan structures) prevents complement activation and amplification on host surfaces. Not surprisingly, mutations and polymorphisms that affect recognition of self by factor H are associated with diseases of complement dysregulation, such as age-related macular degeneration and atypical haemolytic uremic syndrome. In addition, pathogens (i.e., non-self) and cancer cells (i.e., altered-self) can hijack factor H to evade the immune response. Here we review recent (and not so recent) literature on the structure and function of factor H, including the emerging roles of this protein in the pathophysiology of infectious diseases and cancer.

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Section: Interaction Of Factor H With Glycans—discriminating Self Fromentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Complement factor H in host defense and immune evasion

Parente

Clark

Inforzato

et al. 2016

Cell. Mol. Life Sci.

Self Cite

155

147

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“…Their ability to modulate complement activation through interactions with complement regulatory proteins is gaining increased recognition [7, 9]. In the setting of the GBM, complement regulation by heparan sulfate is particularly relevant, given that complement activation mediates glomerular injury in numerous kidney diseases.…”

Section: The Role Of Gbm Heparan Sulfate Chains In Local Complemenmentioning

confidence: 99%

“…As the major determinants of the anionic charge of the GBM, heparan sulfate chains have been presumed important for the charge selectivity of the glomerular filtration, a view challenged by recent studies. An emerging role of heparan sulfate is the local regulation of complement activation in tissues, including in the kidneys [7–9]. Heparan sulfate chains function as so-called “self-associated molecular patterns” [10] recognized by complement regulatory proteins, which enable the complement system to discriminate between host and pathogens.…”

Section: Introductionmentioning

confidence: 99%

Glomerular basement membrane heparan sulfate in health and disease: A regulator of local complement activation

Borza

2017

Matrix Biology

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The glomerular basement membrane (GBM) is an essential component of the glomerular filtration barrier. Heparan sulfate proteoglycans such as agrin are major components of the GBM, along with α345(IV) collagen, laminin-521 and nidogen. A loss of GBM heparan sulfate chains is associated with proteinuria in several glomerular diseases and may contribute to the underlying pathology. As the major determinants of the anionic charge of the GBM, heparan sulfate chains have been thought to impart charge selectivity to the glomerular filtration, a view challenged by the negligible albuminuria in mice that lack heparan sulfate in the GBM. Recent studies provide increasing evidence that heparan sulfate chains modulate local complement activation by recruiting complement regulatory protein factor H, the major inhibitor of the alternative pathway in plasma. Factor H selectively inactivates C3b bound to surfaces bearing host-specific polyanions such as heparan sulfate, thus limiting complement activation on self surfaces such as the GBM, which are not protected by cell-bound complement regulators. We discuss mechanisms whereby the acquired loss of GBM heparan sulfate can impair the local regulation of the alternative pathway, exacerbating complement activation and glomerular injury in immune-mediated kidney diseases such as membranous nephropathy and lupus nephritis.

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“…39 Since HS plays a central role in controlling complement activation in the cellular microenvironment by binding to the alternative pathway inhibitor complement factor H, 14,[40][41][42] the expression of GAGs in ciChEnCs was evaluated. After resolving extracted GAGs by agarose gel electrophoresis, two distinct GAG spots were observed, which comigrated with commercial standards for HS and chondroitin sulfate, and which were efficiently degraded by incubation with the GAG-specific glycosidases heparinase I, II, and III, and chondroitinase ABC (Fig.…”

Section: Cichencs Express Endothelial Glycocalyx Components Heparan Smentioning

confidence: 99%

A Novel Choroidal Endothelial Cell Line Has a Decreased Affinity for the Age-Related Macular Degeneration–Associated Complement Factor H Variant 402H

Loeven

Gemst

Schophuizen

et al. 2018

Invest. Ophthalmol. Vis. Sci.

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PURPOSE. Choroidal endothelial cells play a central role in the pathogenesis of age-related macular degeneration (AMD). Protocols for isolating primary choroidal endothelial cells have been described but require access to human donor eyes, which is a limiting factor. Therefore, a conditionally immortalized choroidal endothelial cell (ciChEnC) line has been established. METHODS.Choroidal endothelial cells were selected by magnetic-activated cell sorting and conditionally immortalized using temperature-sensitive simian virus 40 large T antigen and human telomerase. The cell line obtained was characterized based on expression of endothelial marker proteins and endothelial cell-specific responses to various stimuli. Binding of AMDassociated and non-AMD variants of complement factor H in the context of a recombinant CCP6-8 (complement control protein domains 6-8) construct was determined using ELISA.RESULTS. ciChEnCs maintained morphology and von Willebrand factor and vascular endothelial cadherin expression for up to 27 passages. The cells internalized acetylated low-density lipoprotein, formed tubes on Matrigel, and increased intercellular adhesion molecule-1 expression in response to tumor necrosis factor-a. Cells grew into dense monolayers with barrier function and showed characteristics of choriocapillary cells, such as expression of plasmalemma vesicle-associated protein, human leukocyte antigen ABC, carbonic anhydrase IV, and membrane indentations reflecting fenestrations. ciChEnCs synthesized glycosaminoglycans chondroitin sulfate and the complement factor H ligand heparan sulfate. Interestingly, binding of the AMD-associated 402H variant of factor H to ciChEnC was significantly decreased compared to the 402Y variant. CONCLUSIONS.A novel ciChEnC cell line with choriocapillary characteristics has been established and should greatly facilitate investigation of the pathogenesis of AMD in the context of the choriocapillary microenvironment.

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Complementing the Sugar Code: Role of GAGs and Sialic Acid in Complement Regulation

Cited by 71 publications

References 86 publications

Complement factor H in host defense and immune evasion

Complement factor H in host defense and immune evasion

Glomerular basement membrane heparan sulfate in health and disease: A regulator of local complement activation

A Novel Choroidal Endothelial Cell Line Has a Decreased Affinity for the Age-Related Macular Degeneration–Associated Complement Factor H Variant 402H

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