Sweet turning bitter: Carbohydrate sensing of complement in host defence and disease

Hevey, Rachel; Pouw, Richard B.; Harris, Claire L.; Ricklin, Daniel

doi:10.1111/bph.15307

Cited by 8 publications

(7 citation statements)

References 156 publications

(238 reference statements)

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“…The differential response of the complement system to self and foreign cell surfaces is largely mediated by the pattern recognition capacities of the FH protein family ( 3 , 42 ). Despite valuable insights from molecular and disease-related studies, many aspects concerning the function of FHRs and their surface-dependent interplay with FH remain elusive.…”

Section: Discussionmentioning

confidence: 99%

Deregulation of Factor H by Factor H-Related Protein 1 Depends on Sialylation of Host Surfaces

et al. 2021

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To discriminate between self and non-self surfaces and facilitate immune surveillance, the complement system relies on the interplay between surface-directed activators and regulators. The dimeric modulator FHR-1 is hypothesized to competitively remove the complement regulator FH from surfaces that strongly fix opsonic C3b molecules—a process known as “deregulation.” The C-terminal regions of FH and FHR-1 provide the basis of this competition. They contain binding sites for C3b and host surface markers and are identical except for two substitutions: S1191L and V1197A (i.e., FH “SV”; FHR-1 “LA”). Intriguingly, an FHR-1 variant featuring the “SV” combination of FH predisposes to atypical hemolytic uremic syndrome (aHUS). The functional impact of these mutations on complement (de)regulation, and their pathophysiological consequences, have largely remained elusive. We have addressed these questions using recombinantly expressed wildtype, mutated, and truncated versions of FHR-1 and FH. The “SV” to “LA” substitutions did not affect glycosaminoglycan recognition and had only a small effect on C3b binding. In contrast, the two amino acids substantially affected the binding of FH and FHR-1 to α2,3-linked sialic acids as host surfaces markers, with the S-to-L substitution causing an almost complete loss of recognition. Even with sialic acid-binding constructs, notable deregulation was only detected on host and not foreign cells. The aHUS-associated “SV” mutation converts FHR-1 into a sialic acid binder which, supported by its dimeric nature, enables excessive FH deregulation and, thus, complement activation on host surfaces. While we also observed inhibitory activities of FHR-1 on C3 and C5 convertases, the high concentrations required render the physiological impact uncertain. In conclusion, the SV-to-LA substitution in the C-terminal regions of FH and FHR-1 diminishes its sialic acid-binding ability and results in an FHR-1 molecule that only moderately deregulates FH. Such FH deregulation by FHR-1 only occurs on host/host-like surfaces that recruit FH. Conversion of FHR-1 into a sialic acid binder potentiates the deregulatory capacity of FHR-1 and thus explains the pathophysiology of the aHUS-associated FHR-1 “SV” variant.

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Section: Discussionmentioning

confidence: 99%

Deregulation of Factor H by Factor H-Related Protein 1 Depends on Sialylation of Host Surfaces

et al. 2021

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“…While the basic mechanisms of this well-oiled machinery have long been known, surprising new facets and players have only been identified, or fully appreciated, in recent years. On the initiation side, the lectin pathway gained a large share of attention due to the realization that the pattern recognition functions are not only exerted by mannose-binding lectin (MBL) but a full panel of ficolins and collectins with broad and distinct sensing profiles for carbohydrates but also acetylated structures and other signatures [ 12 , 13 ]. At the same time, our comprehension of the interplay between the three MBL-associated serine proteases (MASPs) has improved, including a functional connection to yet unknown links with the alternative pathway [ 14 – 16 ], and new LP regulators have been described [ 17 , 18 ].…”

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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“…King et al (2021) have recently discovered that intracellular C3 regulates autophagy in pancreatic cells and describe in their contribution the role of complement in autophagy. Hevey et al (2021), as well as Skerka et al (2021), round up the first part by describing the role of complement in carbohydrate sensing in endothelial cells as well as the interaction of complement with ApoE.…”

Section: Figurementioning

confidence: 99%

Canonical and non‐canonical functions of the complement system in health and disease

Wenzel

Kemper

Köhl

2021

British J Pharmacology

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Sweet turning bitter: Carbohydrate sensing of complement in host defence and disease

Cited by 8 publications

References 156 publications

Deregulation of Factor H by Factor H-Related Protein 1 Depends on Sialylation of Host Surfaces

Deregulation of Factor H by Factor H-Related Protein 1 Depends on Sialylation of Host Surfaces

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

Canonical and non‐canonical functions of the complement system in health and disease

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