Self versus nonself discrimination by the soluble complement regulators factor H and FHL-1

Dopler, Arthur; Guntau, Leonie; Harder, Markus J; Palmer, Annette; Höchsmann, Britta; Schrezenmeier, Hubert; Simmet, Thomas; Huber-Lang, Markus; Schmidt, Christoph Q

doi:10.4049/jimmunol.1801545

Cited by 35Complement system in diseasesBiomarkers in Disease MechanismsCoagulation, Bradykinin, Polyphosphates, and Angioedema

Self versus nonself discrimination by the soluble complement regulators factor H and FHL-1

Dopler, Arthur, Guntau, Leonie, Harder, Markus J, Palmer, Annette, Höchsmann, Britta, Schrezenmeier, Hubert, Simmet, Thomas, Huber-Lang, Markus +1 more·2019·The Journal of Immunology

DOI 10.4049/jimmunol.1801545

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Abstract

The plasma proteins Factor H (FH) and its alternate splice variant FH-like protein 1 (FHL-1) are the major regulators of the complement alternative pathway. The indiscriminate nature of alternative pathway activation necessitates the regulators to be host selective, but the underlying principles of selectivity remained largely elusive. By analyzing human FH and FHL-1 for protection of different host and foreign cells (rabbit and yeast), we uncovered a 2-fold discriminatory mechanism of FH in favor of self: relative to FHL-1, FH exhibits a regulatory benefit on self but importantly, also, a regulatory penalty on nonself surfaces, yielding a selectivity factor of ∼2.4 for sialylated host surfaces. We further show that FHL-1 possesses higher regulatory activity than known but is relatively unselective. The reason for this unexpected high activity of FHL-1 is the observation that the complement regulatory site in FH exceeds the established first four domains. Affinity for C3b, cofactor and decay-accelerating activities, and serum assays demonstrate that the regulatory site extends domains 1–4 and includes domains 5–7. But unlike FH, FHL-1 exhibits a fast plasma clearance in mice, occurs sparsely in human plasma (at one fortieth of the FH concentration), and resists deregulation by FH-related proteins. These physiological differences and its late phylogenetic occurrence argue that FHL-1 is crucial for local rather than systemic compartments. In conclusion, we demonstrate a 2-fold discriminatory power of FH to promote selectivity for self over foreign and show that FHL-1 is more active than known but specialized for regulation on local tissues.

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FHL-1 is not as effective at inhibiting AP overactivation as FH, as it has reduced binding to extracellular matrix proteins and cannot alter its conformation to conceal its catalytic domains when not bound to host structures.
“However, FHL-1 is not as effective at inhibiting AP overactivation as FH, as it has reduced binding to extracellular matrix proteins and cannot alter its conformation to conceal its catalytic domains when not bound to host structures [210].”
From Bruch’s Membrane: A Key Consideration with Complement-Based Therapies for Age-Related Macular Degeneration (2023) · cites this paper as [210]
Genetic sequences consistent with FHL-1 expression are found in old world monkeys, but not in their new world ancestors.
“the genetic sequences consistent with FHL-1 expression are found in old world monkeys, but not in their new world ancestors [210].”
From Bruch’s Membrane: A Key Consideration with Complement-Based Therapies for Age-Related Macular Degeneration (2023) · cites this paper as [210]

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Response to Comment on “Self versus Nonself Discrimination by the Soluble Complement Regulators Factor H and FHL-1”
Dopler, A., Guntau, L., Harder, M. J., Palmer, A., Höchsmann, B., Schrezenmeier, H., Simmet, T., Huber-Lang, M. S., & Schmidt, C. Q. (2019) · The Journal of Immunology · doi:10.4049/jimmunol.1900994 · Cited by 1 · see citing works
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Deregulation of Factor H by Factor H-Related Protein 1 Depends on Sialylation of Host Surfaces
Dopler, A., Stibitzky, S., Hevey, R., Mannes, M., Guariento, M., Höchsmann, B., Schrezenmeier, H., Ricklin, D., & Schmidt, C. Q. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.615748 · Cited by 17 · see citing works
Self-citation

Authors: Dopler, A., Guntau, L., Harder, M. J., Palmer, A., Höchsmann, B., Schrezenmeier, H., Simmet, T., Huber-Lang, M., & Schmidt, C. Q.
Affiliations: Universität Ulm (DE)
University Hospital Ulm (DE)
Corresponding author: Dopler, Arthur
Guntau, Leonie
Simmet, Thomas
ORCID: Guntau, Leonie
Höchsmann, Britta
Schrezenmeier, Hubert
Simmet, Thomas
Huber-Lang, Markus
Schmidt, Christoph Q
Venue: The Journal of Immunology
Publisher: Oxford University Press (OUP)
Published: 2019-04-01
Volume: 202
Issue: 7
Pages: 2082-2094
ISSN: 0022-1767 (ISSN-L)
1550-6606
DOI: 10.4049/jimmunol.1801545
OpenAlex: W2912565373
Cited by: 35
References: 63
Citations by year: 2026: 2 · 2025: 2 · 2024: 1 · 2023: 6 · 2022: 3 · 2021: 9 · 2020: 9 · 2019: 3
FWCI: 2.39
Type: journal article
Language: en
Open access: closed
Licence: academic.oup.com/pages/standard-publication-reuse-rights (vor)
Locations: The Journal of Immunology (publishedVersion)
PubMed (publishedVersion)
Topics: Life Sciences › Immunology and Microbiology › Immunology › Complement system in diseases
Life Sciences › Immunology and Microbiology › Immunology › Biomarkers in Disease Mechanisms
Health Sciences › Medicine › Genetics › Coagulation, Bradykinin, Polyphosphates, and Angioedema
Keywords: complement factor H, FHL1, alternative complement pathway, complement regulation, self/non-self discrimination, sialylation, plasma clearance, host selectivity
MeSH terms: Animals, Complement Activation, Complement Pathway, Alternative, Humans, Complement Factor H, Self Tolerance

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Self versus nonself discrimination by the soluble complement regulators factor H and FHL-1

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