Competition between antagonistic complement factors for a single protein on N. meningitidis rules disease susceptibility

Genome-wide association studies have found variation within the complement factor H gene family links to host susceptibility to meningococcal disease caused by infection with Neisseria meningitidis (<xref ref-type="bibr" rid="bib4">Davila et al., 2010</xref>). Mechanistic insights have been challenging since variation within this locus is complex and biological roles of the factor H-related proteins, unlike factor H, are incompletely understood. N. meningitidis subverts immune responses by hijacking a host-immune regulator, complement factor H (CFH), to the bacterial surface (<xref ref-type="bibr" rid="bib25">Schneider et al., 2006</xref>; <xref ref-type="bibr" rid="bib17">Madico et al., 2007</xref>; <xref ref-type="bibr" rid="bib27">Schneider et al., 2009</xref>). We demonstrate that complement factor-H related 3 (CFHR3) promotes immune activation by acting as an antagonist of CFH. Conserved sequences between CFH and CFHR3 mean that the bacterium cannot sufficiently distinguish between these two serum proteins to allow it to hijack the regulator alone. The level of protection from complement attack achieved by circulating N. meningitidis therefore depends on the relative levels of CFH and CFHR3 in serum. These data may explain the association between genetic variation in both CFH and CFHR3 and susceptibility to meningococcal disease.

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A Proteogenomic Signature of Age-related Macular Degeneration in Blood

10.1101/2021.07.27.21261194 ◽

2021 ◽

Author(s):

Valur Emilsson ◽

Elias F Gudmundsson ◽

Thorarinn Jonmundsson ◽

Michael Twarog ◽

Valborg Gudmundsdottir ◽

...

Keyword(s):

Macular Degeneration ◽

Serum Proteins ◽

Association Studies ◽

The Elderly ◽

Factor H ◽

Age Related Macular Degeneration ◽

Genome Wide Association Studies ◽

Complement Factor ◽

Age Related ◽

Common Genetic Variants

Age-related macular degeneration (AMD) is one of the most frequent causes of visual impairment in the elderly population. The overall etiology of AMD is complex and still poorly understood, though age, obesity, smoking, and high-density lipoprotein are known risk factors. In one of the first successful reported genome-wide association studies (GWAS), common genetic variants were strongly associated with AMD, including variants within the complement factor H (CFH) gene. To date, 34 genomic regions have been linked to AMD; however, the genes that mediate the risk remain largely unknown, indicating that novel approaches to identifying causal candidates are needed. Recent advances in proteomic technology have exposed the serum proteome's depth and complexity. In the Age, Gene/Environment Susceptibility Reykjavik Study (AGES-RS), a broad population-based study of the elderly (N = 5764), levels of 4137 human serum proteins and associated networks were integrated with established genetic risk loci for AMD, revealing many predicted as well as novel proteins and pathways, linked to the disease. Serum proteins were also found to reflect AMD severity independent of genetics and predict progression from early to advanced AMD after five years in this population. A two-sample Mendelian randomization study of five proteins associated with AMD found CFHR1, CFHR5, and FUT5 to be causally related to the disease, all of which were directionally consistent with the observational estimates. This study provides a robust and unique framework for elucidating the pathobiology of AMD.

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AMD-associated complement factor H variant Y402H protects from streptococcal infections—Evidence from bacterial in vitro survival and human genetic association studies

Molecular Immunology ◽

10.1016/j.molimm.2011.06.324 ◽

2011 ◽

Vol 48 (14) ◽

pp. 1699

Author(s):

K.H.T. Haapasalo-Tuomainen ◽

J. Vuopio ◽

J. Syrjänen ◽

J. Suvilehto ◽

S. Massinen ◽

...

Keyword(s):

Genetic Association ◽

Association Studies ◽

Genetic Association Studies ◽

Factor H ◽

Complement Factor H ◽

Complement Factor ◽

Streptococcal Infections ◽

In Vitro Survival

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Dimerization of complement factor H-related proteins modulates complement activation in vivo

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1219260110 ◽

2013 ◽

Vol 110 (12) ◽

pp. 4685-4690 ◽

Cited By ~ 167

Author(s):

E. Goicoechea de Jorge ◽

J. J. E. Caesar ◽

T. H. Malik ◽

M. Patel ◽

M. Colledge ◽

...

Keyword(s):

Complement Activation ◽

Factor H ◽

Complement Factor H ◽

Complement Factor ◽

Related Proteins

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Complement factor H and related proteins: an expanding family of complement-regulatory proteins?

Immunology Today ◽

10.1016/0167-5699(94)90155-4 ◽

1994 ◽

Vol 15 (3) ◽

pp. 121-126 ◽

Cited By ~ 99

Author(s):

Peter F. Zipfel ◽

Christine Skerka

Keyword(s):

Factor H ◽

Regulatory Proteins ◽

Complement Factor H ◽

Complement Factor ◽

Complement Regulatory Proteins ◽

Related Proteins

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Deletion Variants of CFHR1 and CFHR3 Associate with Mesangial Immune Deposits but Not with Progression of IgA Nephropathy

Journal of the American Society of Nephrology ◽

10.1681/asn.2017010019 ◽

2017 ◽

Vol 29 (2) ◽

pp. 661-669 ◽

Cited By ~ 11

Author(s):

Perrine Jullien ◽

Blandine Laurent ◽

Guillaume Claisse ◽

Ingrid Masson ◽

Miriana Dinic ◽

...

Keyword(s):

Iga Nephropathy ◽

Association Studies ◽

Alternative Pathway ◽

Factor H ◽

Genome Wide Association Studies ◽

Complement Factor ◽

Gene Deletions ◽

Immune Deposits ◽

Gene Copies ◽

Genome Wide

Activation of complement through the alternative pathway has a key role in the pathogenesis of IgA nephropathy (IgAN). Large, international, genome-wide association studies have shown that deletion of complement factor H–related genes 1 and 3 (CFHR3,1Δ) is associated with a reduced risk of developing IgAN, although the prognostic value of these deletions in IgAN remains unknown. Here, we compared the renal outcomes of patients with IgAN according to their CFHR3,1Δ genotype. This retrospective, monocentric cohort study included 639 white patients with biopsy-proven IgAN since 1979 (mean age at diagnosis, 40.1 years; median follow-up, 132 months). We determined the number of CFHR3 and CFHR1 gene copies by quantitative PCR and collected clinical and biologic data by reviewing the patients’ medical records. In all, 30.5% of the patients were heterozygous and 4% were homozygous for CFHR3,1Δ. We did not detect an association between CFHR3,1Δ and age, eGFR, urinary protein excretion rate, or the presence of hypertension or hematuria at the time of diagnosis. The mean intensities of immune IgA, IgG, and C3 deposits were lower in the group with heterozygous or homozygous gene deletions than in those with no deletion. However, CFHR3,1Δ did not associate with progression to stage 3 CKD or renal death. In conclusion, the CFHR3,1Δ genotype did not associate with progression toward CKD stages 3 and 5 in our white population of patients with IgAN, although it did associate with a reduced level of glomerular immune deposits.

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Complement factor H related proteins (CFHRs)

Molecular Immunology ◽

10.1016/j.molimm.2013.06.001 ◽

2013 ◽

Vol 56 (3) ◽

pp. 170-180 ◽

Cited By ~ 131

Author(s):

Christine Skerka ◽

Qian Chen ◽

Veronique Fremeaux-Bacchi ◽

Lubka T. Roumenina

Keyword(s):

Factor H ◽

Complement Factor H ◽

Complement Factor ◽

Related Proteins

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Case Report: A Rare Truncating Variant of the CFHR5 Gene in IgA Nephropathy

Frontiers in Genetics ◽

10.3389/fgene.2021.529236 ◽

2021 ◽

Vol 12 ◽

Author(s):

Gabriella Guzzo ◽

Salima Sadallah ◽

Heidi Fodstad ◽

Jean-Pierre Venetz ◽

Samuel Rotman ◽

...

Keyword(s):

Iga Nephropathy ◽

Association Studies ◽

Alternative Pathway ◽

Atypical Hemolytic Uremic Syndrome ◽

Factor H ◽

Genome Wide Association Studies ◽

Complement Factor ◽

Loss Of Function ◽

Renal Disease Progression ◽

Therapeutic Implications

IgA nephropathy (IgAN) is the most common primary glomerulonephritis worldwide. Despite appropriate therapy, 20–40% of affected-patients evolve toward end-stage kidney disease (ESKD). Mesangial IgA deposits are the hallmark of IgAN, and complement deposition (C3) seems to differentiate latent IgA mesangial deposits from active IgAN. Atypical hemolytic uremic syndrome (aHUS), another disease in which complement plays an important role, is caused by inherited or acquired deregulation of the alternative pathway (AP) of complement. A subgroup of IgAN shows thrombotic microangiopathy (TMA) lesions in kidney biopsies, the histological characteristic of aHUS. Genetic variants of complement Factor H (CFH), known to be present in aHUS, have been associated with rapidly progressive forms of IgAN and a clinical pattern of aHUS. Genome-wide association studies (GWAS) have confirmed that the 1q32 region, encoding for CFH and its related proteins, is an IgAN susceptibility locus. A 30 year-old man was admitted for seizures and malignant hypertension. The kidney biopsy showed IgAN associated with features of TMA. Despite five plasma exchanges, the patient remained dialysis-dependent, and ESKD was diagnosed. Functional and genetic complement analysis were performed. A monoallelic protein-truncating, likely loss-of-function variant was identified in the CFHR5 gene. Eculizumab is the treatment of aHUS. As it has been successfully used in a few cases of rapidly progressive IgAN, it was decided to administer eculizumab over a period of 12 months in addition to the usual immunosuppression for renal transplantation. After a follow-up of 3 years, there was no clinical disease recurrence. Systematic biologic and genetic screening of complement in individuals with IgAN might be useful to better delineate the role of the AP of complement in renal disease progression, and this may have therapeutic implications.

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Inherited Kidney Complement Diseases

Clinical Journal of the American Society of Nephrology ◽

10.2215/cjn.11830720 ◽

2021 ◽

pp. CJN.11830720

Author(s):

Mathieu Lemaire ◽

Damien Noone ◽

Anne-Laure Lapeyraque ◽

Christoph Licht ◽

Véronique Frémeaux-Bacchi

Keyword(s):

Single Gene ◽

Genetic Diseases ◽

Atypical Hemolytic Uremic Syndrome ◽

Factor H ◽

Complement Factor H ◽

Complement Factor ◽

Complement Dysregulation ◽

Innovative Therapies ◽

Uremic Syndrome ◽

Related Proteins

In the past 20 years, we have witnessed tremendous advances in our ability to diagnose and treat genetic diseases of the kidney caused by complement dysregulation. Staggering progress was realized toward a better understanding of the genetic underpinnings and pathophysiology of many forms of atypical hemolytic uremic syndrome (aHUS) and C3-dominant glomerulopathies that are driven by complement system abnormalities. Many of these seminal discoveries paved the way for the design and characterization of several innovative therapies, some of which have already radically improved patients’ outcomes. This review offers a broad overview of the exciting developments that have occurred in the recent past, with a particular focus on single-gene (or Mendelian), complement-driven aHUS and C3-dominant glomerulopathies that should be of interest to both nephrologists and kidney researchers. The discussion is restricted to genes with robust associations with both aHUS and C3-dominant glomerulopathies (complement factor H, complement component 3, complement factor H–related proteins) or only aHUS (complement factor B, complement factor I, and membrane cofactor protein). Key questions and challenges are highlighted, along with potential avenues for future directions.

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