Systemic Alterations of Immune Response-Related Proteins during Glaucoma Development in the Murine Model DBA/2J

Animal models of glaucoma, a neurodegenerative disease affecting the retina, offer the opportunity to study candidate molecular biomarkers throughout the disease. In this work, the DBA/2J glaucomatous mouse has been used to study the systemic levels of several proteins previously identified as potential biomarkers of glaucoma, along the pre- to post-glaucomatous transition. Serum samples obtained from glaucomatous and control mice at 4, 10, and 14 months, were classified into different experimental groups according to the optic nerve damage at 14 months old. Quantifications of ten serum proteins were carried out by enzyme immunoassays. Changes in the levels of some of these proteins in the transition to glaucomatous stages were identified, highlighting the significative decrease in the concentration of complement C4a protein. Moreover, the five-protein panel consisting of complement C4a, complement factor H, ficolin-3, apolipoprotein A4, and transthyretin predicted the transition to glaucoma in 78% of cases, and to the advanced disease in 89%. Our data, although still preliminary, suggest that disease development in DBA/2J mice is associated with important molecular changes in immune response and complement system proteins and demonstrate the utility of this model in identifying, at systemic level, potential markers for the diagnosis of glaucoma.

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Novel circulating protein biomarkers for thyroid cancer determined through data-independent acquisition mass spectrometry

PeerJ ◽

10.7717/peerj.9507 ◽

2020 ◽

Vol 8 ◽

pp. e9507

Author(s):

Dandan Li ◽

Jie Wu ◽

Zhongjuan Liu ◽

Ling Qiu ◽

Yimin Zhang

Keyword(s):

Mass Spectrometry ◽

Area Under The Curve ◽

High Sensitivity ◽

Factor H ◽

Complement Factor ◽

Protein Biomarkers ◽

Serum Samples ◽

Data Independent Acquisition ◽

Median Serum ◽

And Control

Background Distinguishing between different types of thyroid cancers (TC) remains challenging in clinical laboratories. As different tumor types require different clinical interventions, it is necessary to establish new methods for accurate diagnosis of TC. Methods Proteomic analysis of the human serum was performed through data-independent acquisition mass spectrometry for 29 patients with TC (stages I–IV): 13 cases of papillary TC (PTC), 10 cases of medullary TC (MTC), and six cases follicular TC (FTC). In addition, 15 patients with benign thyroid nodules (TNs) and 10 healthy controls (HCs) were included in this study. Subsequently, 17 differentially expressed proteins were identified in 291 patients with TC, including 247 with PTC, 38 with MTC, and six with FTC, and 69 patients with benign TNs and 176 with HC, using enzyme-linked immunosorbent assays. Results In total, 517 proteins were detected in the serum samples using an Orbitrap Q-Exactive-plus mass spectrometer. The amyloid beta A4 protein, apolipoprotein A-IV, gelsolin, contactin-1, gamma-glutamyl hydrolase, and complement factor H-related protein 1 (CFHR1) were selected for further analysis. The median serum CFHR1 levels were significantly higher in the MTC and FTC groups than in the PTC and control groups (P < 0.001). CFHR1 exhibited higher diagnostic performance in distinguishing patients with MTC from those with PTC (P < 0.001), with a sensitivity of 100.0%, specificity of 85.08%, area under the curve of 0.93, and detection cut-off of 0.92 ng/mL. Conclusion CFHR1 may serve as a novel biomarker to distinguish PTC from MTC with high sensitivity and specificity.

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

eLife ◽

10.7554/elife.04008 ◽

2014 ◽

Vol 3 ◽

Cited By ~ 31

Author(s):

Joseph JE Caesar ◽

Hayley Lavender ◽

Philip N Ward ◽

Rachel M Exley ◽

Jack Eaton ◽

...

Keyword(s):

Meningococcal Disease ◽

Serum Proteins ◽

Association Studies ◽

Factor H ◽

Complement Factor H ◽

Host Susceptibility ◽

Genome Wide Association Studies ◽

Complement Factor ◽

Bacterial Surface ◽

Related Proteins

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 novel monoclonal antibody specific for the 402His variant of complement factor H enables identification of the Tyr402His polymorphic status in serum samples

Molecular Immunology ◽

10.1016/j.molimm.2007.06.101 ◽

2007 ◽

Vol 44 (16) ◽

pp. 3951

Author(s):

Svetlana Hakobyan ◽

Claire L. Harris ◽

Agustin Tortojada ◽

Elena Giocochea de Jorge ◽

Santiago Rodriguez de Cordoba ◽

...

Keyword(s):

Monoclonal Antibody ◽

Factor H ◽

Complement Factor H ◽

Complement Factor ◽

Serum Samples

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Cleavage of Complement C3b to iC3b on the Surface of Staphylococcus aureus Is Mediated by Serum Complement Factor I

Infection and Immunity ◽

10.1128/iai.72.5.2858-2863.2004 ◽

2004 ◽

Vol 72 (5) ◽

pp. 2858-2863 ◽

Cited By ~ 36

Author(s):

K. M. Cunnion ◽

P. S. Hair ◽

E. S. Buescher

Keyword(s):

Staphylococcus Aureus ◽

Human Serum ◽

Serum Proteins ◽

Regulatory Protein ◽

Factor H ◽

Complement Factor ◽

Serum Factor ◽

Complement Protein ◽

Factor I ◽

Serotype 5

ABSTRACT Complement-mediated opsonization of Staphylococcus aureus bearing the dominant capsule serotypes, serotypes 5 and 8, remains incompletely understood. We have previously shown that complement plays a vital role in the efficient phagocytosis of a serotype 5 S. aureus strain and that the opsonic fragments of the central complement protein C3, C3b and iC3b, were present on the bacterial surface after incubation in human serum. In the present studies, C3b and iC3b were found on several serotype 5 and 8 S. aureus strains after incubation in human serum. Using purified classical activation pathway complement proteins and the Western blot assay, we showed that when C3b was generated on the S. aureus surface no iC3b fragments were found, suggesting that other serum proteins may be required for cleaving C3b to iC3b. When C3b-coated S. aureus was incubated with serum factor I, a complement regulatory protein, iC3b was generated. Purified factor H, a serum protein cofactor for factor I, did not enhance factor I-mediated cleavage of C3b. These findings suggest that C3b cleavage to iC3b on S. aureus is mediated by serum factor I and does not require factor H.

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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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Complement factor H and the long pentraxin PTX3 cooperate in the immune response to Aspergillus fumigatus

Molecular Immunology ◽

10.1016/j.molimm.2017.06.117 ◽

2017 ◽

Vol 89 ◽

pp. 156

Author(s):

Antonio Inforzato ◽

Raffaella Parente ◽

Francesca Petroni ◽

Marina Sironi ◽

Roberto Leone ◽

...

Keyword(s):

Immune Response ◽

Aspergillus Fumigatus ◽

Factor H ◽

Complement Factor H ◽

Complement Factor

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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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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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