Anti-ficolin-3 Antibodies in Lupus Nephritis

NCT03842787 | Completed

• 2 other identifiers: 38RC18.3032018-A02942-53
• Study Type: observational
• Target: 4
• Locations: 1 country
• Sites: 1

Brief Summary

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by the production of multiple autoantibodies and accumulation of immune complexes resulting in systemic inflammatory response and tissue damage. Although the underlying mechanisms are complex, defects in dying cells elimination are likely to contribute to autoantigen overload and development of autoimmunity. Molecules important in damaged cell clearance, such as early complement components, may thus have a protective role. According to this hypothesis, deficiencies in C1q and MBL, the recognition proteins of the classical and lectin pathways of complement; are associated with increased susceptibility to SLE. In the proposed project, the investigators will investigate the involvement of another related recognition protein, ficolin-3, which activates the complement lectin pathway and recognizes necrotic cells. The investigators have shown in a recent study a significant association between the presence of anti-ficolin-3 antibodies and active nephritis in patients with SLE. However, the possible involvement of anti-ficolin-3 antibodies in the pathogenesis of SLE and particularly in lupus nephritis (LN) remains to be elucidated. This project plans to investigate the role of ficolin-3 and ficolin-3 autoantibodies in LN. The study associates two aspects, aiming at deciphering the role of anti-ficolin-3 antibodies in dying cells recognition and investigating the role of ficolin-3 in renal tissue damage. This pilot study will be performed for 14 patients with active LN on serum and renal biopsy, realized for routine patient care. The investigators will explore the effect of anti-ficolin-3 antibodies purified from the patient serum on ficolin-3-dependent necrotic cells recognition, in relation with possible altered clearance of dead cells, which is an important hypothesis of the pathogenesis of SLE. The investigators will also investigate ficolin-3 deposition in renal biopsy, which may contribute to the local formation of immune complexes, leading to complement activation and subsequent inflammation and tissue injury.

Conditions

Systemic Lupus Erythematosus Nephritis

Keywords

systemic lupus erythematosus; lupus nephritis; complement; ficolin-3; anti-ficolin-3 autoantibodies

Outcome Measures

Primary Outcomes (1)

• Exploration of the inhibition of anti-ficolin-3 antibodies purified from the serum of 14 patients with active lupus nephritis in ficolin-3-dependent necrotic cells recognition.

  In order to investigate the possible interference of the anti-ficolin-3 antibodies purified from patients'sera with ficolin-3 dependent necrotic cells recognition, recombinant ficolin-3 will be preincubated with the purified specific autoantibodies before addition to Jurkat necrotic cells. Ficolin-3 binding will be measured using the flow cytometry and immunofluorescence assays described above and quantified using the mean fluorescence intensity (MFI). The criterion used is the shift of MFI (Mean Fluorescence Intensity) measured after addition of these antibodies to necrotic Jurkat cells incubated with ficolin-3.

  Measure at day of inclusion = TO

Secondary Outcomes (13)

• Investigation of ficolin-3 deposition in renal biopsy of the same 14 patients with active LN.

  Measure at day of inclusion = TO

• Quantification of anti-ficolin-3 antibodies.

  Measure at day of inclusion = TO

• Quantification of serum levels of ficolin-3.

  Measure at day of inclusion = TO

• Correlation of anti-ficolin-3 antibodies and serum levels of ficolin-3.

  Measure at day of inclusion = TO

• Correlation between serum levels of anti-ficolin-3 antibodies and ficolin-3 deposition in the kidney.

  Measure at day of inclusion = TO

Study Arms (1)

SLE patients with lupus Nephritis

14 SLE patients with lupus Nephritis Biological analysis and biopsy were (routinely) performed Ethics The protocol will be submitted to a randomly chosen Institutional Review Board (Comité de Protection des Personnes), in compliance to French regulation. Investigators will include patients followed for routine care. Patients will be informed that samples (serum and kidney biopsy) that are performed for routine patient care will subsequently be used for research purposes, with no additional blood draw/biopsy. They will sign informed consent.

Other: Biological analysis

Interventions

Biological analysis OTHER

Biological and research analysis: Quantification of ficolin-3, anti-ficolin-3 antibodies, ficolin-2, anti-ficolin-2 antibodies Purification of patients' antibodies (anti-ficolin-3 and -2) Evaluation of effects of anti-ficolin-3 and anti-ficolin-2 purified antibodies Investigation of ficolin-3 and ficolin-2 deposition in renal biopsy

SLE patients with lupus Nephritis

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)
• Sampling Method: Non-Probability Sample

Study Population

SLE patients with lupus Nephritis

You may qualify if:

• Age ≥ 18 years old
• Patients who have valid health insurance
• Non-opposition to participation obtained
• Diagnostic de lupus according to SLICC 2012, performed more than 3 months ago.
• Active lupus nephritis defined by :
• elevated SLEDAI indexes (≥ 4), the presence of a significant proteinuria (≥ 0.5 g/day) and/or the presence of hematuria, aseptic leukocyturia or urinary casts, and documented by renal biopsy and classified according to the ISN/RPS classification.
• Patient with a known progressing cancer
• Patient who had started lupus nephritis flare treatment
• Participant involved in another interventional clinical study
• Person deprived of liberty by judicial order
• Person under guardianship or curatorship
• Hemoglobin level \< 7 g/dL

Sponsors & Collaborators

• University Hospital, Grenoble: lead
• Institut de Biologie Structurale Grenoble: collaborator

Study Sites (1)

JOUVE

La Tronche, France

Location

Related Publications (13)

• Dumestre-Perard C, Clavarino G, Colliard S, Cesbron JY, Thielens NM. Antibodies targeting circulating protective molecules in lupus nephritis: Interest as serological biomarkers. Autoimmun Rev. 2018 Sep;17(9):890-899. doi: 10.1016/j.autrev.2018.03.013. Epub 2018 Jul 29.

  PMID: 30009962 BACKGROUND

• Munoz LE, Lauber K, Schiller M, Manfredi AA, Schett G, Voll RE, Herrmann M. [The role of incomplete clearance of apoptotic cells in the etiology and pathogenesis of SLE]. Z Rheumatol. 2010 Mar;69(2):152, 154-6. doi: 10.1007/s00393-009-0603-7. German.

  PMID: 20107814 BACKGROUND

• Kravitz MS, Shoenfeld Y. Autoimmunity to protective molecules: is it the perpetuum mobile (vicious cycle) of autoimmune rheumatic diseases? Nat Clin Pract Rheumatol. 2006 Sep;2(9):481-90. doi: 10.1038/ncprheum0290.

  PMID: 16951703 BACKGROUND

• Herrmann M, Voll RE, Zoller OM, Hagenhofer M, Ponner BB, Kalden JR. Impaired phagocytosis of apoptotic cell material by monocyte-derived macrophages from patients with systemic lupus erythematosus. Arthritis Rheum. 1998 Jul;41(7):1241-50. doi: 10.1002/1529-0131(199807)41:73.0.CO;2-H.

  PMID: 9663482 BACKGROUND

• Honore C, Hummelshoj T, Hansen BE, Madsen HO, Eggleton P, Garred P. The innate immune component ficolin 3 (Hakata antigen) mediates the clearance of late apoptotic cells. Arthritis Rheum. 2007 May;56(5):1598-607. doi: 10.1002/art.22564.

  PMID: 17469142 BACKGROUND

• Liphaus BL, Kiss MH. The role of apoptosis proteins and complement components in the etiopathogenesis of systemic lupus erythematosus. Clinics (Sao Paulo). 2010 Mar;65(3):327-33. doi: 10.1590/S1807-59322010000300014.

  PMID: 20360925 BACKGROUND

• Sato N, Ohsawa I, Nagamachi S, Ishii M, Kusaba G, Inoshita H, Toki A, Horikoshi S, Ohi H, Matsushita M, Tomino Y. Significance of glomerular activation of the alternative pathway and lectin pathway in lupus nephritis. Lupus. 2011 Nov;20(13):1378-86. doi: 10.1177/0961203311415561. Epub 2011 Sep 5.

  PMID: 21893562 BACKGROUND

• Kuraya M, Ming Z, Liu X, Matsushita M, Fujita T. Specific binding of L-ficolin and H-ficolin to apoptotic cells leads to complement activation. Immunobiology. 2005;209(9):689-97. doi: 10.1016/j.imbio.2004.11.001.

  PMID: 15804047 BACKGROUND

• Nisihara RM, Magrini F, Mocelin V, Messias-Reason IJ. Deposition of the lectin pathway of complement in renal biopsies of lupus nephritis patients. Hum Immunol. 2013 Aug;74(8):907-10. doi: 10.1016/j.humimm.2013.04.030. Epub 2013 Apr 29.

  PMID: 23639552 BACKGROUND

• Tanha N, Pilely K, Faurschou M, Garred P, Jacobsen S. Plasma ficolin levels and risk of nephritis in Danish patients with systemic lupus erythematosus. Clin Rheumatol. 2017 Feb;36(2):335-341. doi: 10.1007/s10067-016-3508-2. Epub 2016 Dec 15.

  PMID: 27981461 BACKGROUND

• Colliard S, Jourde-Chiche N, Clavarino G, Sarrot-Reynauld F, Gout E, Deroux A, Fougere M, Bardin N, Bouillet L, Cesbron JY, Thielens NM, Dumestre-Perard C. Autoantibodies Targeting Ficolin-2 in Systemic Lupus Erythematosus Patients With Active Nephritis. Arthritis Care Res (Hoboken). 2018 Aug;70(8):1263-1268. doi: 10.1002/acr.23449. Epub 2018 Jun 21.

  PMID: 29045037 BACKGROUND

• Plawecki M, Lheritier E, Clavarino G, Jourde-Chiche N, Ouili S, Paul S, Gout E, Sarrot-Reynauld F, Bardin N, Boelle PY, Chiche L, Bouillet L, Thielens NM, Cesbron JY, Dumestre-Perard C. Association between the Presence of Autoantibodies Targeting Ficolin-3 and Active Nephritis in Patients with Systemic Lupus Erythematosus. PLoS One. 2016 Sep 15;11(9):e0160879. doi: 10.1371/journal.pone.0160879. eCollection 2016.

  PMID: 27631981 BACKGROUND

• Trouw LA, Daha MR. Role of anti-C1q autoantibodies in the pathogenesis of lupus nephritis. Expert Opin Biol Ther. 2005 Feb;5(2):243-51. doi: 10.1517/14712598.5.2.243.

  PMID: 15757386 BACKGROUND

MeSH Terms

Conditions

Lupus Erythematosus, Systemic; Lupus Nephritis

Interventions

Biological Oxygen Demand Analysis

Condition Hierarchy (Ancestors)

Connective Tissue Diseases; Skin and Connective Tissue Diseases; Autoimmune Diseases; Immune System Diseases; Glomerulonephritis; Nephritis; Kidney Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases

Intervention Hierarchy (Ancestors)

Environmental Monitoring; Environmental Exposure; Environmental Pollution; Public Health; Environment and Public Health; Public Health Practice

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 22, 2019
• First Posted: February 15, 2019
• Study Start: March 7, 2019
• Primary Completion: June 20, 2020
• Study Completion: June 20, 2020
• Last Updated: September 28, 2021

Record last verified: 2021-09

Data Sharing

• IPD Sharing: Will not share

Locations

FR (1)