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  • Intrarenal activation of adaptive immune effectors is associated with tubular damage and impaired renal function in lupus nephritis

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Basic and translational research
Intrarenal activation of adaptive immune effectors is associated with tubular damage and impaired renal function in lupus nephritis
  1. Cristina Pamfil1,2,
  2. Zuzanna Makowska3,
  3. Aurélie De Groof2,
  4. Gaëlle Tilman1,2,
  5. Sepideh Babaei3,
  6. Christine Galant2,4,
  7. Pauline Montigny1,2,
  8. Nathalie Demoulin5,6,
  9. Michel Jadoul5,6,
  10. Selda Aydin4,
  11. Ralf Lesche3,
  12. Fiona McDonald3,
  13. Frédéric A Houssiau1,2,
  14. Bernard R Lauwerys1,2
  1. 1 Department of Rheumatology, Cliniques Universitaires Saint-Luc, Brussels, Belgium
  2. 2 Pôle de pathologies rhumatismales systémiques et inflammatoires, Institut de Recherche Expérimentale et Clinique, Université catholique de Louvain, Brussels, Belgium
  3. 3 Pharmaceuticals, Research and Development, Bayer AG, Berlin, Germany
  4. 4 Department of Pathology, Cliniques Universitaires Saint-Luc, Brussels, Belgium
  5. 5 Department of Nephrology, Cliniques Universitaires Saint-Luc, Brussels, Belgium
  6. 6 Pôle de Néphrologie, Institut de Recherche Expérimentale et Clinique, Université catholique de Louvain, Brussels, Belgium
  1. Correspondence to Dr Bernard R Lauwerys, Department of Rheumatology, Cliniques Universitaires Saint-Luc, Brussels 1200, Belgium; bernard.lauwerys{at}uclouvain.be

Abstract

Objectives Chronic renal impairment remains a feared complication of lupus nephritis (LN). The present work aimed at identifying mechanisms and markers of disease severity in renal tissue samples from patients with LN.

Methods We performed high-throughput transcriptomic studies (Illumina HumanHT-12 v4 Expression BeadChip) on archived kidney biopsies from 32 patients with LN and eight controls (pretransplant donors). Histological staging (glomerular and tubular scores) and immunohistochemistry experiments were performed on the same and on a replication set of 37 LN kidney biopsy samples.

Results A group of LN samples was identified by unsupervised clustering studies based on their gene expression features, that is, the overexpression of transcripts involved in antigen presentation, T and B cell activation. These samples were characterised by a significantly lower estimated glomerular filtration rate (eGFR) at the time of biopsy (T0) compared with the other systemic lupus erythematosus samples. Yet, apparent disease duration at T0, double-stranded DNA antibody titres at T0 and other relevant characteristics (serum C3, proteinuria, histological scores, numbers of previous flares) were not different between groups.

Immunohistochemistry studies confirmed the association between interstitial infiltration by adaptive immune effectors and decreased renal function in the same and in a replication group of LN kidney biopsies. This was associated with transcriptomic, histological and immunohistochemical evidence of renal tubular cell involvement.

Conclusion Interstitial infiltration of LN kidney biopsies by adaptive immune effectors is associated with impaired renal tubular cell function and decreased eGFR. These results open new perspectives in evaluating and treating patients with LN, focusing on intrarenal mechanisms of immune cell activation.

  • lupus nephritis
  • systemic lupus erythematosus
  • T cells

This is an open access article distributed in accordance with the Creative Commons Attribution 4.0 Unported (CC BY 4.0) license, which permits others to copy, redistribute, remix, transform and build upon this work for any purpose, provided the original work is properly cited, a link to the licence is given, and indication of whether changes were made. See: https://creativecommons.org/licenses/by/4.0/.

https://doi.org/10.1136/annrheumdis-2018-213485

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    Footnotes

    • CP and ZM contributed equally.

    • Handling editor Josef S Smolen

    • Contributors ZM, ADG, GT, SB, CG, RL, FMD, BRL: acquisition of experimental data, data analysis, drafting of the manuscript. ND, MJ, SA, FAH: acquisition of clinical data, data analysis, drafting of the manuscript.

    • Funding The research leading to these results has received support from the Innovative Medicines Initiative Joint Undertaking under grant agreement number 115565, resources of which are composed of financial contribution from the European Union’s Seventh Framework Programme (FP7/2007-2013) and EFPIA companies’ in-kind contribution. This work was also supported by FOREUM (Foundation for Research in Rheumatology) in the context of the REFRACT project. CP was funded in part by a EULAR scientific training bursary, and in part by a mobility grant from the Department of Rheumatology, ’Iuliu Hatieganu' University of Medicine and Pharmacy, Cluj-Napoca, Romania. ADG is funded by the ’Chaire UCL/UCB sur les Rhumatismes Systémiques et Inflammatoires'. PM is funded by the Fondation Saint-Luc, Cliniques Universitaires Saint-Luc, Brussels, Belgium. BRL is funded in part by the Fonds National de la Recherche Scientifique (FNRS, communauté française de Belgique).

    • Competing interests None declared.

    • Patient consent Obtained.

    • Ethics approval The Ethical Committee of the Université catholique de Louvain (UCL) approved the study and initially ruled that patient consent was not required for the use of residual corporal material, in agreement with Belgian regulations on human studies. However, in order to ensure formal compliance with German regulations on the use of residual corporal material, we did ask all patients with SLE included in the study to sign a consent form, after re-approval by the UCL Ethical Committee.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Data sharing statement Raw data are available upon request from the corresponding author.