REFRACT – Refractory lupus nephritis: a tissue-based pathophysiological approach
Concept
Lupus nephritis (LN) remains a severe complication of SLE, impacting long-term survival and quality of life.
In REFRACT, we use kidney biopsies from LN patients in order to study molecular and cellular mechanisms underlying LN refractory disease.
One of the hypotheses to explain resistance to therapy is that the kidney itself is not only a target for autoantibodies but also acts as a true lymphoid organ that hosts immunologically relevant processes resulting in further local adaptive immune cell activation and differentiation.
Facts and Figures
B Lauwerys
Cliniques Universitaires Saint-Luc
Bernard.Lauwerys@uclouvain.be
Meet the Team
Université Paris-Descartes
Karolinska Institutet
University of Cambridge
Fundacio Clinic per a la Recerca Biomedica Barcelona
Université Paris-Est
Lupus Europe
Objectives
The main objective of REFRACT is to unravel cellular and molecular mechanisms underlying renal injury in lupus nephritis (LN), in particular in cases not responding to standard of care immunosuppressive therapy, taking advantage of renal biopsy samples obtained within the frame of our investigator-initiated clinical trials.
Final Results
Our initial results, obtained in two independent sets of LN kidney biopsies, confirmed our hypothesis that intrarenal activation of adaptive immune effectors is associated with tubular damage and decreased renal function in LN (1).
Single cell gene expression profiling of (CD3-CD14-CD16-CD27+ CD38high) plasma cells (PC) was performed using kidney biopsies and blood from patients with a flare of class III/IV LN treated or not with mycophenolate mofetil (MMF). We obtained single kidney plasma cells that we compared with long-lived plasma cells from the bone marrow of heathy donors. In untreated patients, most PC were plasmablasts expressing multiple genes involved in cell division. By contrast, PC from the kidney of MMF-treated patients were over-expressing multiple plasmacell specific genes while not harboring a proliferative profile.
Similarly, single cell RNASeq and clonal expansion of CD8 T cells from kidney, urine and blood from patients with a severe flare of class III/IV LN showed the presence of clonally expanded CD8 T cells with an activated phenotype. One of these clones displayed cytotoxic properties against cultured renal tubular cells that were abrogated after targeted deletion of the T Cell Receptor.
Lay Summary
Lupus nephritis is a severe complication of systemic lupus erythematosus. It is caused by the deposition of anti-chromatin antibodies in the glomerular basement membrane, where they activate complement and recruit inflammatory cells, resulting in glomerulonephritis. Despite the use of corticosteroids and other immunosuppressive agents, 15% of lupus nephritis patients still develop end-stage renal disease after 10 years of evolution, a major issue in a population of mainly young women. The hypothesis underlying this research project is that the first systemic hit in lupus nephritis (deposition of autoantibodies) induces the recruitment in the kidney of a second wave of immune cells that play a predominant role in renal disease progression, independently of what happens at the systemic level. These cells cause persistent renal inflammation and lead to the accumulation of damage in a subset of patients, yet are not adequately tackled by present therapeutic strategies.
We performed in-depth molecular profiling studies on renal biopsies from patients with lupus nephritis, but also on kidneys from mice with lupus, at different stages of disease evolution. Our results confirmed our hypothesis: accumulation of immune effectors in the kidney is toxic for renal resident cells. These cells are recruited and activated locally, and play an independent role in disease progression. Molecules they secrete (such as MMP7) can be measured in the serum, which provides clinicians with a new tool to evaluate disease severity. Our results open new avenues of research in the field of lupus nephritis, aiming at specifically interfering with intra-renal mechanisms of disease progression.
Publications
- Pamfil C, Makowska Z, De Groof A, et al. Intrarenal activation of adaptive immune effectors is associated with tubular damage and impaired renal function in lupus nephritis. Annals of the Rheumatic Diseases Published Online First: 31 July 2018. doi: 10.1136/annrheumdis-2018-213485
Read more - Crickx E, Tamirou F, Huscenot T, Costedoat-Chalumeau N, Rabant M, Karras A, Robbins A, Fadeev T, Le Guern V, Remy P, Hummel A, Aydin S, Lauwerys B, Weill JC, Reynaud CA, Houssiau F, Mahévas M. Molecular Signatures of Kidney Antibody-Secreting Cells in Lupus Patients With Active Nephritis Upon Immunosuppressive Therapy. Arthritis Rheumatol. 2021 Aug;73(8):1461-1466. doi: 10.1002/art.41703. Epub 2021 Jul 16. PMID: 33645886.
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Abstract
Goletti S, Nieuwland S, Houssiau FA, Lauwerys BR. MMP7 and CXCL12: Two Promising Biomarkers in Lupus Nephritis. Arthritis Rheumatol. 2018; 70 (suppl 10).
https://acrabstracts.org/abstract/mmp7-and-cxcl12-two-promising-biomarkers-in-lupus-nephritis/
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Patient Voice
SLE Europe was involved in the elaboration of this project and discussion of the results. Based on our data, SLE Europe and several European groups decided to apply together for follow-up grants, in order to keep characterize intra-renal immune effectors involved in disease progression in LN.