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Title: | Non-canonical immunomodulatory activity of complement regulator C4BP(β-) limits the development of lupus nephritis |
Author: | Luque Gómez, Ana Serrano, Inmaculada Ripoll Llagostera, Èlia Malta, Catarina Gomà, Montse Blom, Anna M. Grinyó Boira, Josep M. Rodríguez de Córdoba, Santiago Torras Ambròs, Joan Aran Perramon, Josep M. |
Keywords: | Malalties del ronyó Malalties autoimmunitàries Kidney diseases Autoimmune diseases |
Issue Date: | 6-Nov-2019 |
Publisher: | Elsevier BV |
Abstract: | Lupus nephritis (LN) is a chronic autoimmune-inflammatory condition that can lead to end-stage renal disease because of the breakage of immune self-tolerance occurring in systemic lupus erythematosus (SLE) patients. Presently available immunosuppressive treatments for LN are suboptimal and can induce significant side effects. We have recently characterized a novel immunomodulatory activity on the minor isoform of the classical pathway complement inhibitor, C4BP(b-). We show here that C4BP(b-) treatment prevented the development of proteinuria and albuminuria, decreased significantly the formation of anti-dsDNA antibodies and, locally, mitigated renal glomerular IgG and C3 deposition and generation of apoptotic cells, with the consequent histological improvement and increased survival in lupus-prone mice. The therapeutic efficacy of C4BP(b-) was analogous to that of the broad-acting immunosuppressant cyclophosphamide (CYP). Remarkably, a comparative transcriptional profiling analysis revealed that: 1) the renal gene expression signature resulting from C4BP(b-) treatment turned out to be 10 times smaller than that induced by CYP treatment, and 2) C4BP(b-) immunomodulation induced significant downregulation of LN relevant transcripts indicating immunopathogenic cell infiltration, including activated T cells (Lat), B cells (Cd19, Ms4a1, Tnfrsf13c), inflammatory phagocytes (Irf7) and neutrophils (Prtn3, S100a8, S100a9). Furthermore, cytokine profiling and immunohistochemistry confirmed that C4BP(b-), through systemic and local CXCL13 downregulation, was able to prevent ectopic lymphoid structures neogenesis in aged LN mice. Thus, because of its anti-inflammatory and immunomodulatory activities and high specificity, C4BP(b-) could be considered for further clinical development in SLE patients. |
Note: | Versió postprint del document publicat a: https://doi.org/10.1016/j.kint.2019.10.016 |
It is part of: | Kidney International, 2020, vol. 97, issue. 3, p. 551-566 |
URI: | http://hdl.handle.net/2445/151537 |
Related resource: | https://doi.org/10.1016/j.kint.2019.10.016 |
Appears in Collections: | Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL)) |
Files in This Item:
File | Description | Size | Format | |
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KI PAPER (Lupus) (Luque et al.) (IDIBELL Repository).pdf | 8.01 MB | Adobe PDF | View/Open |
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