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|Title:||Non-canonical immunomodulatory activity of complement regulator C4BP(β-) limits the development of lupus nephritis|
|Author:||Luque Gómez, Ana|
Ripoll Llagostera, Èlia
Blom, Anna M.
Grinyó Boira, Josep M.
Rodríguez de Córdoba, Santiago
Torras Ambròs, Joan
Aran Perramon, Josep M.
|Keywords:||Malalties del ronyó|
|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|
|Appears in Collections:||Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL))|
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Document embargat fins el 6-11-2020
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