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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:
It is part of: Kidney International, 2020, vol. 97, issue. 3, p. 551-566
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Appears in Collections:Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL))

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