Noncanonical immunomodulatory activity of complement regulator C4BP(β-) limits the development of lupus nephritis
Luque, Ana ; Serrano, Inmaculada ; Ripoll, Elia ; Malta, Catarina ; Gomà, Montserrat ; Blom, Anna M. LU
; Grinyó, Josep M.
; Rodríguez de Córdoba, Santiago
; Torras, Joan
and Aran, Josep M.
(2020)
In Kidney International
97(3).
p.551-566
- Abstract
Lupus nephritis is a chronic autoimmune-inflammatory condition that can lead to end-stage kidney disease. Presently available immunosuppressive treatments for lupus nephritis are suboptimal and can induce significant side effects. Recently, we characterized a novel immunomodulatory activity of the minor isoform of the classical pathway complement inhibitor, C4BP(β-). We show here that C4BP(β-) 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. There was a consequent histological improvement and increased survival in lupus-prone mice. The therapeutic efficacy of... (More)
Lupus nephritis is a chronic autoimmune-inflammatory condition that can lead to end-stage kidney disease. Presently available immunosuppressive treatments for lupus nephritis are suboptimal and can induce significant side effects. Recently, we characterized a novel immunomodulatory activity of the minor isoform of the classical pathway complement inhibitor, C4BP(β-). We show here that C4BP(β-) 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. There was a consequent histological improvement and increased survival in lupus-prone mice. The therapeutic efficacy of C4BP(β-) was analogous to that of the broad-acting immunosuppressant cyclophosphamide. Remarkably, a comparative transcriptional profiling analysis revealed that the kidney gene expression signature resulting from C4BP(β-) treatment turned out to be 10 times smaller than that induced by cyclophosphamide treatment. C4BP(β-) immunomodulation induced significant downregulation of transcripts relevant to lupus nephritis 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(β-), through systemic and local CXCL13 downregulation, was able to prevent ectopic lymphoid structures neogenesis in aged mice with lupus nephritis. Thus, due to its anti-inflammatory and immunomodulatory activities and high specificity, C4BP(β-) could be considered for further clinical development in patients with systemic lupus erythematosus.
(Less)
- author
- Luque, Ana
; Serrano, Inmaculada
; Ripoll, Elia
; Malta, Catarina
; Gomà, Montserrat
; Blom, Anna M.
LU
; Grinyó, Josep M.
; Rodríguez de Córdoba, Santiago
; Torras, Joan
and Aran, Josep M.
- organization
- publishing date
- 2020-03
- type
- Contribution to journal
- publication status
- published
- subject
- keywords
- C4BP(β−), dendritic cells, ectopic lymphoid structures, immunomodulation, inflammation, lupus nephritis
- in
- Kidney International
- volume
- 97
- issue
- 3
- pages
- 16 pages
- publisher
- Nature Publishing Group
- external identifiers
-
- scopus:85078174584
- pmid:31982108
- ISSN
- 0085-2538
- DOI
- 10.1016/j.kint.2019.10.016
- language
- English
- LU publication?
- yes
- id
- 8810b55c-d0d9-467f-b719-70a640095629
- date added to LUP
- 2020-02-06 15:29:26
- date last changed
- 2024-06-26 10:18:46
@article{8810b55c-d0d9-467f-b719-70a640095629,
abstract = {{<p>Lupus nephritis is a chronic autoimmune-inflammatory condition that can lead to end-stage kidney disease. Presently available immunosuppressive treatments for lupus nephritis are suboptimal and can induce significant side effects. Recently, we characterized a novel immunomodulatory activity of the minor isoform of the classical pathway complement inhibitor, C4BP(β-). We show here that C4BP(β-) 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. There was a consequent histological improvement and increased survival in lupus-prone mice. The therapeutic efficacy of C4BP(β-) was analogous to that of the broad-acting immunosuppressant cyclophosphamide. Remarkably, a comparative transcriptional profiling analysis revealed that the kidney gene expression signature resulting from C4BP(β-) treatment turned out to be 10 times smaller than that induced by cyclophosphamide treatment. C4BP(β-) immunomodulation induced significant downregulation of transcripts relevant to lupus nephritis 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(β-), through systemic and local CXCL13 downregulation, was able to prevent ectopic lymphoid structures neogenesis in aged mice with lupus nephritis. Thus, due to its anti-inflammatory and immunomodulatory activities and high specificity, C4BP(β-) could be considered for further clinical development in patients with systemic lupus erythematosus.</p>}},
author = {{Luque, Ana and Serrano, Inmaculada and Ripoll, Elia and Malta, Catarina and Gomà, Montserrat and Blom, Anna M. and Grinyó, Josep M. and Rodríguez de Córdoba, Santiago and Torras, Joan and Aran, Josep M.}},
issn = {{0085-2538}},
keywords = {{C4BP(β−); dendritic cells; ectopic lymphoid structures; immunomodulation; inflammation; lupus nephritis}},
language = {{eng}},
number = {{3}},
pages = {{551--566}},
publisher = {{Nature Publishing Group}},
series = {{Kidney International}},
title = {{Noncanonical immunomodulatory activity of complement regulator C4BP(β-) limits the development of lupus nephritis}},
url = {{http://dx.doi.org/10.1016/j.kint.2019.10.016}},
doi = {{10.1016/j.kint.2019.10.016}},
volume = {{97}},
year = {{2020}},
}