2024-03-29T13:48:13Zhttp://digital.csic.es/dspace-oai/requestoai:digital.csic.es:10261/2009542021-10-21T08:20:54Zcom_10261_86com_10261_1col_10261_339
Luque, Ana
Serrano, Inmaculada
Ripoll, Èlia
Malta, Catarina
Gomá, Montserrat
Blom, Anna M.
Grinyó, Josep María
Rodríguez de Córdoba, Santiago
Torras, Joan
Aràn, Josep Maria
2020-02-17T13:36:26Z
2020-02-17T13:36:26Z
2019-11-06
Kidney Int S0085-2538(19)31049-X (2019)
0085-2538
http://hdl.handle.net/10261/200954
10.1016/j.kint.2019.10.016
1523-1755
http://dx.doi.org/10.13039/501100002809
http://dx.doi.org/10.13039/100012818
http://dx.doi.org/10.13039/501100000780
http://dx.doi.org/10.13039/501100003329
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.
eng
closedAccess
C4BP(β−)
Dendritic cells
Ectopic lymphoid structures
Immunomodulation
Inflammation
Lupus nephritis
Noncanonical immunomodulatory activity of complement regulator C4BP(β-) limits the development of lupus nephritis
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