Noncanonical immunomodulatory activity of complement regulator C4BP(β-) limits the development of lupus nephritis

Luque, Ana; Serrano, Inmaculada; Ripoll, Élia; Malta, Catarina; Gomà, Montserrat; Blom, Anna M.; Grinyó, Josep M.; Córdoba, Santiago Rodrı́guez de; Torrás, Joan; Aran, Josep M.

doi:10.1016/j.kint.2019.10.016

Cited by 13 publications

(8 citation statements)

References 55 publications

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“…SLE is a B cell-mediated autoimmune disease in which autoantibodies, such as anti-double-stranded DNA (dsDNA) autoantibodies, form immune complexes that are deposited in different tissues, resulting in multiple inflammatory lesions and tis-sue damage. [1][2][3] One of the most serious related complications is lupus nephritis (LN), which can lead to severe proteinuria, chronic renal failure, and end-stage kidney disease. This complication remains the leading cause of short-term morbidity and mortality.…”

Section: Introductionmentioning

confidence: 99%

The gene silencing of IRF5 and BLYSS effectively modulates the outcome of experimental lupus nephritis

Guiteras

Ripoll

Bolaños

et al. 2021

Molecular Therapy - Nucleic Acids

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Section: Introductionmentioning

confidence: 99%

The gene silencing of IRF5 and BLYSS effectively modulates the outcome of experimental lupus nephritis

Guiteras

Ripoll

Bolaños

et al. 2021

Molecular Therapy - Nucleic Acids

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“…PRP6-HO7, a recombinant heptamer resulting by joining CCP6 and the oligomerization domains of C4BP, lacks the complement inhibitory activity of C4BP while fully preserving its immunomodulatory activity. We recently confirmed the therapeutic potential of the non-canonical activity of C4BP(β-) to limit the development of lupus nephritis (LN) in two different animal models ( 14 ). We reveal here that PRP6-HO7 reverses the pro-inflammatory phenotype of monocytes isolated from LN patients, which supports its therapeutic potential in autoimmune pathologies.…”

Section: Introductionmentioning

confidence: 81%

“…We recently demonstrated the therapeutic potential of human C4BP(β-) in two autoimmune LN mouse models, which prevented pro-inflammatory immune cell infiltration and the development of ectopic lymphoid structures, suggesting that the putative C4BP(β-) receptor is preserved in mice ( 14 ). Here, we have extended our studies to Mo-DCs and Mo-macrophages obtained from SLE patients with active disease and renal involvement.…”

Section: Discussionmentioning

confidence: 99%

The Hidden Side of Complement Regulator C4BP: Dissection and Evaluation of Its Immunomodulatory Activity

et al. 2022

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C4b-binding protein (C4BP) is a well-known regulator of the complement system that holds additional and important activities unrelated to complement inhibition. Recently, we have described a novel immunomodulatory activity in the minor C4BP(β-) isoform directly acting over inflammatory phagocytes. Here we show that incorporation of the β-chain to the C4BP α-chain oligomer interferes with this immunomodulatory activity of C4BP. Moreover, an oligomeric form including only the complement control protein 6 (CCP6) domain of the C4BP α-chain (PRP6-HO7) is sufficient to “reprogram” monocyte-derived DCs (Mo-DCs) from a pro-inflammatory and immunogenic phenotype to an anti-inflammatory and tolerogenic state. PRP6-HO7 lacks complement regulatory activity but retains full immunomodulatory activity over inflammatory Mo-DCs induced by TLRs, characterized by downregulation of relevant surface markers such as CD83, HLA-DR, co-stimulatory molecules such as CD86, CD80 and CD40, and pro-inflammatory cytokines such as IL-12 and TNF-α. Furthermore, PRP6-HO7-treated Mo-DCs shows increased endocytosis, significantly reduced CCR7 expression and CCL21-mediated chemotaxis, and prevents T cell alloproliferation. Finally, PRP6-HO7 shows also full immunomodulatory activity over Mo-DCs isolated from lupus nephritis patients with active disease, even without further pro-inflammatory stimulation. Therefore PRP6-HO7, retaining the immunomodulatory activity of C4BP(β-) and lacking its complement regulatory activity, might represent a promising and novel alternative to treat autoimmune diseases.

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“…It enables to enzyme binding activity and involved it neutrophil extravasation process ( 35 ). Recently, a complement regulator C4BP was proved to limit the development of LN via inhibition of PRTN3 to significant downregulate neutrophils activity, indicating the possible link between ANCA-associated vasculitis and LN ( 36 ).…”

Section: Discussionmentioning

confidence: 99%

Potential biomarkers for active renal involvement in systemic lupus erythematosus patients

Xiao

Lin

2022

Front. Med.

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ObjectiveThis study aimed to identify the key genes related to active renal involvement in patients with systemic lupus erythematosus (SLE).MethodsMicroarray datasets were downloaded from the Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) between SLE patients with active renal involvement and those who did not have active renal involvement were identified by R software. Hub genes were identified using protein–protein interaction networks. The relationships between the expression levels of identified hub genes and SLEDAI were subjected to linear correlation analysis. The diagnostic accuracy of the hub genes was evaluated with the area under the curve of the receiver operating characteristic curve (ROC-AUC). Transcription factors (TFs) were predicted. The expression levels of different hub genes and histopathological patterns were also examined.ResultsA total of 182 DEGs were identified. Enrichment analysis indicated that DEGs were primarily enriched in neutrophil degranulation, neutrophil activation involved in immune response and neutrophil activation. The expression levels of 12 identified hub genes were verified. Ten of the 12 hub genes were positively associated with SLEDAI. The combination model of DEFA4, CTSG, RETN, CEACAM8, TOP2A, LTF, MPO, ELANE, BIRC5, and LCN2 had a certain diagnostic accuracy in detecting renal involvement with high disease activity in SLE patients. The expressions of five predicted TFs were validated by GSE65391 dataset.ConclusionThis work explored the pathogenesis of renal involvement in SLE. These results may guide future experimental research and clinical transformation.

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Noncanonical immunomodulatory activity of complement regulator C4BP(β-) limits the development of lupus nephritis

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Cited by 13 publications

References 55 publications

The gene silencing of IRF5 and BLYSS effectively modulates the outcome of experimental lupus nephritis

The gene silencing of IRF5 and BLYSS effectively modulates the outcome of experimental lupus nephritis

The Hidden Side of Complement Regulator C4BP: Dissection and Evaluation of Its Immunomodulatory Activity

Potential biomarkers for active renal involvement in systemic lupus erythematosus patients

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