CD40 ligand deficiency causes functional defects of peripheral neutrophils that are improved by exogenous IFN-γ

Cabral-Marques, Otávio; França, Tábata Takahashi; Al-Sbiei, Ashraf; Schimke, Lena Friederike; Khan, Taj Ali; Feriotti, Cláudia; Costa, Tânia Alves da; Reis, Osvaldo; Weber, Cristiane Seganfredo; Ferreira, Janaíra Fernandes Severo; Tavares, Fabíola Scancetti; Valente, Cláudia França Cavalcante; Gesu, Regina Sumiko Watanabe Di; Iqbal, Asif; Riemekasten, Gabriela; Amarante-Mendes, Gustavo P.; Barbuto, José Alexandre Marzagão; Costa‐Carvalho, Beatriz Tavares; Pereira, Pedro Paulo; Fernández-Cabezudo, Maria J.; Calich, Vera Lúcia Garcia; Notarangelo, Luigi D.; Torgerson, Troy R.; al-Ramadi, Basel K.; Ochs, Hans D.; Condino‐Neto, Antônio

doi:10.1016/j.jaci.2018.02.026

Cited by 25 publications

(29 citation statements)

References 126 publications

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“…Notably, the effect of EDNRA inhibition on cell migration by sitaxsentan was not due to cytotoxic effects since neutrophils in vitro did not display signs of apoptosis or necrosis when EDNRA was inhibited by sitaxsentan (Supplementary Figure 7 ). HD-IgG did not affect other physiological functions, such as the neutrophil or monocyte oxidative burst or lymphocyte proliferation (Supplementary Figure 8 ; both performed as previously described 30 , 31 ). In addition, the HD-IgG used was endotoxin-free, as demonstrated by endotoxin testing (PTS cartridge <0.05 EU/ml).…”

Section: Resultssupporting

confidence: 65%

“…The capacity of antibodies to induce neutrophil chemotaxis was analyzed using the transwell migration assay (24-well plate, Corning Inc., Corning, NY, USA) as previously described 32 . For the analysis of HD-IgG-induced migration, neutrophils were isolated from heparinized blood by dextran sedimentation followed by Ficoll-Hypaque centrifugation as previously described 30 . The purity, based on CD15 expression, was always above 97%, as was the viability before the migration assays.…”

Section: Methodsmentioning

confidence: 99%

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GPCR-specific autoantibody signatures are associated with physiological and pathological immune homeostasis

et al. 2018

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Autoantibodies have been associated with autoimmune diseases. However, studies have identified autoantibodies in healthy donors (HD) who do not develop autoimmune disorders. Here we provide evidence of a network of immunoglobulin G (IgG) autoantibodies targeting G protein-coupled receptors (GPCR) in HD compared to patients with systemic sclerosis, Alzheimer’s disease, and ovarian cancer. Sex, age and pathological conditions affect autoantibody correlation and hierarchical clustering signatures, yet many of the correlations are shared across all groups, indicating alterations to homeostasis. Furthermore, we identify relationships between autoantibodies targeting structurally and functionally related molecules, such as vascular, neuronal or chemokine receptors. Finally, autoantibodies targeting the endothelin receptor type A (EDNRA) exhibit chemotactic activity, as demonstrated by neutrophil migration toward HD-IgG in an EDNRA-dependent manner and in the direction of IgG from EDNRA-immunized mice. Our data characterizing the in vivo signatures of anti-GPCR autoantibodies thus suggest that they are a physiological part of the immune system.

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Section: Resultssupporting

confidence: 65%

Section: Methodsmentioning

confidence: 99%

GPCR-specific autoantibody signatures are associated with physiological and pathological immune homeostasis

et al. 2018

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“…The inhibitory effect of Ambrisentan was analyzed using cancer cell lines: COLO-357 of metastatic pancreatic adenocarcinoma, OvCar3 ovarian carcinoma, HL-60, and MDA-MB231 breast adenocarcinoma cell lines. The HL-60 promyelocytic leukemia cell line was cultured for 6 days in the presence of 1% dimethyl sulfoxide (DMSO) as previously described 80 . After 6 days of incubation, cells were harvested, counted, and their viability determined by Trypan blue exclusion before performing migration assays.…”

Section: Methodsmentioning

confidence: 99%

Ambrisentan, an endothelin receptor type A-selective antagonist, inhibits cancer cell migration, invasion, and metastasis

Kappes

Amer

Sommerlatte

et al. 2020

Sci Rep

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Several studies reported a central role of the endothelin type A receptor (ETAR) in tumor progression leading to the formation of metastasis. Here, we investigated the in vitro and in vivo anti-tumor effects of the FDA-approved ETAR antagonist, Ambrisentan, which is currently used to treat patients with pulmonary arterial hypertension. In vitro, Ambrisentan inhibited both spontaneous and induced migration/invasion capacity of different tumor cells (COLO-357 metastatic pancreatic adenocarcinoma, OvCar3 ovarian carcinoma, MDA-MB-231 breast adenocarcinoma, and HL-60 promyelocytic leukemia). Whole transcriptome analysis using RNAseq indicated Ambrisentan’s inhibitory effects on the whole transcriptome of resting and PAR2-activated COLO-357 cells, which tended to normalize to an unstimulated profile. Finally, in a pre-clinical murine model of metastatic breast cancer, treatment with Ambrisentan was effective in decreasing metastasis into the lungs and liver. Importantly, this was associated with a significant enhancement in animal survival. Taken together, our work suggests a new therapeutic application for Ambrisentan in the treatment of cancer metastasis.

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“…CD40 ligand (CD40L) deficiency (55, 56) is a X-linked disease related to hemizygous mutations in CD40LG gene, encoding CD40L, a glycoprotein (5, 57-61) mainly involved in co-stimulatory T-lymphocyte function. Impaired CD40L expression alters B-cell isotype switching and antibody production, dendritic cell signaling, and myeloid cell function and development (62,63). Generally, disease onset occurs during early childhood, with frequent respiratory tract infections, diarrhea and neutropenia.…”

Section: The Example Of Cd40l Deficiency: Hsct Vs Long-term Supportimentioning

confidence: 99%

Hematopoietic Stem Cell Transplantation for Combined Immunodeficiencies, on Behalf of IEWP-EBMT

Neven

Ferrua

2020

Front. Pediatr.

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CD40 ligand deficiency causes functional defects of peripheral neutrophils that are improved by exogenous IFN-γ

Abstract: Our data suggest a nonredundant role of CD40L-CD40 interaction in neutrophil development and function that could be improved in vitro by rhIFN-γ, indicating a potential novel therapeutic application for this cytokine.

Cited by 25 publications

References 126 publications

GPCR-specific autoantibody signatures are associated with physiological and pathological immune homeostasis

GPCR-specific autoantibody signatures are associated with physiological and pathological immune homeostasis

Ambrisentan, an endothelin receptor type A-selective antagonist, inhibits cancer cell migration, invasion, and metastasis

Hematopoietic Stem Cell Transplantation for Combined Immunodeficiencies, on Behalf of IEWP-EBMT

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