Stimulatory Autoantibodies to the PDGF Receptor in Systemic Sclerosis

Svegliati, Silvia; Santillo, Mariarosaria; Bevilacqua, Federica; Luchetti, Michele Maria; Spadoni, Tatiana; Mancini, Matteo; Fraticelli, Paolo; Sambo, Paola; Funaro, Ada; Kazlauskas, Andrius; Avvedimento, Enrico V.; Gabrielli, Armando

doi:10.1056/nejmoa052955

Cited by 520 publications

(140 citation statements)

References 13 publications

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“…10 We have recently shown that patients with cGVHD showing fibrotic/sclerotic manifestations have agonistic antibodies activating the platelet-derived growth factor receptor (PDGF) receptor. 11 The presence and biologic activity of these autoantibodies argue for a common pathogenic trait in both cGVDH and SSc, 11,12 in that up-regulation of the PDGF receptor intracellular pathway leads to increased reactive oxygen species, with consequent exaggerated collagen synthesis, which, in turn, contributes to the pathologic lesions observed in both cGVHD and SSc.…”

Section: Introductionmentioning

confidence: 99%

Imatinib for refractory chronic graft-versus-host disease with fibrotic features

Olivieri

Locatelli

Zecca

et al. 2009

Blood

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We previously reported that patients with fibrotic, chronic graft-versus-host disease (cGVHD) have antibodies activating the platelet-derived growth factor receptor pathway. Because this pathway can be inhibited by imatinib, we performed a pilot study including 19 patients with refractory cGVHD, given imatinib at a starting dose of 100 mg per day. All patients had active cGVHD with measurable involvement of skin or other districts and had previously failed at least 2 treatment lines. Patient median age was 29 years (range, 10-62 years), and median duration of cGvHD was 37 months (range, 4-107 months). The organs involved were skin (n ‫؍‬ 17), lung (n ‫؍‬ 11), and bowel (n ‫؍‬ 5); 15 patients had sicca syndrome. Imatinib-related, grade 3 to 4 toxicity included fluid retention, infections, and anemia. Imatinib was discontinued in 8 patients: in 3 because of toxicity and in 5 because of lack of response (n ‫؍‬ 3) or relapse of malignancy (n ‫؍‬ 2). Overall response rate at 6 months was 79%, with 7 complete remissions (CRs) and 8 partial remissions (PRs). With a median follow-up of 17 months, 16 patients are alive, 14 still in CR or PR. The 18-month probability of overall survival is 84%. This study suggests that imatinib is a promising treatment for patients with refractory fibrotic cGVHD. (Blood.

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Section: Introductionmentioning

confidence: 99%

Imatinib for refractory chronic graft-versus-host disease with fibrotic features

Olivieri

Locatelli

Zecca

et al. 2009

Blood

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206

146

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“…Antibodies that activate PDGFRs are present in sera of patients with scleroderma and are implicated in facilitating the fibrotic component of this pathology (4). Growth factors outside the PDGF family (PDGFs) are present in vitreous (the viscous fluid that fills the space between the lens and retina) from patients with proliferative vitreoretinopathy (PVR) and trigger indirect activation of PDGF receptor ␣ (PDGFR␣), which is a key event in the pathogenesis of this fibroproliferative disease in animal models (5).…”

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confidence: 99%

A Reactive Oxygen Species-Mediated, Self-Perpetuating Loop Persistently Activates Platelet-Derived Growth Factor Receptor α

Lei

Kazlauskas

2014

Molecular and Cellular Biology

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The platelet-derived growth factor (PDGF) receptors (PDGFRs) are central to a spectrum of human diseases. When PDGFRs are activated by PDGF, reactive oxygen species (ROS) and Src family kinases (SFKs) act downstream of PDGFRs to enhance PDGFmediated tyrosine phosphorylation of various signaling intermediates. In contrast to these firmly established principles of signal transduction, much less is known regarding the recently appreciated ability of ROS and SFKs to indirectly and chronically activate monomeric PDGF receptor ␣ (PDGFR␣) in the setting of a blinding condition called proliferative vitreoretinopathy (PVR). In this context, we made a series of discoveries that substantially expands our appreciation of epigenetic-based mechanisms to chronically activate PDGFR␣. Vitreous, which contains growth factors outside the PDGF family but little or no PDGFs, promoted formation of a unique SFK-PDGFR␣ complex that was dependent on SFK-mediated phosphorylation of PDGFR␣ and activated the receptor's kinase activity. While vitreous engaged a total of five receptor tyrosine kinases, PDGFR␣ was the only one that was activated persistently (at least 16 h). Prolonged activation of PDGFR␣ involved mTOR-mediated inhibition of autophagy and accumulation of mitochondrial ROS. These findings reveal that growth factor-containing biological fluids, such as vitreous, are able to tirelessly activate PDGFR␣ by engaging a ROS-mediated, self-perpetuating loop.

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“…Предполагается стимуляторный про-фиброзный эффект антител к РТФР, поскольку их связы-вание с лигандом приводит к активации фибробластов и последующей гиперпродукции реактивных кислородных радикалов (РКР), которые, в свою очередь, поддерживают фибробласты в состоянии активации, стимулируя проли-ферацию клеток и синтез компонентов внеклеточного ма-трикса [93]. Авторы обнаружили антитела к РТФР у всех больных ССД, но не у здоровых лиц, больных СКВ, РА, идиопатическим легочным фиброзом и первичным фено-меном Рейно.…”

Section: ау тоантитела к поверхностным клеточным (мембранным) и вunclassified

Autoantibodies in Systemic Sclerosis: Spectrum, Clinical Associations, and Prognostic Value

Ананьева¹,

Александрова²

2016

rsp

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Stimulatory Autoantibodies to the PDGF Receptor in Systemic Sclerosis

Abstract: Stimulatory autoantibodies against PDGFR appear to be a specific hallmark of scleroderma. Their biologic activity on fibroblasts strongly suggests that they have a causal role in the pathogenesis of the disease.

Cited by 520 publications

References 13 publications

Imatinib for refractory chronic graft-versus-host disease with fibrotic features

Imatinib for refractory chronic graft-versus-host disease with fibrotic features

A Reactive Oxygen Species-Mediated, Self-Perpetuating Loop Persistently Activates Platelet-Derived Growth Factor Receptor α

Autoantibodies in Systemic Sclerosis: Spectrum, Clinical Associations, and Prognostic Value

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