Adeno-Associated Virus Type 5 Infection via PDGFRα Is Associated With Interstitial Lung Disease in Systemic Sclerosis and Generates Composite Peptides and Epitopes Recognized by the Agonistic Immunoglobulins Present in Patients With Systemic Sclerosis.

Autor: Moroncini G; Università Politecnica delle Marche and Azienda Ospedaliero Universitaria delle Marche, Ancona, Italy., Svegliati S; Università Politecnica delle Marche, Ancona, Italy., Grieco A; Università Politecnica delle Marche, Ancona, Italy., Cuccioloni M; Università di Camerino, Camerino, Italy., Mozzicafreddo M; Università Politecnica delle Marche, Ancona, Italy., Paolini C; Università Politecnica delle Marche, Ancona, Italy., Agarbati S; Università Politecnica delle Marche, Ancona, Italy., Spadoni T; Università Politecnica delle Marche, Ancona, Italy., Amoresano A; Federico II University, Napoli, Italy., Pinto G; Federico II University, Napoli, Italy., Chen Q; German Cancer Research Center (DKFZ), Heidelberg, Germany., Benfaremo D; Università Politecnica delle Marche and Azienda Ospedaliero Universitaria delle Marche, Ancona, Italy., Tonnini C; Università Politecnica delle Marche, Ancona, Italy., Senzacqua M; Università Politecnica delle Marche, Ancona, Italy., Alizzi S; Università di Torino and Azienda Ospedaliera Universitaria Città della Salute e della Scienza, di Torino, Torino, Italy., Nieto K; German Cancer Research Center (DKFZ), Heidelberg, Germany., Finke D; Università Politecnica delle Marche, Ancona, Italy., Viola N; Azienda Ospedaliero Universitaria delle Marche, Ancona, Italy., Amico D; Ospedali Riuniti Marche Nord, Pesaro, Italy., Galgani M; Federico II University, Napoli, Italy., Gasparini S; Università Politecnica delle Marche and Azienda Ospedaliero Universitaria delle Marche, Ancona, Italy., Zuccatosta L; Azienda Ospedaliero Universitaria delle Marche, Ancona, Italy., Menzo S; Università Politecnica delle Marche and Azienda Ospedaliero Universitaria delle Marche, Ancona, Italy., Müller M; German Cancer Research Center (DKFZ), Heidelberg, Germany., Kleinschmidt J; German Cancer Research Center (DKFZ), Heidelberg, Germany., Funaro A; Università di Torino, Torino, Italy., Giordano A; Università Politecnica delle Marche, Ancona, Italy., La Cava A; Federico II University, Napoli, Italy.; University of California, Los Angeles, CA., Dorfmüller P; University of Giessen and Marburg Lung Center, Giessen, Germany., Amoroso A; Università di Torino and Azienda Ospedaliera Universitaria Città della Salute e della Scienza, di Torino, Torino, Italy., Pucci P; Federico II University, Napoli, Italy., Pezone A; Federico II University, Napoli, Italy., Avvedimento EV; Federico II University, Napoli, Italy., Gabrielli A; Università Politecnica delle Marche, Ancona, Italy, Azienda Ospedaliero Universitaria delle Marche, Ancona, Italy, and Heinrich Heine University, Düsseldorf, Germany.
Jazyk: angličtina
Zdroj: Arthritis & rheumatology (Hoboken, N.J.) [Arthritis Rheumatol] 2024 Apr; Vol. 76 (4), pp. 620-630. Date of Electronic Publication: 2024 Feb 15.
DOI: 10.1002/art.42746
Abstrakt: Objective: The etiopathogenesis of systemic sclerosis (SSc) is unknown. Platelet-derived growth factor receptors (PDGFRs) are overexpressed in patients with SSc. Because PDGFRα is targeted by the adeno-associated virus type 5 (AAV5), we investigated whether AAV5 forms a complex with PDGFRα exposing epitopes that may induce the immune responses to the virus-PDGFRα complex.
Methods: The binding of monomeric human PDGFRα to the AAV5 capsid was analyzed by in silico molecular docking, surface plasmon resonance (SPR), and genome editing of the PDGFRα locus. AAV5 was detected in SSc lungs by in situ hybridization, immunohistochemistry, confocal microscopy, and molecular analysis of bronchoalveolar lavage (BAL) fluid. Immune responses to AAV5 and PDGFRα were evaluated by SPR using SSc monoclonal anti-PDGFRα antibodies and immunoaffinity-purified anti-PDGFRα antibodies from sera of patients with SSc.
Results: AAV5 was detected in the BAL fluid of 41 of 66 patients with SSc with interstitial lung disease (62.1%) and in 17 of 66 controls (25.75%) (P < 0.001). In SSc lungs, AAV5 localized in type II pneumocytes and in interstitial cells. A molecular complex formed of spatially contiguous epitopes of the AAV5 capsid and of PDGFRα was identified and characterized. In silico molecular docking analysis and binding to the agonistic anti-PDGFRα antibodies identified spatially contiguous epitopes derived from PDGFRα and AAV5 that interacted with SSc agonistic antibodies to PDGFRα. These peptides were also able to bind total IgG isolated from patients with SSc, not from healthy controls.
Conclusion: These data link AVV5 with the immune reactivity to endogenous antigens in SSc and provide a novel element in the pathogenesis of SSc.
(© 2023 The Authors. Arthritis & Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology.)
Databáze: MEDLINE
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