Journal Article

DKFZ-2023-02390

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png 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.

Moroncini, G. ; Svegliati, S. ; Grieco, A. ; Cuccioloni, M. ; Mozzicafreddo, M. ; Paolini, C. ; Agarbati, S. ; Spadoni, T. ; Amoresano, A. ; Pinto, G. ; Chen, Q.DKFZ* ; Benfaremo, D. ; Tonnini, C. ; Senzacqua, M. ; Alizzi, S. ; Nieto, K.DKFZ* ; Finke, D. ; Viola, N. ; Amico, D. ; Galgani, M. ; Gasparini, S. ; Zuccatosta, L. ; Menzo, S. ; Müller, M.DKFZ* ; Kleinschmidt, J.DKFZ* ; Funaro, A. ; Giordano, A. ; La Cava, A. ; Dorfmuller, P. ; Amoroso, A. ; Pucci, P. ; Pezone, A. ; Avvedimento, E. V. ; Gabrielli, A.

2024
Wiley Hoboken, NJ

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Please use a persistent id in citations: doi:10.1002/art.42746

Abstract: The etiopathogenesis of systemic sclerosis (SSc) is unknown. Platelet-derived growth factor receptors (PDGFRs) are overexpressed in SSc patients. Since PDGFRα is targeted of 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.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). 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 SSc patients.AAV5 was detected in the BAL of 41 out of 66 (62.1%) SSc patients with interstitial lung disease 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 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 SSc patients, not from healthy controls.These data link AVV5 with the immune reactivity to endogenous antigens in SSc, and provide a novel element in the pathogenesis of SSc.

Note: 2024 Apr;76(4):620-630

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Contributing Institute(s):

1. Tumorvirus-spez. Vakzinierungsstrategie (F035)

Research Program(s):

1. 316 - Infektionen, Entzündung und Krebs (POF4-316) (POF4-316)

Appears in the scientific report 2023

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Database coverage:
; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Clinical Medicine ; Current Contents - Life Sciences ; DEAL Wiley ; Ebsco Academic Search ; Essential Science Indicators ; IF >= 10 ; JCR ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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