Neutrophils drive type I interferon production and autoantibodies in patients with Wiskott-Aldrich syndrome
| Autor: | Giulia Maria Piperno, Federica Benvenuti, Genni Enza Marcovecchio, Asma Naseem, Maria Carmina Castiello, Maria Pia Cicalese, Anna Villa, Elena Fontana, Luigi D. Notarangelo, Karla E Cervantes-Luevano, Marita Bosticardo, Alessandro Aiuti, Nicoletta Caronni, Paolo Uva |
|---|---|
| Rok vydání: | 2018 |
| Předmět: |
Adult
Male 0301 basic medicine Adolescent Neutrophils Immunology Gene Expression Plasmacytoid dendritic cell Granulocyte medicine.disease_cause Extracellular Traps Article Autoimmunity Young Adult 03 medical and health sciences 0302 clinical medicine medicine Animals Humans Immunology and Allergy B-cell activating factor Autoantibodies Mice Knockout B-Lymphocytes biology business.industry Infant Dendritic Cells Neutrophil extracellular traps Type I interferon production Wiskott-Aldrich Syndrome Mice Inbred C57BL 030104 developmental biology medicine.anatomical_structure Child Preschool Neutrophil elastase Myeloperoxidase Interferon Type I biology.protein Female business 030215 immunology |
| Zdroj: | Journal of Allergy and Clinical Immunology. 142:1605-1617.e4 |
| ISSN: | 0091-6749 |
| Popis: | Background Wiskott-Aldrich syndrome (WAS) is a rare primary immunodeficiency caused by mutations in Wiskott-Aldrich syndrome protein (WASp), a key regulator of cytoskeletal dynamics in hematopoietic cells. A high proportion of patients experience autoimmunity caused by a breakdown in T- and B-cell tolerance. Moreover, excessive production of type I interferon (IFN-I) by plasmacytoid dendritic cells (pDCs) contributes to autoimmune signs; however, the factors that trigger excessive innate activation have not been defined. Objective Neutrophil extracellular traps (NETs) emerged as major initiating factors in patients with diseases such as systemic lupus erythematosus and rheumatoid arthritis. In this study we explored the possible involvement of aberrant neutrophil functions in patients with WAS. Methods We evaluated the expression of a set of granulocyte genes associated with NETs in a cohort of patients with WAS and the presence of NET inducers in sera. Using a mouse model of WAS, we analyzed NET release by WASp-null neutrophils and evaluated the composition and homeostasis of neutrophils in vivo . By using depletion experiments, we assessed the effect of neutrophils in promoting inflammation and reactivity against autoantigens. Results Transcripts of genes encoding neutrophil enzymes and antimicrobial peptides were increased in granulocytes of patients with WAS, and serum-soluble factors triggered NET release. WASp-null neutrophils showed increased spontaneous NETosis, induced IFN-I production by pDCs, and activated B cells through B-cell activating factor. Consistently, their depletion abolished constitutive pDC activation, normalized circulating IFN-I levels, and, importantly, abolished production of autoantibodies directed against double-stranded DNA, nucleosomes, and myeloperoxidase. Conclusions These findings reveal that neutrophils are involved in the pathogenic loop that causes excessive activation of innate cells and autoreactive B cells, thus identifying novel mechanisms that contribute to the autoimmunity of WAS. |
| Databáze: | OpenAIRE |
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