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J Allergy Clin Immunol. 2018 Nov;142(5):1605-1617.e4. doi: 10.1016/j.jaci.2017.11.063. Epub 2018 Feb 13.

Neutrophils drive type I interferon production and autoantibodies in patients with Wiskott-Aldrich syndrome.

Author information

1
International Centre for Genetic Engineering and Biotechnology, Trieste, Italy.
2
San Raffaele Telethon Institute for Gene Therapy (TIGET), Division of Regenerative Medicine, Stem Cells and Gene Therapy, San Raffaele Scientific Institute, Milan, Italy.
3
Humanitas Clinical and Research Center, Rozzano, Milan, Italy; Milan Unit, Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche, Milan, Italy.
4
CRS4, Science and Technology Park Polaris, Pula, Italy.
5
San Raffaele Telethon Institute for Gene Therapy (TIGET), Division of Regenerative Medicine, Stem Cells and Gene Therapy, San Raffaele Scientific Institute, Milan, Italy; Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md.
6
Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md.
7
San Raffaele Telethon Institute for Gene Therapy (TIGET), Division of Regenerative Medicine, Stem Cells and Gene Therapy, San Raffaele Scientific Institute, Milan, Italy; San Raffaele Telethon Institute for Gene Therapy and the Pediatric Immunohematology and Bone Marrow Transplantation Unit, San Raffaele Scientific Institute, Milan, Italy.
8
San Raffaele Telethon Institute for Gene Therapy (TIGET), Division of Regenerative Medicine, Stem Cells and Gene Therapy, San Raffaele Scientific Institute, Milan, Italy; Milan Unit, Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche, Milan, Italy.
9
International Centre for Genetic Engineering and Biotechnology, Trieste, Italy. Electronic address: benvenuti@icgeb.org.

Abstract

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.

KEYWORDS:

Neutrophil extracellular traps; Wiskott-Aldrich syndrome; autoimmunity; type I interferon

PMID:
29447842
PMCID:
PMC6089666
[Available on 2019-05-01]
DOI:
10.1016/j.jaci.2017.11.063

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