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

Publication date: Available online 13 February 2018
Source:Journal of Allergy and Clinical Immunology
Author(s): K.E. Cervantes-Luevano, N. Caronni, M.C. Castiello, E. Fontana, G. Piperno, A. Naseem, P. Uva, M. Bosticardo, G.E. Marcovecchio, L.D. Notarangelo, M.P. Cicalese, A. Aiuti, A. Villa, F. Benvenuti
BackgroundWiskott-Aldrich syndrome (WAS) is a rare primary immunodeficiency caused by mutations in WASp, a key regulator of cytoskeletal dynamics in hematopoietic cells. A high proportion of patients develop autoimmunity due to a breakdown in T and B cell tolerance. Moreover, excessive production of type-I interferon by plasmacytoid DCs contribute to autoimmune signs, however, the factors that triggers excessive innate activation have not been defined.ObjectiveNeutrophils extracellular traps (NETs) emerged as major initiating factors in diseases such as systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). In this study, we explored the possible involvement of aberrant neutrophil functions in WAS.MethodsWe evaluated the expression of a set of granulocyte genes associated with NETs in a cohort of WAS patients and the presence of NET-inducers in sera. Using a mouse model of WAS, we analyzed NET release by WASp-null neutrophils, and we evaluated the composition and homeostasis of neutrophils in vivo. By means of depletion experiments, we assessed the impact of neutrophils in promoting inflammation and reactivity against auto-antigens.ResultsTranscripts of genes encoding neutrophil enzymes and antimicrobial peptides were elevated in granulocytes of WAS patients, and serum soluble factors triggered NET release. WASp-null neutrophils showed increased spontaneous NETosis, induced type-I interferon production by plasmacytoid DCs (pDCs), and activated B cells via BAFF. Consistently, their depletion abolished constitutive pDCs activation, normalized circulating IFN-I levels and, importantly, abolished production of autoantibodies directed against dsDNA, nucleosomes and MPO.ConclusionsThese findings reveal that neutrophils are involved in the pathogenic loop that causes excessive activation of innate cells and autoreactive B cell, thus identifying novel mechanisms that contribute to the autoimmunity of WAS.

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