Role of DOCK8 in cytokine storm syndromes - 07/11/24

Doi : 10.1016/j.jaci.2024.10.004

Mingce Zhang, MD, PhD ^a, Remy R. Cron ^a, Niansheng Chu, MD ^b, Junior Nguyen, BS ^b, Scott M. Gordon, MD, PhD ^b, Esraa M. Eloseily, MD, MSc ^c,^d, T. Prescott Atkinson, MD, PhD ^a, Peter Weiser, MD ^a, Mark R. Walter, PhD ^a, Portia A. Kreiger, MD ^b, Scott W. Canna, MD ^b, Edward M. Behrens, MD ^b, Randy Q. Cron, MD, PhD ^a,^⁎
^a University of Alabama at Birmingham, Birmingham, Ala
^b University of Pennsylvania, Philadelphia, Pa
^c University of Texas Southwestern, Dallas, Tex
^d Faculty of Medicine, Assiut University, Asyut, Egypt

^∗Corresponding author: Randy Q. Cron, MD, PhD, Division of Rheumatology, Children’s of Alabama, 1601 7th Ave South, CPPN, Ste G10, Birmingham, AL 35233.Division of RheumatologyChildren’s of Alabama1601 7th Ave SouthCPPNSte G10BirminghamAL35233

Sous presse. Épreuves corrigées par l'auteur. Disponible en ligne depuis le Thursday 07 November 2024

Abstract

Background

Cytokine storm syndromes (CSSs), including hemophagocytic lymphohistiocytosis (HLH), are increasingly recognized as hyperinflammatory states leading to multiorgan failure and death. Familial HLH in infancy results from homozygous genetic defects in perforin-mediated cytolysis by CD8 T lymphocytes and natural killer (NK) cells. Later-onset CSSs are often associated with heterozygous defects in familial HLH genes, but genetic etiologies for most are unknown. We identified rare dedicator of cytokinesis 8 (DOCK8) variants in patients with CSS.

Objective

We sought to explore the role of CSS patient–derived DOCK8 mutations on cytolytic activity in NK cells and to further study effects of DOCK8 deficiency in murine models of CSSs.

Methods

DOCK8 cDNAs from 2 unrelated patients with CSS with different missense mutations were introduced into human NK-92 cells by foamy virus transduction. NK-cell degranulation (CD107a), cytolytic activity against K562 target cells, and IFN-γ production were explored by flow cytometry. A third patient with CSS with DOCK8 mRNA splice acceptor site variant was explored by exon trapping. Dock8^−/− mice were assessed for features of CSS (weight loss, splenomegaly, hepatic inflammation, cytopenias, and IFN-γ levels) on challenge with lymphocytic choriomeningitis virus and excess IL-18.

Results

Both patient DOCK8 missense mutations decreased cytolytic function in NK cells in a partial dominant-negative fashion in vitro. The patient DOCK8 splice variant disrupted mRNA splicing in vitro. Lymphocytic choriomeningitis virus infection promoted CSS in Dock8^−/− mice and interacted with excess IL-18, limiting T-cell numbers while promoting CD8 T-cell hyperactivation.

Conclusions

Mutations in DOCK8 may contribute to CSS-like hyperinflammatory states by altering cytolytic function in a threshold model of disease.

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Key words : Cytokine storm syndrome, cytolysis, degranulation, hemophagocytic lymphohistiocytosis, hyperinflammation, IFN-γ, macrophage activation syndrome, missense mutation, natural killer cell, splice site

Abbreviations used : APC, crRNA, CSS, DOCK8, EGFP, ERA, FCM, fHLH, FV, gRNA, HLH, HScore, JIA, LCMV, MAS, NK, PID, sHLH, siRNA, WT