1. Natural killer cell memory precedes HLH in monozygotic twins discordant for chronic active Epstein-Barr virus disease
- Author
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Chrissie K. Lim, Youjia Zhong, Richard Hopkins, Wei-Xiang Sin, Bijin Veonice Au, Sriram Narayanan, Chiung-Hui Huang, Colin YC Lee, Ming Liang Oon, Avisha Chowdhury, Benjamin Wong, Frances Yeap, Mariflor Villegas, Julien Pompon, Patricia PL Ng, Siok-Bian Ng, Thuan Chong T Quah, Poh-Lin Tan, Keh-Chuang Chin, John E Connolly, National University Hospital [Singapore] (NUH), University Health Network, Duke-NUS Medical School [Singapore], Maladies infectieuses et vecteurs : écologie, génétique, évolution et contrôle (MIVEGEC), Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD [France-Sud])-Université de Montpellier (UM), National University of Singapore (NUS), Baylor University, and Parker Institute for Cancer Immunotherapy [San Francisco, CA] (PICI)
- Subjects
MESH: Killer Cells, Natural ,MESH: Humans ,MESH: Epstein-Barr Virus Infections ,[SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases ,Immunology ,MESH: Herpesvirus 4, Human ,[SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology ,Cell Biology ,Hematology ,MESH: Twins, Monozygotic ,[SDV.IMM.ALL]Life Sciences [q-bio]/Immunology/Allergology ,Biochemistry - Abstract
International audience; Severe mosquito bite allergy (SMBA) is a manifestation of chronic active Epstein-Barr virus (CAEBV) infection defined by necrotic ulceration of the stings. CAEBV with SMBA has a high mortality rate as most patients eventually develop fulminant and refractory hemophagocytic lymphohistiocytosis (HLH). However, how self-resolving SMBA escalates to systemic lethal HLH remains unclear. Through comprehensive immune profiling of a SMBA patient with CAEBV and her healthy monozygotic twin, we found that both twins were seropositive for EBV but showed high discordance in their circulating natural killer (NK) cells. The patient's EBV-infected NK cells displayed memory-like properties, including low CD16, high CD226 and induction of enhanced IFNγ production by IL-2 or IL-12. Her leukocytes also produced high levels of IL-2 and IL-12 when stimulated with salivary gland extract (SGE) specifically from A. albopictus mosquitoes, connected again with hyperproduction of IFNγ by her NK cells. Strikingly, pharmacological inhibition of STAT3 suppressed the NK memory-associated cytokine axis of IFNγ, IL-2 and IL-12 that is generated by A. albopictus SGE stimulation. Altogether, this study shows that NK memory is promoted during CAEBV with SMBA by repeated cytokine restimulation leading up to lethal HLH, and proposes STAT3 as a therapeutic target to halt its progression.
- Published
- 2023
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