ResearchIn-Press PreviewImmunologyInfectious disease Open Access | 10.1172/jci.insight.176162
1Division of Infectious Diseases, Department of Medicine, Massachusetts General Hospital, Boston, United States of America
2Harvard Medical School, Boston, United States of America
3Beth Israel Deaconess Medical Center, Boston, United States of America
4Division of Infectious Diseases, Department of Medicine, Massachusetts General Hospital, Boston, United States of America
5Center for Lymphoma, Mass General Cancer Center, Boston, United States of America
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1Division of Infectious Diseases, Department of Medicine, Massachusetts General Hospital, Boston, United States of America
2Harvard Medical School, Boston, United States of America
3Beth Israel Deaconess Medical Center, Boston, United States of America
4Division of Infectious Diseases, Department of Medicine, Massachusetts General Hospital, Boston, United States of America
5Center for Lymphoma, Mass General Cancer Center, Boston, United States of America
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1Division of Infectious Diseases, Department of Medicine, Massachusetts General Hospital, Boston, United States of America
2Harvard Medical School, Boston, United States of America
3Beth Israel Deaconess Medical Center, Boston, United States of America
4Division of Infectious Diseases, Department of Medicine, Massachusetts General Hospital, Boston, United States of America
5Center for Lymphoma, Mass General Cancer Center, Boston, United States of America
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1Division of Infectious Diseases, Department of Medicine, Massachusetts General Hospital, Boston, United States of America
2Harvard Medical School, Boston, United States of America
3Beth Israel Deaconess Medical Center, Boston, United States of America
4Division of Infectious Diseases, Department of Medicine, Massachusetts General Hospital, Boston, United States of America
5Center for Lymphoma, Mass General Cancer Center, Boston, United States of America
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1Division of Infectious Diseases, Department of Medicine, Massachusetts General Hospital, Boston, United States of America
2Harvard Medical School, Boston, United States of America
3Beth Israel Deaconess Medical Center, Boston, United States of America
4Division of Infectious Diseases, Department of Medicine, Massachusetts General Hospital, Boston, United States of America
5Center for Lymphoma, Mass General Cancer Center, Boston, United States of America
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1Division of Infectious Diseases, Department of Medicine, Massachusetts General Hospital, Boston, United States of America
2Harvard Medical School, Boston, United States of America
3Beth Israel Deaconess Medical Center, Boston, United States of America
4Division of Infectious Diseases, Department of Medicine, Massachusetts General Hospital, Boston, United States of America
5Center for Lymphoma, Mass General Cancer Center, Boston, United States of America
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1Division of Infectious Diseases, Department of Medicine, Massachusetts General Hospital, Boston, United States of America
2Harvard Medical School, Boston, United States of America
3Beth Israel Deaconess Medical Center, Boston, United States of America
4Division of Infectious Diseases, Department of Medicine, Massachusetts General Hospital, Boston, United States of America
5Center for Lymphoma, Mass General Cancer Center, Boston, United States of America
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1Division of Infectious Diseases, Department of Medicine, Massachusetts General Hospital, Boston, United States of America
2Harvard Medical School, Boston, United States of America
3Beth Israel Deaconess Medical Center, Boston, United States of America
4Division of Infectious Diseases, Department of Medicine, Massachusetts General Hospital, Boston, United States of America
5Center for Lymphoma, Mass General Cancer Center, Boston, United States of America
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1Division of Infectious Diseases, Department of Medicine, Massachusetts General Hospital, Boston, United States of America
2Harvard Medical School, Boston, United States of America
3Beth Israel Deaconess Medical Center, Boston, United States of America
4Division of Infectious Diseases, Department of Medicine, Massachusetts General Hospital, Boston, United States of America
5Center for Lymphoma, Mass General Cancer Center, Boston, United States of America
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1Division of Infectious Diseases, Department of Medicine, Massachusetts General Hospital, Boston, United States of America
2Harvard Medical School, Boston, United States of America
3Beth Israel Deaconess Medical Center, Boston, United States of America
4Division of Infectious Diseases, Department of Medicine, Massachusetts General Hospital, Boston, United States of America
5Center for Lymphoma, Mass General Cancer Center, Boston, United States of America
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1Division of Infectious Diseases, Department of Medicine, Massachusetts General Hospital, Boston, United States of America
2Harvard Medical School, Boston, United States of America
3Beth Israel Deaconess Medical Center, Boston, United States of America
4Division of Infectious Diseases, Department of Medicine, Massachusetts General Hospital, Boston, United States of America
5Center for Lymphoma, Mass General Cancer Center, Boston, United States of America
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1Division of Infectious Diseases, Department of Medicine, Massachusetts General Hospital, Boston, United States of America
2Harvard Medical School, Boston, United States of America
3Beth Israel Deaconess Medical Center, Boston, United States of America
4Division of Infectious Diseases, Department of Medicine, Massachusetts General Hospital, Boston, United States of America
5Center for Lymphoma, Mass General Cancer Center, Boston, United States of America
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1Division of Infectious Diseases, Department of Medicine, Massachusetts General Hospital, Boston, United States of America
2Harvard Medical School, Boston, United States of America
3Beth Israel Deaconess Medical Center, Boston, United States of America
4Division of Infectious Diseases, Department of Medicine, Massachusetts General Hospital, Boston, United States of America
5Center for Lymphoma, Mass General Cancer Center, Boston, United States of America
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1Division of Infectious Diseases, Department of Medicine, Massachusetts General Hospital, Boston, United States of America
2Harvard Medical School, Boston, United States of America
3Beth Israel Deaconess Medical Center, Boston, United States of America
4Division of Infectious Diseases, Department of Medicine, Massachusetts General Hospital, Boston, United States of America
5Center for Lymphoma, Mass General Cancer Center, Boston, United States of America
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1Division of Infectious Diseases, Department of Medicine, Massachusetts General Hospital, Boston, United States of America
2Harvard Medical School, Boston, United States of America
3Beth Israel Deaconess Medical Center, Boston, United States of America
4Division of Infectious Diseases, Department of Medicine, Massachusetts General Hospital, Boston, United States of America
5Center for Lymphoma, Mass General Cancer Center, Boston, United States of America
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1Division of Infectious Diseases, Department of Medicine, Massachusetts General Hospital, Boston, United States of America
2Harvard Medical School, Boston, United States of America
3Beth Israel Deaconess Medical Center, Boston, United States of America
4Division of Infectious Diseases, Department of Medicine, Massachusetts General Hospital, Boston, United States of America
5Center for Lymphoma, Mass General Cancer Center, Boston, United States of America
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1Division of Infectious Diseases, Department of Medicine, Massachusetts General Hospital, Boston, United States of America
2Harvard Medical School, Boston, United States of America
3Beth Israel Deaconess Medical Center, Boston, United States of America
4Division of Infectious Diseases, Department of Medicine, Massachusetts General Hospital, Boston, United States of America
5Center for Lymphoma, Mass General Cancer Center, Boston, United States of America
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1Division of Infectious Diseases, Department of Medicine, Massachusetts General Hospital, Boston, United States of America
2Harvard Medical School, Boston, United States of America
3Beth Israel Deaconess Medical Center, Boston, United States of America
4Division of Infectious Diseases, Department of Medicine, Massachusetts General Hospital, Boston, United States of America
5Center for Lymphoma, Mass General Cancer Center, Boston, United States of America
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Published May 7, 2024 - More info
Inhibition of Bruton's tyrosine kinase (BTK) through covalent modifications of its active site (e.g., ibrutinib [IBT]) is a preferred treatment for multiple B cell malignancies. However, IBT-treated patients are more susceptible to invasive fungal infections, although the mechanism is poorly understood. Neutrophils are the primary line of defense against these infections; therefore, we examined the impact of IBT on primary human neutrophil effector activity against Aspergillus fumigatus. IBT significantly impaired the ability of neutrophils to kill A. fumigatus and potently inhibited reactive oxygen species (ROS) production, chemotaxis, and phagocytosis. Importantly, exogenous TNFα fully compensated for defects imposed by IBT and newer-generation BTK inhibitors and restored the ability of neutrophils to contain A. fumigatus hyphal growth. Blocking TNFα did not impact ROS production in healthy neutrophils but prevented exogenous TNFα from rescuing the phenotype of IBT-treated neutrophils. The restorative capacity of TNFα was independent of transcription. Moreover, the addition of TNFα immediately rescued ROS production in IBT-treated neutrophils indicating that TNFα worked through a BTK-independent signaling pathway. Finally, TNFα restored effector activity of primary neutrophils from patients on IBT therapy. Altogether, our data indicate that TNFα rescues the antifungal immunity block imposed by inhibition of BTK in primary human neutrophils.