Identification of a neutrophil-specific PIK3R1 mutation facilitates targeted treatment in a patient with Sweet syndrome
Shreya Bhattacharya, Sayon Basu, Emily Sheng, Christina Murphy, Jenny Wei, Anna E. Kersh, Caroline A. Nelson, Joshua S. Bryer, Hovik A. Ashchyan, Katherine Steele, Amy Forrestel, John T. Seykora, Robert G. Micheletti, William D. James, Misha Rosenbach, Thomas H. Leung
Shreya Bhattacharya, Sayon Basu, Emily Sheng, Christina Murphy, Jenny Wei, Anna E. Kersh, Caroline A. Nelson, Joshua S. Bryer, Hovik A. Ashchyan, Katherine Steele, Amy Forrestel, John T. Seykora, Robert G. Micheletti, William D. James, Misha Rosenbach, Thomas H. Leung
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Clinical Research and Public Health Dermatology Inflammation

Identification of a neutrophil-specific PIK3R1 mutation facilitates targeted treatment in a patient with Sweet syndrome

Abstract

Background Acute febrile neutrophilic dermatosis (Sweet syndrome) is a potentially fatal multiorgan inflammatory disease characterized by fever, leukocytosis, and a rash with a neutrophilic infiltrate. The disease pathophysiology remains elusive, and current dogma suggests that Sweet syndrome is a process of reactivity to an unknown antigen. Corticosteroids and steroid-sparing agents remain frontline therapies, but refractory cases pose a clinical challenge.Methods A 51-year-old woman with multiorgan Sweet syndrome developed serious corticosteroid-related side effects and was refractory to steroid-sparing agents. Blood counts, liver enzymes, and skin histopathology supported the diagnosis. Whole-genome sequencing, transcriptomic profiling, and cellular assays of the patient’s skin and neutrophils were performed.Results We identified elevated IL-1 signaling in lesional Sweet syndrome skin caused by a PIK3R1 gain-of-function mutation specifically found in neutrophils. This mutation increased neutrophil migration toward IL-1β and neutrophil respiratory burst. Targeted treatment of the patient with an IL-1 receptor 1 antagonist resulted in a dramatic therapeutic response and enabled a tapering off of corticosteroids.Conclusion Dysregulated PI3K/AKT signaling is the first signaling pathway linked to Sweet syndrome and suggests that this syndrome may be caused by acquired mutations that modulate neutrophil function. Moreover, integration of molecular data across multiple levels identified a distinct subtype within a heterogeneous disease that resulted in a rational and successful clinical intervention. Future patients will benefit from efforts to identify potential mutations. The ability to directly interrogate the diseased skin allows this method to be generalizable to other inflammatory diseases and demonstrates a potential personalized medicine approach for patients with clinically challenging disease.Funding Sources Berstein Foundation, NIH, Veterans Affairs (VA) Administration, Moseley Foundation, and H.T. Leung Foundation.

Authors

Shreya Bhattacharya, Sayon Basu, Emily Sheng, Christina Murphy, Jenny Wei, Anna E. Kersh, Caroline A. Nelson, Joshua S. Bryer, Hovik A. Ashchyan, Katherine Steele, Amy Forrestel, John T. Seykora, Robert G. Micheletti, William D. James, Misha Rosenbach, Thomas H. Leung

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Figure 3

PIK3R1 gain-of-function mutation increases neutrophil migration toward IL-1β.

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PIK3R1 gain-of-function mutation increases neutrophil migration toward I...
(A) Venn diagram illustrates the intersection between differentially expressed genes and neutrophil-specific gene mutations in the patient with refractory disease. Gene names are listed in the box. (B) Schematic depicting the PIK3R1 gene. The mutation location is identified by the black arrow. Below the schematic is the DNA sequence chromatogram that confirms the mutation. (C) Western blot demonstrates increased phosphorylation of AKT at S473 in overexpressed p.W335C p85 (MT) cells compared with overexpressed p85 (WT) cells. The experiment was repeated independently 3 times. (D) Cellular respiratory burst detected by DCFDA in LPS-treated WT and MT p85 cells (n = 8/group). (E) Transwell migration of WT and MT p85 cells in response to IL-1β (n = 6/group). (F) qPCR (n = 3/group) and (G) Western blot show increased IL-1R1 expression in MT p85 cells compared with WT p85 cells. The experiment was repeated independently 3 times. (H) Pharmacologic treatment with an IL-1RA blocked IL-1β–mediated Transwell migration (n = 3/group). Data represent the mean ± SEM. *P < 0.05 and **P < 0.01, and ***P < 0.001, by 2-tailed Student’s t test.