Severe allergic dysregulation due to a gain of function mutation in the transcription factor STAT6

BARIŞ S., Benamar M., Chen Q., Catak M. C., Martínez-Blanco M., Wang M., ...Daha Fazla

Journal of Allergy and Clinical Immunology, cilt.152, sa.1, ss.182, 2023 (SCI-Expanded) identifier identifier

  • Yayın Türü: Makale / Tam Makale
  • Cilt numarası: 152 Sayı: 1
  • Basım Tarihi: 2023
  • Doi Numarası: 10.1016/j.jaci.2023.01.023
  • Dergi Adı: Journal of Allergy and Clinical Immunology
  • Derginin Tarandığı İndeksler: Science Citation Index Expanded (SCI-EXPANDED), Scopus, PASCAL, BIOSIS, CAB Abstracts, EMBASE, Food Science & Technology Abstracts, International Pharmaceutical Abstracts, MEDLINE, Veterinary Science Database
  • Sayfa Sayıları: ss.182
  • Anahtar Kelimeler: gain-of-function mutation, Inborn errors of immunity, Jakinibs, Janus kinase inhibitors, primary atopic disorders, STAT6
  • Marmara Üniversitesi Adresli: Evet

Özet

Background: Inborn errors of immunity have been implicated in causing immune dysregulation, including allergic diseases. STAT6 is a key regulator of allergic responses. Objectives: This study sought to characterize a novel gain-of-function STAT6 mutation identified in a child with severe allergic manifestations. Methods: Whole-exome and targeted gene sequencing, lymphocyte characterization, and molecular and functional analyses of mutated STAT6 were performed. Results: This study reports a child with a missense mutation in the DNA binding domain of STAT6 (c.1114G>A, p.E372K) who presented with severe atopic dermatitis, eosinophilia, and elevated IgE. Naive lymphocytes from the affected patient displayed increased TH2- and suppressed TH1- and TH17-cell responses. The mutation augmented both basal and cytokine-induced STAT6 phosphorylation without affecting dephosphorylation kinetics. Treatment with the Janus kinase 1/2 inhibitor ruxolitinib reversed STAT6 hyperresponsiveness to IL-4, normalized TH1 and TH17 cells, suppressed the eosinophilia, and improved the patient's atopic dermatitis. Conclusions: This study identified a novel inborn error of immunity due to a STAT6 gain-of-function mutation that gave rise to severe allergic dysregulation. Janus kinase inhibitor therapy could represent an effective targeted treatment for this disorder.