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

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

JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY, cilt.152, sa.1, 2023 (SCI-Expanded, Scopus) 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, Food Science & Technology Abstracts, International Pharmaceutical Abstracts, MEDLINE, Veterinary Science Database, Nature Index
  • Recep Tayyip Erdoğan 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. (J Allergy Clin Immunol 2023;152:182-94.)