Phenotypes of STAT3 gain-of-function variant related to disruptive regulation of CXCL8/STAT3, KIT/STAT3, and IL-2/CD25/Treg axes

Autor(es)

Marega, Lia Furlaneto ^[1] ; Sabino, Janine Schincariol ^[1] ; Pedroni, Marcus Vinicius ^[1] ; Teocchi, Marcelo ^[1] ; Lanaro, Carolina ^[2] ; de Albuquerque, Dulcineia Martins ^[2] ; dos Santos, Irene Pereira ^[3] ; Costa, Fernando Ferreira ^[2] ; dos Santos Vilela, Maria Marluce ^[1]

Afiliação do(s) autor(es)

^[1] Univ Estadual Campinas, UNICAMP, Sch Med Sci, Lab Pediat Immunol, Ctr Invest Pediat, Rua Tessalia Vieira de Camargo 126, BR-13083887 Campinas, SP - Brazil

^[2] Univ Estadual Campinas, UNICAMP, Hematol & Hemotherapy Ctr Hemoctr Campinas, Campinas, SP - Brazil

^[3] Univ Estadual Campinas, UNICAMP, Hematol & Hemotherapy Ctr, Flow Cytometry Lab, Campinas, SP - Brazil

• Tipo de documento: Artigo Científico
• Fonte: IMMUNOLOGIC RESEARCH; v. 69, n. 5 AUG 2021.
• Citações Web of Science: 0

Resumo

STAT3 is a cytokine-signaling transcription factor critical for gene regulation. Gain-of-function (GOF) mutations in STAT3 are associated with lymphoproliferation, autoimmune cytopenias, increased susceptibility to infection, early-onset solid-organ autoimmunity, short stature, and eczema. We studied the JAK/STAT signaling pathway gene expression and the cytokine profile in two families carrying STAT3-GOF variants to shed light on the STAT3-GOF-associated variable expressivity, including the identification of disease markers. Considering 92 target genes, KIT and IL2RA were downregulated only in patients with high clinical penetrance, while CXCL8 was markedly downregulated for all of them. Unlike previous studies, SOCS3-a STAT3 inhibitor-was not upregulated in patients. In addition, low levels of IL-2 and a reduced numbers of Tregs cells were strikingly prevalent in patients. This study shows a disruptive role of STAT3-GOF variants in the regulatory axis activities CXCL8/STAT3, KIT/STAT3, IL2/CD25/Treg, which, by slightly different mechanisms, underlie the broad clinical spectrum seen in the studied patients. In addition, we suggest the investigation of CXCL8 as a biomarker for identifying STAT3-GOF mutation. (AU)

• Processo FAPESP: 16/25615-6 - Identificação de alvos moleculares críticos associados à etiologia e a fisiopatologia de imunodeficiências primárias com ênfase nas manifestações clínicas de inflamação, imunodesregulação e autoimunidade
• Beneficiário: Maria Marluce dos Santos Vilela
• Modalidade de apoio: Auxílio à Pesquisa - Regular