Epigenetic and immunological indicators of IPEX disease in subjects with FOXP3 gene mutation

• DOI: 10.1016/j.jaci.2022.09.013
• Publication Date: 2022-09-21T13:12:32Z
• Authors: Mansi Narula; Uma Lakshmanan; Simon Borna; Janika J. Schulze; Tyson H. Holmes; Nicholas Harre; Matthew Kirkey; Akshaya Ramachandran; Veronica Maria Tagi; Federica Barzaghi; Eyal Grunebaum; Julia E.M. Upton; Vy Hong-Diep Kim; Christian Wysocki; Victoria R. Dimit...; Kenneth Weinberg; Katja G. Weinacht; Yael Gernez; Bindu K. Sathi; Magdalena Schelotto; Matthew Johnson; Sven Olek; Christoph Sachsen...; Maria-Grazia Ronc...; Rosa Bacchetta
• Keywords: Immune Dysregulation

Forkhead box protein 3 (FOXP3) is the master transcription factor in CD4+CD25hiCD127lo regulatory T (Treg) cells. Mutations FOXP3 result IPEX (immune dysregulation, polyendocrinopathy, enteropathy, X-linked) syndrome. Clinical presentation of syndrome broader than initially described, challenging understanding disease, its evolution, and treatment choice.We sought to study type extent immunologic abnormalities that remain ill-defined IPEX, across genetic clinical heterogeneity.We performed Treg-cell-specific epigenetic quantification characterization severe "typical" (n = 6) "atypical" or asymptomatic 9) patients with IPEX.Increased number cells Treg-cell-Specific Demethylated Region demethylation a consistent feature (1) highest values those typical (2) increased subjects pathogenic but still no symptoms, (3) gradual increase over course disease progression. Large-scale profiling using Luminex identified plasma inflammatory signature macrophage activation TH2 polarization, cytokines previously not associated pathology, including CCL22, CCL17, CCL15, IL-13, markers TNF-α, IL-1A, IL-8, sFasL, CXCL9. Similarly, both Treg-cell Teff compartments, studied by Mass Cytometry Time-Of-Flight, were skewed toward compartment, especially IPEX.Elevated TSDR-demethylated cells, combined elevation plasmatic cellular polarized 2 immune response, extends our diagnosis heterogeneity.