Multi-Omics Profiling in PGM3 and STAT3 Deficiencies: A Tale of Two Patients

Abstract

Hyper-IgE Syndrome (HIES) is a heterogeneous group of primary immune-deficiency disorders characterized by elevated levels of IgE, eczema, and recurrent skin and lung infections. HIES that is autosomally dominant in the signal transducer and activator of transcription 3 (STAT3), and autosomal recessive mutations in phosphoglucomutase 3 (PGM3) have been reported in humans. An early diagnosis, based on clinical suspicion and immunological assessments, is challenging. Patients’ metabolomics, proteomics, and cytokine profiles were compared to DOCK 8-deficient and atopic dermatitis patients. The PGM3 metabolomics profile identified significant dysregulation in hypotaurine, hypoxanthine, uridine, and ribothymidine. The eight proteins involved include bifunctional arginine demethylase and lysyl hydroxylase (JMJD1B), type 1 protein phosphatase inhibitor 4 (PPI 4), and platelet factor 4 which aligned with an increased level of the cytokine GCSF. Patients with STAT3 deficiency, on the other hand, showed significant dysregulation in eight metabolites, including an increase in protocatechuic acid, seven proteins including ceruloplasmin, and a plasma protease C1 inhibitor, in addition to cytokine VEGF being dysregulated. Using multi-omics profiling, we identified the dysregulation of endothelial growth factor (EGFR) and tumor necrosis factor (TNF) signaling pathways in PGM3 and STAT3 patients, respectively. Our findings may serve as a stepping stone for larger prospective HIES clinical cohorts to validate their future use as biomarkers.

Revisiting the immunopathology of congenital disorders of glycosylation: an updated review

“…This results in abnormal levels of various cytokines (e.g., IL-6, IL-17, IL-27, and granulocyte colony stimulating factor - GCSF) which impairs cytokine-mediated immune responses, such as memory cell differentiation, and elevates IgE associated allergy and atopy – a hallmark of PGM3-CDG ( 55 , 57 ). The dysregulation of the metabolic profile of PGM3-deficient cells was also proposed as a contributing factor to the immune issues ( 58 ).…”