Inborn Error of STAT2-Dependent IFN-I Immunity in a Patient Presented with Hemophagocytic Lymphohistiocytosis and Multisystem Inflammatory Syndrome in Children

Abstract

Human inborn errors of immunity (IEI) affecting the type I interferon (IFN-I) induction pathway have been associated with predisposition to severe viral infections. Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening systemic hyperinflammatory syndrome that has been increasingly associated with inborn errors of IFN-I-mediated innate immunity. Here is reported a novel case of complete deficiency of STAT2 in a 3-year-old child that presented with typical features of HLH after mumps, measles, and rubella vaccination at the age of 12 months. Due to the life-threatening risk of viral infection, she received SARS-CoV-2 mRNA vaccination. Unfortunately, she developed multisystem inflammatory syndrome in children (MIS-C) after SARS-CoV-2 infection, 4 months after the last dose. Functional studies showed an impaired IFN-I-induced response and a defective IFNα expression at later stages of STAT2 pathway induction. These results suggest a possible more complex mechanism for hyperinflammatory reactions in this type of patients involving a possible defect in the IFN-I production. Understanding the cellular and molecular links between IFN-I-induced signaling and hyperinflammatory syndromes can be critical for the diagnosis and tailored management of these patients with predisposition to severe viral infection. Supplementary Information The online version contains supplementary material available at 10.1007/s10875-023-01488-6.

HLH Syndrome in a Community Hospital: The Challenge of an Early Diagnosis

“…Patients with virus-induced HLH may have abnormalities in the genes associated with the innate immune response to viral infections, especially in the IFN-1 pathway, such as STAT2, STAT1, IFNAR1, and IFNAR1. 22 STAT2 deficiency was elegantly reported by López-Nevado et al, 22 who suggested that these genes should be evaluated in patients with virus-induced HLH. Unfortunately, these abnormalities were not evaluated in the present study.…”

The lack of either IRF9, or STAT2, has surprisingly little effect on human natural killer cell development and function

“…The clinical histories of the IRF9‐and STAT2‐deficient patients have been described previously [14, 16]. The blood samples used in the experiments presented in this work were obtained during follow‐up analyses of immune cell function and responses to vaccination, at around 10 and 1 year of age for the IRF9‐deficient patients and about 3 years of age for the STAT2‐deficient patient.…”

“…We, and others, have previously identified and characterized patients with mutations inactivating IRF9 and STAT2 gene expression and shown that peripheral blood mononuclear cells (PBMCs) and fibroblasts from these patients do not upregulate ISG expression after IFNαβ stimulation [13–16]. Here we have addressed the importance of type I interferon signalling for human NK cell development and function by studying the phenotype and function of circulating NK cells isolated from these patients.…”