Mechanisms of resilience to cytokinopathy flares

The National Institute of Allergy and Infectious Diseases awarded Yale University $105,402 on September 27, 2026, under the Allergy and Infectious Diseases Research program (CFDA 93.855) to investigate mechanisms of resilience to inflammatory cytokine flares.

The research examines how the transcription factor ELF4 regulates recovery from inflammatory insults and hypercytokinemia following immune system activation. Prior work established that mutations in the X-linked ELF4 gene cause an autoinflammatory condition termed Deficiency in ELF4, X-Linked (DEX), characterized by excessive secretion of IL-17, interferon gamma, and IL-1 beta. The project generates experimental cytokine flares in vivo to decode the cytokine regulatory machinery necessary to restore immune homeostasis after inflammatory episodes, with the hypothesis that ELF4 functions as a key mediator of negative regulatory circuits supporting recovery and resolution of hypercytokinemia.

Performance occurs in New Haven, Connecticut from the award date through April 15, 2029. The assistance type is a project grant supporting basic research in infectious diseases and immunologic conditions.

Abstract

Intricate cytokine networks mediate effective immune responses and their subsequent return to homeostasis. Inflammatory stimuli trigger orchestrated responses to potential threats, and failure to return to homeostasis results in a pathogenic cytokine environment that can manifest as an inflammatory flare. Recurrent flares impart significant physical and psychological burden in patients of lifelong autoimmune and autoinflammatory diseases. Previously, we discovered mutation in the x-linked ETS transcription factor E74-like factor-4 (ELF4) to be causal of a cytokinopathy with a behçet's- and inflammatory bowel disease-like autoinflammatory syndrome in males, termed 'deficiency in ELF4, x-linked' (DEX). We have previously established that ELF4 restrains hyper-cytokine secretion of IL-17, ifnγ and IL-1Β upon activation in vitro and restrains systemic hypercytokinemia upon lipopolysaccharide (LPS) challenge in vivo. Through a bone marrow chimera system, i have demonstrated that ELF4 is not necessary for the development, or suppressive capacity of regulatory t cells at homeostasis, implicating alternative control mechanisms. ELF4 heterozygotes are somatic mosaics of ELF4-expressing and ELF4-deficient cells, that, interestingly are predominantly asymptomatic. Yet, recent evidence highlights that skewed x-inactivation may be responsible for newly discovered symptomatic ELF4 heterozygous variants, suggesting a critical threshold of wild-type cells may be necessary to restrain hypercytokinemia in the setting of DEX. Leveraging these insights and generating experimental cytokine flares in vivo, this proposal seeks to decode the cytokine machinery necessary to restore homeostasis after flares. We hypothesize that ELF4 functions as a key mediator of negative regulatory circuits supporting recovery after inflammatory insults, thereby resolving hypercytokinemia and preserving homeostasis. In aim 1, i seek to determine the cell-intrinsic roles of ELF4 in tuning responses to anti-CD3/LPS induced cytokine flares, delineating the magnitude and dynamics of the cytokine codes during the perturbation and restoration of cytokine homeostasis. In aim 2, i aim to examine the contribution of STAT1- and STAT3- inducing cytokines to feedback circuits during experimental cytokinopathy flares, to unravel the mechanisms by which ELF4-expressing cells functionally mitigate cytokinopathy resilience in the setting of ELF4- heterozygosity. The results of these investigations will not only guide our clinical approach to DEX patients but also broaden our fundamental understanding of the mechanisms of resilience to cytokinopathy.