Special Article of Interest

A recent study from the Mhlanga lab published in Nature Genetics, “A chromatin-regulated biphasic circuit coordinates IL-1β-mediated inflammation” sheds light on an intriguing locus harboring the proinflammatory cytokine IL1b and the anti inflammatory cytokine IL37. Their study focuses on a region between these two genes that harbors SNPs associated with altered immune responses in individuals during infection. They show that this region encodes the long noncoding RNA they name AMANZI (A MAster Noncoding RNA antagoniZing Inflammation) where the common variant RS16944 resides. [READ MORE]

Over a million studies have highlighted the central role of cytokines in immune function, yet we never had a comprehensive view of how every immune cell type responds to every cytokine. The large number of immune cell types and cytokines and complex cellular responses make it challenging.

In the recent Nature paper “Dictionary of immune responses to cytokines at single-cell resolution” (Cui et al., Nature 2023), the Immune Dictionary was created. This is a large-scale compendium of single-cell transcriptomic profiles of more than 17 immune cell types in response to each of 86 cytokines (>1,400 cytokine–cell type combinations) in mouse lymph nodes in vivo. The dictionary revealed many immune cell responses to cytokines that were previously uncharacterized. Based on this dictionary, they developed companion software, Immune Response Enrichment Analysis (IREA), that allows any researcher to assess cytokine activities, immune cell polarization, and cytokine networks from gene expression data. The dictionary generates new hypotheses for cytokine functions, illuminates pleiotropic effects of cytokines, expands our knowledge of activation states of each immune cell type, and provides a framework to deduce the roles of specific cytokines and cell–cell communication networks in any immune response. [READ MORE]

2023 has been marked by the discovery of over 10 new inborn errors of immunity, as well as novel consequences of anticytokine antibodies and somatic disease-causing variants. Amongst these were three new diseases caused by mutations in the JAK-STAT pathway. Baris et al and Sharma et al independently described a novel atopic syndrome caused by heterozygous germline gain-of-function (GOF) mutations in STAT6 1,2. This included 11 separate families across multiple continents and included atopic dermatitis, peripheral hypereosinophilia, eosinophilic gastrointestinal disease, allergic asthma, elevated total serum IgE, food allergy, and anaphylaxis. Mutations were found in the DNA-binding, linker, and SH2 domains: functional evaluation revealed sustained STAT6 phosphorylation and enhanced Th2 differentiation. Three families with disabling pansclerotic morphea due to heterozygous STAT4 GOF were described by Bhagdassarian et al 3. All three activating mutations were in the SH2 domain of STAT4; the mutant protein exhibited enhanced basal (unstimulated) phosphorylation and delayed dephosphorylation kinetics in skin fibroblasts. Patient skin and serum was characterized by markedly increased expression of IL-6. Further supporting a primary role for JAK-STAT pathway activation, both STAT6 GOF and STAT4 GOF patients responded to treatment with systemic JAK inhibitions like ruxolitinib and baricitinib. [READ MORE]

The last several years have seen a virtual explosion of novel inborn errors of immunity (IEI), with 56 novel diseases discovered between 2020-2022 1. It should therefore come as no surprise that the spectrum of genetic immune dysregulation has continued to expand dramatically over the last year. While it is impossible to review all the major advances in the field, several recent publications will be of particular interest to cytokine biologists [READ MORE]