Issues

Sarah Gaffen, PhD, is a professor of medicine and rheumatology and holds the Gerald P. Rodnan endowed chair at the University of Pittsburgh. Her lab explores the biological function of IL-17 and its receptor in the context of fungal host defense and autoimmunity. We spoke to Sarah about where her interest in cytokines began, the importance of saying no in your career, and her interest in paleogenetics.

In this issue of JEM, Watkins et al. show that the nasal mucosa of children is characterized by often asymptomatic viral and/or bacterial infections that regulate distinct innate immune programs.

FOXP3 hijacks DNA-binding proteins to regulate gene expression. In this issue of JEM, He et al. propose a dynamic model in which FOXP3 associates with DNA-binding proteins to regulate Treg cell function in response to environmental cues.

Identification of monogenic causes of immune dysregulation provides insight into human immune response and signaling pathways associated with autoimmunity. Jeanpierre et al. identify new germline variants in the gene encoding PTPN2 associated with loss of regulatory function, enhanced JAK/STAT signaling, and early-onset autoimmunity.

This year at JEM, we are highlighting women in science by sharing their stories and amplifying their voices. In this Viewpoint, we hear from a cross section of women, across multiple research fields, discussing their science and the process of setting up a lab as an independent researcher.

There are myriad conflicting hypotheses surrounding the retinoid nuclear receptor pathway. This review integrates key clinical, genetic, and pharmacologic data to suggest human disease settings where retinoic acid nuclear signaling plays a pathogenic role and suggests opportunities for therapeutic intervention.

We review how technological advances have expanded our ability to map immune receptor repertoires across B cell states in health and disease, and how these datasets reveal distinct processes involved in the generation of autoantibodies.

After leaving the bone marrow, transitional B cells split into subsets with a biased expression of homing receptors accompanied by different levels of surface IgM. Here, Spencer and Dionisi discuss how this could contribute to human lymphoid tissue content and function.

Chan et al. report inherited DBR1 deficiency as a genetic etiology of isolated SARS-CoV-2 brainstem encephalitis. DBR1 I120T/I120T patient-specific hPSC-derived hindbrain neurons display enhanced accumulation of RNA lariats resulting in increased susceptibility to SARS-CoV-2 infection, thereby underlying SARS-CoV-2 brainstem encephalitis.

Children being tested for SARS-CoV-2 show heightened nasal innate immune responses compared with adults. Here, comprehensive PCR testing and cytokine profiling reveal that nasal respiratory viruses and bacterial pathobionts are highly prevalent in children and drive heightened nasal innate immunity.

Although considered as a master transcription factor controlling Treg fate and function statically, He et al. report that Foxp3 dynamically binds to chromatin via other DNA-binding proteins, acting like a transcriptional cofactor sensing immunological contexts to tune Treg function.

Exome sequencing in pediatric systemic lupus and Evans syndrome identified six novel monoallelic PTPN2 mutations, impairing its regulatory function. This caused T cell hyperproliferation and high inflammatory cytokines, highlighting the druggable JAK/STAT pathway’s importance in systemic autoimmunity.

Valeri et al. identify a novel STING variant (F269S) that causes SAVI disease. They highlight the activation of interferon and inflammation across patient cell types and underscore the importance of the crosstalk between endothelial and immune cells in disease pathology.

Rare autoantibodies neutralizing type I IFNs can underlie viral disease severity. Here, the authors dissect immunological and age-related factors associated with anti-IFN-I autoantibody development in individuals over a 35-year period and further reveal the lifelong infection susceptibility that results.

Alippe et al. use directed breeding schemes, in situ hybridization, and single nuclear RNA sequencing analysis to establish key roles of fetal MAVS and type I IFN signaling pathways in regulating ZIKV cell tropism in the placenta and maternal–fetal infection.

There is a major unmet need to understand kidney-intrinsic events that control pathology in autoimmune conditions. Li et al. demonstrate that a noncanonical RNA binding protein, Arid5a, is a biomarker and driver of IL-17–dependent glomerulonephritis through control of RNA translation.

This study uses reporter cells engineered with a minimal expression construct and cells cultured directly from the reservoir of HIV-1 infected individuals to show that proviral transcription in latently infected cells is predominantly dependent on the site of proviral integration.

How cell-intrinsic metabolism regulates T cell function to shape immune outcomes is unclear. Kaymak, Watson, and colleagues demonstrate production of cytosolic acetyl-CoA by ACLY and ACSS2 links CD8 T cell metabolic state and effector function through effects on chromatin accessibility.