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Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is a life-threatening monogenic autoimmune disorder primarily caused by biallelic deleterious variants in the autoimmune regulator ( AIRE ) gene. We prospectively evaluated 104 patients with clinically diagnosed APECED syndrome and identified 17 patients (16%) from 14 kindreds lacking biallelic AIRE variants in exons or flanking intronic regions; 15 had Puerto Rican ancestry. Through whole-genome sequencing, we identified a deep intronic AIRE variant (c.1504-818 G>A) cosegregating with the disease in all 17 patients. We developed a culture system of AIRE -expressing primary patient monocyte-derived dendritic cells and demonstrated that c.1504-818 G>A creates a cryptic splice site and activates inclusion of a 109-base pair frame-shifting pseudoexon. We also found low-level AIRE expression in patient-derived lymphoblastoid cell lines (LCLs) and confirmed pseudoexon inclusion in independent extrathymic AIRE -expressing cell lines. Through protein modeling and transcriptomic analyses of AIRE -transfected human embryonic kidney 293 and thymic epithelial cell 4D6 cells, we showed that this variant alters the carboxyl terminus of the AIRE protein, abrogating its function. Last, we developed an antisense oligonucleotide (ASO) that reversed pseudoexon inclusion and restored the normal AIRE transcript sequence in LCLs. Thus, our findings revealed c.1504-818 G>A as a founder APECED-causing AIRE variant in the Puerto Rican population and uncovered pseudoexon inclusion as an ASO-reversible genetic mechanism underlying APECED.

Correctly identifying perturbed biological pathways is a critical step in uncovering basic disease mechanisms and developing much-needed therapeutic strategies. However, whether current tools are optimal for unbiased discovery of relevant pathways remains unclear. Here, we create "Benchmark" to critically evaluate existing tools and find that most function sub-optimally. We thus develop the "Pathway Ensemble Tool" (PET), which outperforms existing methods. Deploying PET, we identify prognostic pathways across 12 cancer types. PET-identified prognostic pathways offer additional insights, with genes within these pathways serving as reliable biomarkers for clinical outcomes. Additionally, normalizing these pathways using drug repurposing strategies represents therapeutic opportunities. For example, the top predicted repurposed drug for bladder cancer, a CDK2/9 inhibitor, represses cell growth in vitro and in vivo. We anticipate that using Benchmark and PET for unbiased pathway discovery will offer additional insights into disease mechanisms across a spectrum of diseases, enabling biomarker discovery and therapeutic strategies., (© 2024. The Author(s).)

Background: Autoimmune polyendocrine syndrome type 1 (APS-1) is a life-threatening, autosomal recessive syndrome caused by autoimmune regulator (AIRE) deficiency. In APS-1, self-reactive T cells escape thymic negative selection, infiltrate organs, and drive autoimmune injury. The effector mechanisms governing T-cell-mediated damage in APS-1 remain poorly understood., Methods: We examined whether APS-1 could be classified as a disease mediated by interferon-γ. We first assessed patients with APS-1 who were participating in a prospective natural history study and evaluated mRNA and protein expression in blood and tissues. We then examined the pathogenic role of interferon-γ using Aire -/- Ifng -/- mice and Aire -/- mice treated with the Janus kinase (JAK) inhibitor ruxolitinib. On the basis of our findings, we used ruxolitinib to treat five patients with APS-1 and assessed clinical, immunologic, histologic, transcriptional, and autoantibody responses., Results: Patients with APS-1 had enhanced interferon-γ responses in blood and in all examined autoimmunity-affected tissues. Aire -/- mice had selectively increased interferon-γ production by T cells and enhanced interferon-γ, phosphorylated signal transducer and activator of transcription 1 (pSTAT1), and CXCL9 signals in multiple organs. Ifng ablation or ruxolitinib-induced JAK-STAT blockade in Aire -/- mice normalized interferon-γ responses and averted T-cell infiltration and damage in organs. Ruxolitinib treatment of five patients with APS-1 led to decreased levels of T-cell-derived interferon-γ, normalized interferon-γ and CXCL9 levels, and remission of alopecia, oral candidiasis, nail dystrophy, gastritis, enteritis, arthritis, Sjögren's-like syndrome, urticaria, and thyroiditis. No serious adverse effects from ruxolitinib were identified in these patients., Conclusions: Our findings indicate that APS-1, which is caused by AIRE deficiency, is characterized by excessive, multiorgan interferon-γ-mediated responses. JAK inhibition with ruxolitinib in five patients showed promising results. (Funded by the National Institute of Allergy and Infectious Diseases and others.)., (Copyright © 2024 Massachusetts Medical Society.)

Lung cancer demands innovative approaches for early detection and targeted treatment. In addressing this urgent need, exosomes play a pivotal role in revolutionizing both the early detection and targeted treatment of lung cancer. Their remarkable capacity to encapsulate a diverse range of biomolecules, traverse biological barriers, and be engineered with specific targeting molecules makes them highly promising for both diagnostic markers and precise drug delivery to cancer cells. Furthermore, an in-depth analysis of exosomal content and biogenesis offers crucial insights into the molecular profile of lung tumors. This knowledge holds significant potential for the development of targeted therapies and innovative diagnostic strategies for cancer. Despite notable progress in this field, challenges in standardization and cargo loading persist. Collaborative research efforts are imperative to maximize the potential of exosomes and advance the field of precision medicine for the benefit of lung cancer patients.

Forkhead box protein 3-expressing (FOXP3 + ) regulatory T cells (T reg cells) suppress conventional T cells and are essential for immunological tolerance. FOXP3, the master transcription factor of T reg cells, controls the expression of multiples genes to guide T reg cell differentiation and function. However, only a small fraction (<10%) of T reg cell-associated genes are directly bound by FOXP3, and FOXP3 alone is insufficient to fully specify the T reg cell programme, indicating a role for other accessory transcription factors operating upstream, downstream and/or concurrently with FOXP3 to direct T reg cell specification and specialized functions. Indeed, the heterogeneity of T reg cells can be at least partially attributed to differential expression of transcription factors that fine-tune their trafficking, survival and functional properties, some of which are niche-specific. In this Review, we discuss the emerging roles of accessory transcription factors in controlling T reg cell identity. We specifically focus on members of the basic helix-loop-helix family (AHR), basic leucine zipper family (BACH2, NFIL3 and BATF), CUT homeobox family (SATB1), zinc-finger domain family (BLIMP1, Ikaros and BCL-11B) and interferon regulatory factor family (IRF4), as well as lineage-defining transcription factors (T-bet, GATA3, RORγt and BCL-6). Understanding the imprinting of T reg cell identity and specialized function will be key to unravelling basic mechanisms of autoimmunity and identifying novel targets for drug development., (© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Background: Identifying individuals with a higher risk of developing severe coronavirus disease 2019 (COVID-19) outcomes will inform targeted and more intensive clinical monitoring and management. To date, there is mixed evidence regarding the impact of preexisting autoimmune disease (AID) diagnosis and/or immunosuppressant (IS) exposure on developing severe COVID-19 outcomes., Methods: A retrospective cohort of adults diagnosed with COVID-19 was created in the National COVID Cohort Collaborative enclave. Two outcomes, life-threatening disease and hospitalization, were evaluated by using logistic regression models with and without adjustment for demographics and comorbidities., Results: Of the 2 453 799 adults diagnosed with COVID-19, 191 520 (7.81%) had a preexisting AID diagnosis and 278 095 (11.33%) had a preexisting IS exposure. Logistic regression models adjusted for demographics and comorbidities demonstrated that individuals with a preexisting AID (odds ratio [OR], 1.13; 95% confidence interval [CI]: 1.09-1.17; P < .001), IS exposure (OR, 1.27; 95% CI: 1.24-1.30; P < .001), or both (OR, 1.35; 95% CI: 1.29-1.40; P < .001) were more likely to have a life-threatening disease. These results were consistent when hospitalization was evaluated. A sensitivity analysis evaluating specific IS revealed that tumor necrosis factor inhibitors were protective against life-threatening disease (OR, 0.80; 95% CI: .66-.96; P = .017) and hospitalization (OR, 0.80; 95% CI: .73-.89; P < .001)., Conclusions: Patients with preexisting AID, IS exposure, or both are more likely to have a life-threatening disease or hospitalization. These patients may thus require tailored monitoring and preventative measures to minimize negative consequences of COVID-19., Competing Interests: Potential conflicts of interest. D. K. S. reports owning Pfizer stock. E. R. P. reports grants or contracts paid to their institution from NHLBI and PCORI; consulting fees from NCATS paid to author; and payment for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Cincinnati Children's Hospital. All remaining authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed. Source code. The code for this study (DUR: RP-42D046) is located within the N3C Data Enclave and can be accessed upon request, provided the user already has access to the N3C. Authorship was determined using ICMJE recommendations., (Published by Oxford University Press on behalf of Infectious Diseases Society of America 2023.)

Arginase 1 (Arg1), the enzyme catalyzing the conversion of arginine to ornithine, is a hallmark of IL-10-producing immunoregulatory M2 macrophages. However, its expression in T cells is disputed. Here, we demonstrate that induction of Arg1 expression is a key feature of lung CD4 + T cells during mouse in vivo influenza infection. Conditional ablation of Arg1 in CD4 + T cells accelerated both virus-specific T helper 1 (Th1) effector responses and its resolution, resulting in efficient viral clearance and reduced lung pathology. Using unbiased transcriptomics and metabolomics, we found that Arg1-deficiency was distinct from Arg2-deficiency and caused altered glutamine metabolism. Rebalancing this perturbed glutamine flux normalized the cellular Th1 response. CD4 + T cells from rare ARG1-deficient patients or CRISPR-Cas9-mediated ARG1-deletion in healthy donor cells phenocopied the murine cellular phenotype. Collectively, CD4 + T cell-intrinsic Arg1 functions as an unexpected rheostat regulating the kinetics of the mammalian Th1 lifecycle with implications for Th1-associated tissue pathologies., Competing Interests: Declaration of interests M.S. is an inventor on a patent describing the use of RBD ligands for cell-surface evaluation of CAT1/solute carrier family 7 member 1 (SLC7A1) and other solute carrier (SLC) expression (N.T. gave up her rights); he is a co-founder and head of the scientific board of METAFORA-Biosystems, a start-up company that focuses on metabolite transporters under physiological and pathological conditions., (Published by Elsevier Inc.)