Pulmonary hypertension (PH), increased blood pressure within the lungs, is classified into five diagnostic groups based on etiology, with treatment assigned on this basis. Currently, only Group 1 pulmonary arterial hypertension (PAH) and Group 4 chronic thromboembolic PH (CTEPH) have pharmacological treatments available. The role of the endothelial cell in pulmonary hypertension has long been debated, and in this issue of the JCI, Culley et al. present evidence for the reduction in frataxin expression across multiple groups of PH. Reduced frataxin expression led to endothelial cell senescence and associated with the development of PH. Removal of the senescent cells using the senolytic drug Navitoclax in multiple models of PH effectively treated PH, suggesting a new class of treatments that may work beyond Group 1 and Group 4 PH in patients with evidence of pulmonary vascular endothelial senescence.
Allan Lawrie, Sheila E. Francis
Calcineurin inhibitors (CNIs) such as cyclosporin A and FK506 are widely administered immunosuppressive drugs. Calcineurin relieves inhibitory phosphorylation from nuclear factor of activated T cells (NFAT) transcription factors downstream of T cell receptor engagement, resulting in their nuclear translocation and the production of cytokines, including IL-2, IFN-γ, and TNF-α. It was previously believed that CNIs downregulate immunity by reducing NFAT activation. However, work from Otsuka et al. in this issue of the JCI revealed a second mechanism by which CNIs suppress T cell function. The authors previously reported that calcineurin removes an inhibitory phosphate from the tyrosine kinase Lck at Ser59 (Lck-S59) and that this dephosphorylation positively regulates T cell activation. In the present work, the authors showed that inhibition of Lck-S59 dephosphorylation was essential for the CNI-mediated suppression of acute graft-versus-host disease (aGVHD). These findings have important implications for future approaches to the management of aGVHD, organ transplant rejection, and autoimmune disease.
Nicole M. Carter, Joel L. Pomerantz
The SARS-CoV-2 virus, which causes COVID-19, has been associated globally with substantial morbidity and mortality. Numerous reports over the past year have described the clinical and immunological profiles of COVID-19 patients, and while some trends have emerged for risk stratification, they do not provide a complete picture. Therefore, efforts are ongoing to identify genetic susceptibility factors of severe disease. In this issue of the JCI, Povysil et al. performed a large, multi-country study, sequencing genomes from patients with mild and severe COVID-19, along with population controls. Contrary to previous reports, the authors observed no enrichment of predicted loss-of-function variants in genes in the type I interferon pathway, which might predispose to severe disease. These studies suggest that more evidence is needed to substantiate the hypothesis for a genetic immune predisposition to severe COVID-19, and highlights the importance of considering experimental design when implicating a monogenic basis for severe disease.
Chris Cotsapas, Janna Saarela, Jocelyn R. Farmer, Vinod Scaria, Roshini S. Abraham
Efforts to best protect the world from SARS-CoV-2 as variants emerge and despite limited vaccine supply are ongoing. One strategy that may maximize vaccine quantities and expedite immunization campaigns involves providing single mRNA vaccine doses to individuals with previous COVID-19. In this issue of the JCI two independent studies, Levi et al. and Mazzoni et al., explored vaccine responses in individuals previously infected with the virus. Levi and colleagues used multilinear regression models to correlate exposure, as well as symptoms, with antibody response to the vaccine. Mazzoni and colleagues characterized B cell and T cell kinetics in whole blood after one and two doses of vaccine in health care workers with and without previous infection. Both studies indicate that one vaccine dose may sufficiently protect individuals who have recovered from COVID-19. Implementing a single dose mRNA vaccine protocol in previously symptomatic individuals may facilitate and expedite immunization campaigns.
Gonzalo Perez Marc, Damian Alvarez-Paggi, Fernando P. Polack
Kidney diseases affect more than 15% of adults in the US, yet drug development in the kidney field, when compared with that for other common diseases, has been lagging behind. Modifiers that increase the susceptibility to injury and contribute to the pathogenesis and progression of kidney disease include genetic and environmental factors and epigenetic mechanisms. In this issue of the JCI, Cao et al. and Doke et al. independently report the identification of a susceptibility factor called Dachshund homolog 1 (DACH1). Both groups identify an association of reduced DACH1 expression with kidney disease, using different screening approaches, studying different types of human kidney diseases, and using different experimental models, making the fact that both stumbled over the same protein very compelling. Combined, these studies highlight DACH1 as a key safeguard in the kidney, granting various cell types proper function by modulating several molecular pathways.
Sandra Merscher, Christian Faul
Sites of acute inflammation become austere environments for the procurement of energy. The combination of oxygen depletion (hypoxia) and decreased glucose availability requires surprising metabolic adaptability. In this issue of the JCI, Watts et al. examined the metabolic adaptability of murine neutrophils to the setting of acute pulmonary inflammation elicited by exposure to nebulized endotoxin. While neutrophils are generally considered a primarily glycolytic cell type, Watts et al. used a combination of labeled amino acids and high-resolution proteomics to reveal that the harsh environment of the inflammatory lesion drives neutrophils toward de novo protein synthesis and extracellular protein scavenging as a primary fuel. This study provides compelling evidence that tissue neutrophils scavenge extracellular proteins to fuel carbon metabolism, which aids in de novo protein synthesis and the promotion of an inflammatory phenotype. These observations reveal the surprisingly creative extent to which cells and tissues might adapt to energy-deficient inflammatory environments.
Ian M. Cartwright, Sean P. Colgan
Inflammatory bowel disease (IBD) is a chronic inflammatory disease of the intestine associated with genetic susceptibility and alterations in the intestinal microbiome. Multiomics data developed and analyzed over the last several decades have yielded an unprecedented amount of genetic and microbial data. But how do we pinpoint mechanistic insight into the host-microbe relationship that will ultimately enable better care for patients with IBD? In this issue of the JCI, Grasberger et al. undertook a major decoding effort to decipher this multiomic data matrix. The authors analyzed anonymized data from more than 2800 individuals to discover a link between heterozygous carriers of deleterious DUOX2 variants and high levels of plasma IL-17C. These findings provide an example of how harnessing big data can drive mechanistic discovery to define disease biomarkers that have the potential to improve clinical care in IBD.
Monica Viladomiu, Randy S. Longman
Recognition of self-peptides in association with distinct HLA class II alleles by autoreactive CD4+ T cells is central for loss of immunological tolerance leading to autoimmune disease. However, identifying immunodominant self-peptides and characterizing autoreactive T cells is challenging. In this issue of the JCI, Falta et al. identify a disease-associated complementarity-determining region 3β motif specific for beryllium-modified C-C motif ligand 4 (CCL4) and CCL3 self-peptides in patients with chronic beryllium disease (CBD), a granulomatous lung disorder with a known HLA class II allelic association. Detection of these antigen-specific CD4+ T cells by beryllium-pulsed HLA-DP2 tetramers presenting CCL4/CCL3 confirms these autoantigens in humans and mice and enables monitoring in the progress of disease. Detection of autoreactive CD4+ T cells by peptide–MHC class II multimers allows for the detailed characterization of disease-promoting T cells. This knowledge has profound implications for the monitoring and development of targeted therapies in human autoimmune disorders.
Karolin Wieber, Christine L. Zimmer, Michael Hertl
Recurrent genital herpes lesions are infiltrated by various leukocytes, yet the role of B cell subsets in this process is unknown. In this issue of the JCI, Ford et al. describe the presence and antibody-secreting role of local B cell populations in herpes simplex virus 2 (HSV-2) recurrent lesions. The authors analyzed a comprehensive array of sequential skin biopsy specimens from HSV-2–infected patients over time and at various stages of infection. Using immunofluorescence and in situ hybridization, the authors show the presence of rare IgD+ naive B cells and IgG-expressing antibody-secreting cells (ASCs) in recurrent HSV-2 lesions embedded in CD4+ T cell–rich dermal immune infiltrates, levels of which transiently increase during lesion reactivation and healing. Notably, local increases in HSV-2–specific antibodies in recurrent lesions were detected, whereas serum HSV-2 antibody levels remained stable. Future research is needed to understand the precise role of these tissue-visiting B cells in disease resolution.
Jeff R. Gehlhausen, Akiko Iwasaki
It has long been known that fatty acids can either adversely or positively affect insulin signaling in skeletal muscle, depending on chain length or saturation, and can therefore be primary drivers of systemic insulin sensitivity. However, the detailed mechanisms linking fatty acids to insulin signaling in skeletal muscle have been elusive. In this issue of the JCI, Ferrara et al. suggest a model whereby membrane lipid remodeling mediates skeletal muscle insulin sensitivity. The authors demonstrate that membrane glycerophospholipid fatty acid remodeling by lysophosphatidylcholine acyltransferase 3 (LPCAT3) in skeletal muscle from subjects with obesity was induced, suppressing insulin signaling and glucose tolerance. Loss or gain of LPCAT3 function in mouse models showed that Lpcat3 was both required and sufficient for high-fat diet–induced muscle insulin resistance. These results suggest that the physiochemical properties of muscle cell membranes may drive insulin sensitivity and, therefore, systemic glucose intolerance.
Michael J. Wolfgang
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