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Keeping the peace: commensal Cutibacterium acnes trains CD4+ TH17 cells to trap and kill
Diane M. Thiboutot, Amanda M. Nelson
Diane M. Thiboutot, Amanda M. Nelson
Published January 19, 2021
Citation Information: J Clin Invest. 2021;131(2):e145379. https://doi.org/10.1172/JCI145379.
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Keeping the peace: commensal Cutibacterium acnes trains CD4+ TH17 cells to trap and kill

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Abstract

Commensal or pathogenic bacterial communities of the skin interact with the host immune system to preserve homeostasis or sustain disease. In this issue of the JCI, Agak et al. substantially advance our conceptual understanding of TH17 cell biology. The researchers identified IL-26–independent mechanisms by which CD4+ TH17 clones directly kill bacteria. These CD4+ TH17 clones share antimicrobial properties with cytotoxic T cells and granulocytes as evidenced by secretion of granulysin, granzyme B, and histone-laden DNA extracellular traps. Interestingly, these clones emerged following monocyte education by Cutibacterium acnes strains associated with healthy skin, but not those associated with acne. Overall, the antimicrobial mechanisms employed by these TH17 subsets suggest a unique link between innate and adaptive immune responses.

Authors

Diane M. Thiboutot, Amanda M. Nelson

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Dysbiosis in food allergy and implications for microbial therapeutics
M. Cecilia Berin
M. Cecilia Berin
Published January 19, 2021
Citation Information: J Clin Invest. 2021;131(2):e144994. https://doi.org/10.1172/JCI144994.
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Dysbiosis in food allergy and implications for microbial therapeutics

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Abstract

The increase in food allergy prevalence in recent years suggests that environmental factors, such as diet and intestinal microbiota, play contributory roles. In this issue of the JCI, Bao et al. compared twins that differed with respect to food allergies. The researchers analyzed sequences from microbe ribosomal RNA and profiled microbe metabolites, identifying health-associated microbes at the species level. In addition to revealing microbes from the Clostridia class enriched in healthy twins, the authors identified two commensal species (Phascolarctobacterium faecium and Ruminococcus bromii) related to the healthy fecal metabolome. This study advances the goal for next-generation probiotic therapies that effectively treat or prevent food allergy.

Authors

M. Cecilia Berin

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Proteomic and metabolomic advances uncover biomarkers of mitochondrial disease pathophysiology and severity
Marjan Gucek, Michael N. Sack
Marjan Gucek, Michael N. Sack
Published January 19, 2021
Citation Information: J Clin Invest. 2021;131(2):e145158. https://doi.org/10.1172/JCI145158.
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Proteomic and metabolomic advances uncover biomarkers of mitochondrial disease pathophysiology and severity

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Abstract

Advancing proteomic and metabolomic technologies that integrate curated omic databases have crossed a threshold to enable their clinical utility. In this issue of the JCI, Sharma et al. exploit emerging technologies to evaluate whether biomarkers identified in the mitochondrial encephalomyopathy lactic acidosis and stroke-like episodes (MELAS) syndrome could refine disease characterization, uncover pathways to monitor therapeutic efficacy, and/or delineate disease-modifying targets. The authors analyzed blood and urine samples from patients with this genetic mitochondrial disease and elucidated proteins and metabolites related to NADH-reductive stress. These circulating biomarkers have intriguing clinical potential that implicate disease pathophysiology and may prove important biomarkers for the future management of MELAS.

Authors

Marjan Gucek, Michael N. Sack

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Unraveling the genomic basis of congenital heart disease
Dawood Darbar
Dawood Darbar
Published January 19, 2021
Citation Information: J Clin Invest. 2021;131(2):e145377. https://doi.org/10.1172/JCI145377.
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Unraveling the genomic basis of congenital heart disease

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Abstract

The genetic, epigenetic, and environmental etiologic basis of congenital heart disease (CHD) for most heart anomalies remains unexplained. In this issue of the JCI, Lahm et al. performed the largest genome-wide association study (GWAS) to date of European individuals with CHD and clinical subtypes. The comprehensive meta-analysis included over 4000 patients and 8000 controls and uncovered common genetic variants that associated with cardiac anomalies. Lahm and colleagues performed single-cell analysis of induced pluripotent stem cells and heart cells, revealing a role for MACROD2, GOSR2, WNT3, and MSX1 in the developing heart. This study advances our understanding of the genetic basis of common forms of CHD.

Authors

Dawood Darbar

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Doubling up on function: dual-specificity tyrosine-regulated kinase 1A (DYRK1A) in B cell acute lymphoblastic leukemia
Jung-Hyun Kim, … , Liping Li, Linda M.S. Resar
Jung-Hyun Kim, … , Liping Li, Linda M.S. Resar
Published January 4, 2021
Citation Information: J Clin Invest. 2021;131(1):e142627. https://doi.org/10.1172/JCI142627.
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Doubling up on function: dual-specificity tyrosine-regulated kinase 1A (DYRK1A) in B cell acute lymphoblastic leukemia

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Abstract

DYRK1A, the dual-specificity kinase, is again doubling up on function, as reported by Bhansali, Rammohan, and colleagues in this issue of the JCI. DYRK1A is an evolutionarily conserved protein kinase with dual specificity; it adds phosphates to serine/threonine residues of diverse regulatory proteins and activates its own function by autophosphorylating a critical tyrosine at position 321 in the activation loop. Bhansali, Rammohan, and colleagues investigated B cell acute lymphoblastic leukemia (B-ALL) in individuals with Down syndrome (DS) and in children with leukemia characterized by aneuploidy. The study revealed a DYRK1A/FOXO1 and STAT3 signaling pathway in B-ALL that could be targeted pharmacologically, thus opening the door to therapeutic strategies for patients with leukemia with or without DS.

Authors

Jung-Hyun Kim, Liping Li, Linda M.S. Resar

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Complement C3a receptor–mediated vascular dysfunction: a complex interplay between aging and neurodegeneration
Kanchan Bhatia, … , Adam Kindelin, Andrew F. Ducruet
Kanchan Bhatia, … , Adam Kindelin, Andrew F. Ducruet
Published January 4, 2021
Citation Information: J Clin Invest. 2021;131(1):e144348. https://doi.org/10.1172/JCI144348.
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Complement C3a receptor–mediated vascular dysfunction: a complex interplay between aging and neurodegeneration

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Abstract

Vascular dysfunction resulting in compromised blood-brain barrier (BBB) integrity is evident in aging and disease. Although the complement C3a/C3a receptor (C3a/C3aR) axis influences normal brain aging and disease progression, the mechanisms governing endothelial C3aR–mediated neurovascular inflammation and BBB permeability remain unexplored. In this issue of the JCI, Propson et al. investigated endothelial C3a/C3aR signaling in normal, aged, and neurodegenerative mouse models. Endothelial C3aR signaling modulated age-dependent increases in VCAM1, initiated peripheral lymphocyte infiltration, and enhanced microglial activity. Increased calcium release downstream of C3aR signaling disrupted the vascular endothelial cadherin (VE-cadherin) junctions, increased BBB permeability, and degraded vascular structure and function. Mice lacking C3aR (C3ar1–/–) and mice treated with a C3aR antagonist showed attenuated age-related microglial reactivity and neurodegeneration. These results confirm that complement-mediated signaling impacts vascular health and BBB function in normal aging and neurodegenerative disease, suggesting that complement inhibitors represent a therapeutic option for cerebral microvascular dysfunction.

Authors

Kanchan Bhatia, Saif Ahmad, Adam Kindelin, Andrew F. Ducruet

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Targeting the mutant p53 secretome
Kartik Sehgal, David A. Barbie
Kartik Sehgal, David A. Barbie
Published January 4, 2021
Citation Information: J Clin Invest. 2021;131(1):e143945. https://doi.org/10.1172/JCI143945.
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Targeting the mutant p53 secretome

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Abstract

While p53 is the most highly mutated and perhaps best studied tumor suppressor protein related to cancer, it remains refractory to targeted therapeutic strategies. In this issue of the JCI, Tan and colleagues investigated the mechanistic basis of the mutant p53 secretome in preclinical models of lung adenocarcinoma. The authors uncovered miR-34a as a regulator of a conventional protein secretion axis, which is mediated by three proteins: the Golgi reassembly and stacking protein 55 kDa (GRASP55), basic leucine zipper nuclear factor 1, and myosin IIA. Inhibition of GRASP55 in TP53-deficient lung adenocarcinoma suppressed protumorigenic secretion of osteopontin/secreted phosphoprotein 1 and insulin-like growth factor binding protein 2 and reduced tumor growth and metastases in mice as well as in patient-derived xenografts. These results provide a therapeutic opportunity to target downstream effects of p53 loss.

Authors

Kartik Sehgal, David A. Barbie

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Epigenetic reprogramming to prevent genetic cardiomyopathy
Jamie R. Johnston, … , Daniel F. Selgrade, Elizabeth M. McNally
Jamie R. Johnston, … , Daniel F. Selgrade, Elizabeth M. McNally
Published January 4, 2021
Citation Information: J Clin Invest. 2021;131(1):e143684. https://doi.org/10.1172/JCI143684.
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Epigenetic reprogramming to prevent genetic cardiomyopathy

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Abstract

Mutations in the gene that codes for lamin A/C (LMNA) are a common cause of adult-onset cardiomyopathy and heart failure. In this issue of the JCI, Guénantin and Jebeniani et al. identify impaired cardiomyocyte development and maturation as a prenatal feature in a model of laminopathy. Cardiomyocytes carrying the Lmna point mutation H222P misexpressed genes involved in the epithelial-mesenchymal transition and showed decreased methylation at the fourth lysine of histone H3 (H3K4). Notably, inhibiting lysine-specific demethylase 1 in the LMNA H222P mouse model treated this congenital form of cardiomyopathy and improved survival in utero. These data highlight early epigenomic modifications in lamin A/C-mediated pathology and indicate a unique therapeutic strategy for cardiomyopathy.

Authors

Jamie R. Johnston, Daniel F. Selgrade, Elizabeth M. McNally

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You are when you eat: on circadian timing and energy balance
Jonathan Cedernaes, Joseph Bass
Jonathan Cedernaes, Joseph Bass
Published January 4, 2021
Citation Information: J Clin Invest. 2021;131(1):e144655. https://doi.org/10.1172/JCI144655.
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You are when you eat: on circadian timing and energy balance

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The neuronal mechanisms that establish 24-hour rhythms in feeding and metabolism remain incompletely understood. In this issue of the JCI, Adlanmerini and colleagues explored the relationship between temporal and homeostatic control of energy balance by focusing on mice that lacked the genes encoding the clock repressor elements REV-ERBα and –β, specifically in the tuberal hypothalamus. Notably, the clock transcription cycle mediated intraneuronal response to the adipostatic hormone leptin. These results show that REV-ERBα and –β in the hypothalamus are necessary for maintaining leptin responsiveness and metabolic homeostasis and lay the foundation to explore how transcriptional changes may link energy-sensing cell types with day/night rhythms. Such information may lead to therapeutics that alleviate the adverse effects of chronic shift work.

Authors

Jonathan Cedernaes, Joseph Bass

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Immune MAL2-practice: breast cancer immunoevasion via MHC class I degradation
Devin Dersh, Jonathan W. Yewdell
Devin Dersh, Jonathan W. Yewdell
Published January 4, 2021
Citation Information: J Clin Invest. 2021;131(1):e144344. https://doi.org/10.1172/JCI144344.
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Immune MAL2-practice: breast cancer immunoevasion via MHC class I degradation

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Abstract

The success of tumor immunotherapy, while partial, confirms the existence and importance of tumor immunosurveillance. CD8+ T cell recognition of tumor-specific peptides bound to MHC class I (MHC-I) molecules is central to this process. In this issue of the JCI, Fang, Wang, et al. describe a unique tumor immunoevasion strategy based on endocytosis and degradation of MHC-I complexes mediated by the trafficking factor MAL2. Notably, MAL2 expression was associated with poor prognosis of breast cancer, and its downregulation enhanced CD8+ T cell recognition of breast cancer in various experimental models. This work demonstrates that a deeper understanding of tumor interference with MHC-I stability and trafficking has considerable potential for enhancing immunotherapies.

Authors

Devin Dersh, Jonathan W. Yewdell

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