Commentary
Abstract
Approximately 25% of individuals with type 1 diabetes (T1D) experience impaired awareness of hypoglycemia (IAH), a weakening of symptomatic neurohumoral responses to falling glucose levels that sharply increases risk of severe hypoglycemia. A recent study by Filip et al. used MRI-based arterial spin labeling to compare regional cerebral blood flow (CBF) responses to experimental hypoglycemia across 3 groups: individuals without T1D and individuals with T1D, with or without IAH. All groups showed a CBF response to hypoglycemia in brain regions involved in learning and interoception, among others, but the responses were qualitatively different between groups and blunted in the presence of IAH. The association between the regional CBF and the hormonal responses to hypoglycemia was inverted in IAH, compared with that in individuals with preserved awareness. The findings add to work linking changes in cognitive processing to IAH development and its persistence in some individuals.
Authors
Stephanie A Amiel, Fernando O Zelaya
Abstract
Alcohol use disorder (AUD) is linked with changes in brain structure and function, with robust evidence for neurodegenerative changes, including synaptic loss in preclinical models. Developing therapeutic strategies to target synaptic loss will require human studies that clarify their clinical relevance of these changes. In the current issue, Zakiniaeiz et al. demonstrate that AUD and alcohol consumption are associated with lower synaptic vesicle glycoprotein 2a (SV2A) expression, indexed by regional [11C]UCB-J PET. This is, to our knowledge, the first in vivo evidence of relationships between synaptic density and alcohol use, and, as such, it represents an important step toward understanding how AUD influences brain structure and function. Here, we describe two longstanding clinical issues in the AUD population — relapse and dementia risk — and how the results of the present study may guide future investigations of these issues.
Authors
Sarah K. Royse, Rajesh Narendran
Abstract
Crohn’s disease can occur anywhere along the small and/or large intestines, but most commonly occurs in the terminal ileum or ascending colon. Factors governing this region-specific inflammation are poorly understood. In this issue of the JCI, Spencer et al. used a TNF-driven mouse model of small intestinal Crohn’s disease to identify a specific bacterial pathobiont, Chlamydia muridarum, as a necessary and sufficient driver of region-restricted inflammation. C. muridarum triggered increased goblet cell expression of indoleamine 2,3-dioxygenase 1 (IDO1) in the mouse proximal colon, analogous to the human ascending colon. IDO1 metabolism of tryptophan stimulated increased levels of kyneurine, and suppression of this IDO1/kyneurine axis alleviated C. muridarum–provoked inflammation in the proximal colon but not the terminal ileum. Analysis of scRNA-seq datasets from patients with Crohn’s disease with ascending colon involvement also supported increased IDO1 expression in a subpopulation of crypt surface epithelial cells. The study highlights a process by which bacterial pathobionts promote region-specific intestinal inflammation.
Authors
Declan F. McCole
Abstract
Cellular senescence in osteogenic mesenchymal cells contributes to age-related bone loss. The bone marrow hosts myeloid cells, the precursors of immune cells, as well as mesenchymal cells, which give rise to osteoblasts and osteocytes. The senotype and senolytic response of bone marrow cells, particularly hematopoietic cells, in age-related bone loss is unclear. In this issue, Doolittle et al. showed that of all immune cells, myeloid cells had the strongest senescence profile, yet the relative level of senescence remained lower than that of mesenchymal stromal cells. Mesenchymal cells displayed a profound senotype, rendering them susceptible to senolytic clearance protecting against bone loss. By contrast, selective clearance of p16+ myeloid cells was not long-lasting and, hence, did not fully protect against age-related bone loss. These findings underscore the challenges of developing senolytic strategies for tissues with mixed senotypes, such as bone.
Authors
Lorenz C. Hofbauer, Martina Rauner
Abstract
Mismatch repair (MMR) deficiency is classically associated with microsatellite instability, a high tumor mutational burden (TMB), and sensitivity to immune checkpoint blockade in cancer. In this issue of the JCI, Puigdelloses Vallcorba et al. reported that this paradigm does not hold true in glioblastoma (GBM). Using genetically engineered mouse models, the authors demonstrated that loss of core MMR genes was insufficient to induce hypermutation or improve survival rates with PD-1 blockade. Instead, mouse models of germline MMR deficiency accelerated malignant progression by promoting the immune milieu toward a myeloid cell-dominant and T cell–suppressed tumor microenvironment. Importantly, the imidazotetrazine agent N3-(2-fluoroethyl) imidazotetrazine (KL-50) bypassed MMR dependence and overcame temozolomide resistance. These findings suggest MMR deficiency in GBM as a driver of immune suppression rather than tumor immunogenicity and carry important implications for therapy selection.
Authors
Andrew Li, Thomas K. Sears, Craig M. Horbinski
Abstract
Coronaviruses, both known and yet to emerge, pose persistent zoonotic and pandemic threats. While current parenteral COVID-19 mRNA vaccines effectively mitigate severe disease caused by SARS-CoV-2, they primarily elicit systemic immunity restricted to specific variants within clade 1b of the sarbecovirus subgenus and provide limited mucosal protection. Addressing these shortcomings, Cheang et al. developed a DC-targeting intranasal booster vaccine that induces robust and durable mucosal and systemic immunity across sarbecovirus clades 1a and 1b. This study highlights a promising strategy for pan-sarbecovirus vaccines by leveraging mucosal immune induction to prevent viral transmission and enhance pandemic preparedness.
Authors
Charlie Fricke, Stanley Perlman
Abstract
The TMPRSS2:ERG gene fusion is a truncal oncogenic event in a large subset of prostate cancers, yet its clinical relevance has remained unclear. In this issue of the JCI, Köcher et al. have demonstrated that ERG overexpression in human prostate cancer cells rewired DNA double-strand break repair toward a poly(ADP-ribose) polymerase 1–dependent (PARP1-dependent) alternative end-joining pathway without disrupting canonical repair. This repair bias created a conditional dependency on PARP1 that was exposed by radiotherapy, rendering ERG-positive tumors selectively sensitive to PARP inhibition–mediated radiosensitization. The tumor-selective cytotoxic effect of combined PARP1 inhibition and irradiation was corroborated in human-derived prostate cancer organoids. These findings establish ERG as a predictive biomarker for precision radiotherapy and highlight a tumor-selective strategy to enhance radiotherapeutic efficacy in prostate cancer.
Authors
Xiaoju Wang, Arul M. Chinnaiyan
Abstract
For over a decade, sepsis phenotyping has identified hyperinflammatory and hypoinflammatory subphenotypes using host biomarkers and clinical variables, without factoring in contributions from infectious insults across patients. In this issue, Chanderraj and colleagues challenge this host-centric paradigm by demonstrating that pathogen characteristics independently contribute to sepsis subphenotypes. They reported that Enterobacterales infections, particularly Escherichia coli, strongly associated with hyperinflammatory subphenotypes, independent of illness severity. Bacterial burden, anatomic barrier breach, and circulating pathogen-associated molecular patterns influence phenotypic classification, with implications extending to culture-negative sepsis. Animal models supported causality, while reanalysis of an observational cohort and a clinical trial revealed that lactate clearance’s prognostic value and therapeutic effects of endotoxin removal with polymyxin B hemoadsorption vary by subphenotype and pathogen. These findings lay groundwork for integrative host-pathogen phenotyping; for precision medicine in critical illness, we must know not only who is sick, but what made them sick, and how the two interact.
Authors
Georgios D. Kitsios, Rebecca M. Baron
Abstract
Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive sarcomas that constitute a major cause of mortality in individuals with neurofibromatosis type 1 (NF-1) and exhibit highly variable responses to radiotherapy. In this issue of the JCI, Zhu and colleagues integrated functional genomics, single-cell transcriptomics, and analysis of human tumors to show that type I IFN signaling shapes both tumor-intrinsic radiation sensitivity of MPNSTs and local recruitment and activation of T cells. Their findings establish IFN signaling as a central coordinator of the radiotherapy response in MPNSTs and suggest that incorporating targeted immunomodulation strategies may improve radiotherapy outcomes. The work also has direct implications for the role of the immune system and IFN signaling radiation–based treatment of soft tissue sarcomas beyond those involved in NF-1.
Authors
Sean P. Pitroda, Ralph R. Weichselbaum
Abstract
Organized adaptive immunity can emerge in the CNS under specific inflammatory and stromal conditions. The study by Yang et al. in this issue of the JCI reports that experimental ischemic stroke induced germinal center–like B cell follicles through microglial MIF–CD74/CXCR4 signaling and in situ B cell proliferation, promoting chronic neuroinflammation. These findings align with a growing body of evidence that the brain and meninges can support ectopic lymphoid structures in multiple sclerosis, during aging, and in certain gliomas. This Commentary integrates these observations to highlight shared principles, disease-specific outcomes, and unresolved questions regarding the identity and function of lymphoid aggregates in the CNS.
Authors
Catalina Lee-Chang
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ISSN: 0021-9738 (print), 1558-8238 (online)