Megakaryocytes (MKs) give rise to platelets, which are blood cells that are essential to prevent hemorrhage. Although the majority of MKs localize to the bone marrow, there is a distinct population of lung-residing MKs (MKL). In this issue of the JCI, Pariser et al. examined gene expression patterns of MKs collected from murine and nonhuman primate bone marrow or lung. This Commentary explores the premise that environmental factors from the lung determine the genetic and phenotypic similarity of MKL to lung dendritic cells, distinguishing MKL from bone marrow MKs. Indeed, while MKL retain the ability to make platelets, they also process and present antigens that activate CD4+ lymphocytes. These data suggest that MKL may play an important role in immune processes beyond platelet production.
Eric Boilard, Kellie R. Machlus
A number of COVID-19 vaccine candidates have shown promising results, but substantial uncertainty remains regarding their effectiveness and global roll-out. Boosting innate immunity with Bacillus Calmette Guerin (BCG) or other live attenuated vaccines may also play a role in the fight against the COVID-19 pandemic. BCG has long been known for its non-specific beneficial effects, most likely explained by epigenetic and metabolic reprogramming of innate immune cells, termed trained immunity. In this issue of the JCI, Rivas et al. add to these arguments by showing that BCG-vaccinated healthcare providers from a Los Angeles healthcare organization had less COVID-19 diagnosis and serology, compared to unvaccinated individuals. Prospective clinical trials are thus warranted to explore BCG effects in COVID-19. We posit that beyond COVID-19, vaccines that elicit trained immunity, such as the BCG, may mitigate the impact of emerging pathogens in future pandemics.
Mihai G. Netea, Jos W.M. van der Meer, Reinout van Crevel
The coronavirus disease 2019 (COVID 19) pandemic continues to cause morbidity and mortality. Since severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) was identified as the cause for COVID 19, some have questioned whether exposure to seasonal common cold coronaviruses (CCCs) could provide tangible protection against SARS-CoV-2 infection or disease. In this issue of the JCI, Sager, et al. examined SARS-CoV-2 infections and outcomes from patients previously tested for CCC as part of a comprehensive respiratory panel using PCR and were segregated into negative (CCC–) or positive (CCC+) exposure. No differences were seen between groups in terms of susceptibility to SARS-CoV-2 infection. However, hospitalized patients with a documented history of CCC+ infection had lower rates of ICU admissions and higher rates of survival than hospitalized CCC– patients. While these findings are associative and not causative, they highlight evidence suggesting that previous CCC+ infection may influence the disease course of SARS-CoV-2 infection.
David K. Meyerholz, Stanley Perlman
Many individuals possess B cells capable of recognizing epitopes on the spike glycoprotein of SARS-CoV-2. In this issue of the JCI, Paschold and Simnica et al. interrogated the frequency of SARS-CoV-2–specific B cell receptor rearrangements in healthy subjects based on age and cancer status. The authors found that, while SARS-CoV-2–specific antibody signatures can be identified in the repertoires of young, healthy individuals, such sequences are less frequent in elderly subjects or cancer patients. Overall, this study sheds light on B cell repertoire restrictions that might lead to an unfavorable clinical course of COVID-19 infection in risk populations.
Andrew I. Flyak
Patients with type 2 diabetes (T2D) fail to secrete insulin in response to increased glucose levels that occur with eating. Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are two incretins secreted from gastrointestinal cells that amplify insulin secretion when glucose is high. In this issue of the JCI, Oduori et al. explore the role of ATP-sensitive K+ (KATP) channels in maintaining glucose homeostasis. In persistently depolarized β cells from KATP channel knockout (KO) mice, the researchers revealed a shift in G protein signaling from the Gs family to the Gq family. This shift explains why GLP-1, which signals via Gq, but not GIP, which signals preferentially via Gs, can effectively potentiate secretion in islets from the KATP channel–deficient mice and in other models of KATP deficiency, including diabetic KK-Ay mice. Their results provide one explanation for differential insulinotropic potential of incretins in human T2D and point to a potentially unifying model for T2D progression itself.
Colin G. Nichols, Nathaniel W. York, Maria S. Remedi
Some germ cell tumors (GCTs) in men develop into hematologic malignancies; however, the clonal origins of such malignancies remain unknown. In this issue of the JCI, Taylor, Donoghue, et al. unravel the clonal relationship between primary mediastinal nonseminomas (PMNs) and hematologic somatic-type malignancies (HSTMs). Whole-exome sequencing was used to construct phylogenetic trees of the PMNs and the ensuing HSTM clones. HSTMs were derived from multiple distinct clones not detected within the PMNs. Clones from PMNs and HSTMs shared a common precursor, arguably an embryonal carcinoma cell resulting from a reprogrammed primordial germ cell from the thymus. Mutational and copy number variation analysis of a large cohort of patients with PMNs also demonstrated a high prevalence of TP53 mutations not found in testicular nonseminomas. These data likely explain why patients with PMNs are frequently resistant to platinum-based chemotherapy and provide TP53 mutations as potential targets.
J. Wolter Oosterhuis, Leendert H.J. Looijenga
Identifying genes that result in monogenic diabetes can provide insights that can build a scientific foundation for precision medicine. At present, nearly 20% of neonatal diabetes cases have unknown causes. In this issue of the JCI, De Franco and Lytrivi et al. sequenced the genome of two probands with a rare neonatal diabetes subtype that also associated with microcephaly and epilepsy. The authors revealed mutations in the YIPF5 gene. YIPF5 resides in the Golgi apparatus and is thought to play a critical role in vesicular trafficking. Notably, disrupting YIPF5 in β cell–based models induced ER stress signaling and resulted in the accumulation of intracellular proinsulin. We believe that utilizing registries and biobanks to reveal other monogenic atypical forms of diabetes is an important approach to gaining insight and suggest that an insulin sensitizer may alleviate ER stress associated with YIPF5 disruption by decreasing the demand for insulin secretion.
Toni I. Pollin, Simeon I. Taylor
The genetic factors that determine a patient’s risk for developing the acute respiratory distress syndrome (ARDS) remain understudied. In this issue of the JCI, Reilly and colleagues analyzed three cohorts of critically-ill patients and observed an association between the ABO allele A1 and the onset of moderate-severe ARDS. This association was most notable in patients with non-pulmonary sepsis (an indirect, vascular-targeted mechanism of lung injury) and persisted in patients who lacked epithelial expression of the A antigen, suggesting an endothelial mechanism of A1-associated ARDS susceptibility. Critically-ill patients with blood type A had increased circulating concentrations of endothelial-derived glycoproteins von Willebrand Factor and soluble thrombomodulin, and marginal lungs from blood type A donors were less likely to recover function during ex vivo perfusion. These findings implicate A antigen glycosylation of endothelial cells as a critical, genetically-determined risk factor for indirect lung injury that may contribute to the mechanistic heterogeneity of ARDS.
Alicia N. Rizzo, Eric P. Schmidt
Ongoing observational clinical research has prioritized understanding the human immune response to the SARS-CoV-2 during the COVID-19 pandemic. Several recent studies suggest that immune dysregulation with early and prolonged adaptive immune system activation can result in cellular exhaustion. In this issue of the JCI, Files et al. compared cellular immune phenotypes during the first two months of COVID-19 in hospitalized and less severe, non-hospitalized patients. The authors utilized flow cytometry to analyze circulating peripheral blood mononuclear cells. Both patient-cohorts maintained B and T cell phenotypes consistent with activation and cellular exhaustion throughout the first two months of infection. Additionally, follow-up samples from the non-hospitalized patient cohort showed that activation markers and cellular exhaustion increased over time. These findings illustrate the persistent nature of the adaptive immune system changes that have been noted in COVID-19 and suggest longer-term effects that may shape the maintenance of immunity to SARS-CoV-2.
Philip A. Mudd, Kenneth E. Remy
Useful animal models of disease in neuroscience can make accurate predictions about a therapeutic outcome, a feature known as predictive validity. In this issue of the JCI, Knowland et al. provide an improved model to assess nicotinic acetylcholine receptor (nAChR) ligands for treating chronic pain. The authors identify two proteins, the voltage-dependent calcium channel auxiliary subunit BARP and the unfolded protein response sensor IRE1α, that are required for robust heterologous expression of α6β4, an nAChR subtype in dorsal root ganglia (DRG). This nAChR is a candidate for the analgesic effects of nicotine as well as the frog toxin epibatidine. Now researchers can efficiently screen for α6β4 nAChR–selective agonists using heterologous expression systems. Candidates that emerge will enable researchers to test the predictive validity of mouse models for chronic pain in the nAChR context. If all these steps work, one can envision a class of non-opioid nAChR-targeted analgesics for chronic pain.
Stephen Grant, Henry A. Lester
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