HIV latently infects T cells, and the survival and continued division of these cells constitute the major barrier to an HIV cure, necessitating lifelong treatment. To determine whether interactions with specific antigens affects the expansion of HIV-infected T cell populations, Francesco Simonetti and colleagues investigated antigen responses in T cells isolated from HIV-infected individuals on antiretroviral therapy. Their findings indicate that antigen-driven clonal selection contributes to HIV persistence, which has important consequences for HIV cure strategies that aim to activate the latent reservoir. The cover schematic depicts proliferation of antigen-responsive HIV-infected T cells. Image credit: David Rini; reproduced with permission from Johns Hopkins University.
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Monogenic diabetes refers to diabetes mellitus (DM) caused by a mutation in a single gene and accounts for approximately 1%–5% of diabetes. Correct diagnosis is clinically critical for certain types of monogenic diabetes, since the appropriate treatment is determined by the etiology of the disease (e.g., oral sulfonylurea treatment of HNF1A/HNF4A-diabetes vs. insulin injections in type 1 diabetes). However, achieving a correct diagnosis requires genetic testing, and the overlapping of the clinical features of monogenic diabetes with those of type 1 and type 2 diabetes has frequently led to misdiagnosis. Improvements in sequencing technology are increasing opportunities to diagnose monogenic diabetes, but challenges remain. In this Review, we describe the types of monogenic diabetes, including common and uncommon types of maturity-onset diabetes of the young, multiple causes of neonatal DM, and syndromic diabetes such as Wolfram syndrome and lipodystrophy. We also review methods of prioritizing patients undergoing genetic testing, and highlight existing challenges facing sequence data interpretation that can be addressed by forming collaborations of expertise and by pooling cases.
Haichen Zhang, Kevin Colclough, Anna L. Gloyn, Toni I. Pollin
Humans have been infected with Mycobacterium tuberculosis (Mtb) for thousands of years. While tuberculosis (TB), one of the deadliest infectious diseases, is caused by uncontrolled Mtb infection, over 90% of presumed infected individuals remain asymptomatic and contain Mtb in a latent TB infection (LTBI) without ever developing disease, and some may clear the infection. A small number of heavily Mtb-exposed individuals appear to resist developing traditional LTBI. Because Mtb has mechanisms for intracellular survival and immune evasion, successful control involves all of the arms of the immune system. Here, we focus on immune responses to Mtb in humans and nonhuman primates and discuss new concepts and outline major knowledge gaps in our understanding of LTBI, ranging from the earliest events of exposure and infection to success or failure of Mtb control.
W. Henry Boom, Ulrich E. Schaible, Jacqueline M. Achkar
Since the COVID-19 pandemic swept across the globe, researchers have been trying to understand its origin, life cycle, and pathogenesis. There is a striking variability in the phenotypic response to infection with SARS-CoV-2 that may reflect differences in host genetics and/or immune response. It is known that the human epigenome is influenced by ethnicity, age, lifestyle, and environmental factors, including previous viral infections. This Review examines the influence of viruses on the host epigenome. We describe general lessons and methodologies that can be used to understand how the virus evades the host immune response. We consider how variation in the epigenome may contribute to heterogeneity in the response to SARS-CoV-2 and may identify a precision medicine approach to treatment.
Elizabeth J. Hennessy, Garret A. FitzGerald
The etiopathogenesis of systemic lupus erythematosus (SLE), a clinically heterogeneous multisystemic syndrome that derives its name from the initial characterization of facial lesions that resemble the bite of a wolf, is considered a complex, multifactorial interplay between underlying genetic susceptibility factors and the environment. Prominent pathogenic factors include the induction of aberrant cell death pathways coupled with defective cell death clearance mechanisms that promote excessive externalization of modified cellular and nuclear debris with subsequent loss of tolerance to a wide variety of autoantigens and innate and adaptive immune dysregulation. While abnormalities in adaptive immunity are well recognized and are key to the pathogenesis of SLE, recent findings have emphasized fundamental roles of the innate immune system in the initiation and propagation of autoimmunity and the development of organ damage in this disease. This Review focuses on recent discoveries regarding the role of components of the innate immune system, specifically neutrophils and interferons, in promoting various aspects of lupus pathogenesis, with potential implications for novel therapeutic strategies.
Sarthak Gupta, Mariana J. Kaplan
Following type 1 diabetes (T1D) diagnosis, declining C-peptide levels reflect deteriorating β cell function. However, the precise C-peptide levels that indicate protection from severe hypoglycemia remain unknown. In this issue of the JCI, Gubitosi-Klug et al. studied participants from the landmark and ongoing Diabetes Control and Complications Trial (DCCT) and the Epidemiology of Diabetes Interventions and Complications (EDIC) study that had long-standing (about 35 years) T1D. The authors correlated severe hypoglycemia and other disease outcomes with residual C-peptide levels. While C-peptide secretion failed to associate with hemoglobin A1c (HbA1c) or microvascular complications, C-peptide levels greater than 0.03 nmol/L were linked with fewer episodes of severe hypoglycemia. These findings suggest that efforts to preserve finite β cell function early in T1D can have meaningful, long-standing health benefits for patients.
Anna Lam, Colin Dayan, Kevan C. Herold
Due to progressive inflammation, chronic pancreatitis destroys both the exocrine and endocrine pancreas and sensitizes pancreatic nerves, leading to unremitting pain. Unfortunately, there are no treatments for pancreatic inflammation and approaches to ameliorate pain are suboptimal. Pancreatic inflammation is particularly problematic because damage to acinar cells causes local release of digestive enzymes, which initiate pancreatic autodigestion. The combination of autodigestion and inflammation is unique to pancreatitis and undoubtedly contributes to the difficulty in devising effective treatments. In this issue of the JCI, Saleh et al. describe a nonsurgical technique to ablate pancreatic acinar cells, thus eliminating the source of digestive enzymes and preventing autodigestion. In mice and a nonhuman primate model, this approach effectively reduced inflammation and pain while preserving islet cell function. These findings support the concept that ongoing acinar cell damage is at the root of chronic pancreatitis and provide a possible strategy for clinical treatment.
Rodger A. Liddle
The mechanism by which only some individuals infected with Mycobacterium tuberculosis develop necrotic granulomas with progressive disease while others form controlled granulomas that contain the infection remains poorly defined. Mice carrying the sst1-suscepible (sst1S) genotype develop necrotic inflammatory lung lesions, similar to human tuberculosis (TB) granulomas, which are linked to macrophage dysfunction, while their congenic counterpart (B6) mice do not. In this study we report that (a) sst1S macrophages developed aberrant, biphasic responses to TNF characterized by superinduction of stress and type I interferon pathways after prolonged TNF stimulation; (b) the late-stage TNF response was driven via a JNK/IFN-β/protein kinase R (PKR) circuit; and (c) induced the integrated stress response (ISR) via PKR-mediated eIF2α phosphorylation and the subsequent hyperinduction of ATF3 and ISR-target genes Chac1, Trib3, and Ddit4. The administration of ISRIB, a small-molecule inhibitor of the ISR, blocked the development of necrosis in lung granulomas of M. tuberculosis–infected sst1S mice and concomitantly reduced the bacterial burden. Hence, induction of the ISR and the locked-in state of escalating stress driven by the type I IFN pathway in sst1S macrophages play a causal role in the development of necrosis in TB granulomas. Interruption of the aberrant stress response with inhibitors such as ISRIB may offer novel host-directed therapy strategies.
Bidisha Bhattacharya, Shiqi Xiao, Sujoy Chatterjee, Michael Urbanowski, Alvaro Ordonez, Elizabeth A. Ihms, Garima Agrahari, Shichun Lun, Robert Berland, Alexander Pichugin, Yuanwei Gao, John Connor, Alexander R. Ivanov, Bo-Shiun Yan, Lester Kobzik, Bang-Bon Koo, Sanjay Jain, William Bishai, Igor Kramnik
Cutaneous T cell lymphoma (CTCL) has a poorly understood etiology and no known cure. Using conditional knockout mice, we found that ablation of the genomic organizer special AT-rich sequence–binding protein 1 (Satb1) caused malignant transformation of mature, skin-homing, Notch-activated CD4+ and CD8+ T cells into progressively fatal lymphoma. Mechanistically, Satb1 restrained Stat5 phosphorylation and the expression of skin-homing chemokine receptors in mature T cells. Notably, methyltransferase-dependent epigenetic repression of SATB1 was universally found in human Sézary syndrome, but not in other peripheral T cell malignancies. H3K27 and H3K9 trimethylation occluded the SATB1 promoter in Sézary cells, while inhibition of SUV39H1/2 methyltransferases (unlike EZH2 inhibition) restored protective SATB1 expression and selectively abrogated the growth of primary Sézary cells more effectively than romidepsin. Therefore, inhibition of methyltransferases that silence SATB1 could address an unmet need for patients with mycosis fungoides/Sézary syndrome, a set of incurable diseases.
Carly M. Harro, Jairo Perez-Sanz, Tara Lee Costich, Kyle K. Payne, Carmen M. Anadon, Ricardo A. Chaurio, Subir Biswas, Gunjan Mandal, Kristen E. Rigolizzo, Kimberly B. Sprenger, Jessica A. Mine, Louise C. Showe, Xiaoqing Yu, Kebin Liu, Paulo C. Rodriguez, Javier Pinilla-Ibarz, Lubomir Sokol, Jose R. Conejo-Garcia
Pulmonary ischemia-reperfusion injury (IRI) is a clinical syndrome of acute lung injury that occurs after lung transplantation or remote organ ischemia. IRI causes early mortality and has no effective therapies. While NK cells are innate lymphocytes capable of recognizing injured cells, their roles in acute lung injury are incompletely understood. Here, we demonstrated that NK cells were increased in frequency and cytotoxicity in 2 different IRI mouse models. We showed that NK cells trafficked to the lung tissue from peripheral reservoirs and were more mature within lung tissue. Acute lung ischemia-reperfusion injury was blunted in a NK cell–deficient mouse strain but restored with adoptive transfer of NK cells. Mechanistically, NK cell NKG2D receptor ligands were induced on lung endothelial and epithelial cells following IRI, and antibody-mediated NK cell depletion or NKG2D stress receptor blockade abrogated acute lung injury. In human lung tissue, NK cells were increased at sites of ischemia-reperfusion injury and activated NK cells were increased in prospectively collected human bronchoalveolar lavage in subjects with severe IRI. These data support a causal role for recipient peripheral NK cells in pulmonary IRI via NK cell NKG2D receptor ligation. Therapies targeting NK cells may hold promise in acute lung injury.
Daniel R. Calabrese, Emily Aminian, Benat Mallavia, Fengchun Liu, Simon J. Cleary, Oscar A. Aguilar, Ping Wang, Jonathan P. Singer, Steven R. Hays, Jeffrey A. Golden, Jasleen Kukreja, Daniel Dugger, Mary Nakamura, Lewis L. Lanier, Mark R. Looney, John R. Greenland
Novel approaches are needed to boost the efficacy of immune checkpoint blockade (ICB) therapy. Ataxia telangiectasia mutated (ATM) protein plays a central role in sensing DNA double-stranded breaks (DSBs) and coordinating their repair. Recent data indicated that ATM might be a promising target to enhance ICB therapy. However, the molecular mechanism involved has not been clearly elucidated. Here, we show that ATM inhibition could potentiate ICB therapy by promoting cytoplasmic leakage of mitochondrial DNA (mtDNA) and activation of the cGAS/STING pathway. We show that genetic depletion of ATM in murine cancer cells delayed tumor growth in syngeneic mouse hosts in a T cell–dependent manner. Furthermore, chemical inhibition of ATM potentiated anti–PD-1 therapy of mouse tumors. ATM inhibition potently activated the cGAS/STING pathway and enhanced lymphocyte infiltration into the tumor microenvironment by downregulating mitochondrial transcription factor A (TFAM), which led to mtDNA leakage into the cytoplasm. Moreover, our analysis of data from a large patient cohort indicated that ATM mutations, especially nonsense mutations, predicted for clinical benefits of ICB therapy. Our study therefore provides strong evidence that ATM may serve as both a therapeutic target and a biomarker to enable ICB therapy.
Mengjie Hu, Min Zhou, Xuhui Bao, Dong Pan, Meng Jiao, Xinjian Liu, Fang Li, Chuan-Yuan Li
INTRODUCTION Acute kidney injury and chronic kidney disease (CKD) are common in hospitalized patients. To inform clinical decision making, more accurate information regarding risk of long-term progression to kidney failure is required.METHODS We enrolled 1538 hospitalized patients in a multicenter, prospective cohort study. Monocyte chemoattractant protein 1 (MCP-1/CCL2), uromodulin (UMOD), and YKL-40 (CHI3L1) were measured in urine samples collected during outpatient follow-up at 3 months. We followed patients for a median of 4.3 years and assessed the relationship between biomarker levels and changes in estimated glomerular filtration rate (eGFR) over time and the development of a composite kidney outcome (CKD incidence, CKD progression, or end-stage renal disease). We paired these clinical studies with investigations in mouse models of renal atrophy and renal repair to further understand the molecular basis of these markers in kidney disease progression.RESULTS Higher MCP-1 and YKL-40 levels were associated with greater eGFR decline and increased incidence of the composite renal outcome, whereas higher UMOD levels were associated with smaller eGFR declines and decreased incidence of the composite kidney outcome. A multimarker score increased prognostic accuracy and reclassification compared with traditional clinical variables alone. The mouse model of renal atrophy showed greater Ccl2 and Chi3l1 mRNA expression in infiltrating macrophages and neutrophils, respectively, and evidence of progressive renal fibrosis compared with the repair model. The repair model showed greater Umod expression in the loop of Henle and correspondingly less fibrosis.CONCLUSIONS Biomarker levels at 3 months after hospitalization identify patients at risk for kidney disease progression.FUNDING NIH.
Jeremy Puthumana, Heather Thiessen-Philbrook, Leyuan Xu, Steven G. Coca, Amit X. Garg, Jonathan Himmelfarb, Pavan K. Bhatraju, T. Alp Ikizler, Edward D. Siew, Lorraine B. Ware, Kathleen D. Liu, Alan S. Go, James S. Kaufman, Paul L. Kimmel, Vernon M. Chinchilli, Lloyd G. Cantley, Chirag R. Parikh
Germline mutations in BRCA1 and BRCA2 (BRCA1/2) genes considerably increase breast and ovarian cancer risk. Given that tumors with these mutations have elevated genomic instability, they exhibit relative vulnerability to certain chemotherapies and targeted treatments based on poly (ADP-ribose) polymerase (PARP) inhibition. However, the molecular mechanisms that influence cancer risk and therapeutic benefit or resistance remain only partially understood. BRCA1 and BRCA2 have also been implicated in the suppression of R-loops, triple-stranded nucleic acid structures composed of a DNA:RNA hybrid and a displaced ssDNA strand. Here, we report that loss of RNF168, an E3 ubiquitin ligase and DNA double-strand break (DSB) responder, remarkably protected Brca1-mutant mice against mammary tumorigenesis. We demonstrate that RNF168 deficiency resulted in accumulation of R-loops in BRCA1/2-mutant breast and ovarian cancer cells, leading to DSBs, senescence, and subsequent cell death. Using interactome assays, we identified RNF168 interaction with DHX9, a helicase involved in the resolution and removal of R-loops. Mechanistically, RNF168 directly ubiquitylated DHX9 to facilitate its recruitment to R-loop–prone genomic loci. Consequently, loss of RNF168 impaired DHX9 recruitment to R-loops, thereby abrogating its ability to resolve R-loops. The data presented in this study highlight a dependence of BRCA1/2-defective tumors on factors that suppress R-loops and reveal a fundamental RNF168-mediated molecular mechanism that governs cancer development and vulnerability.
Parasvi S. Patel, Karan Joshua Abraham, Kiran Kumar Naidu Guturi, Marie-Jo Halaby, Zahra Khan, Luis Palomero, Brandon Ho, Shili Duan, Jonathan St-Germain, Arash Algouneh, Francesca Mateo, Samah El Ghamrasni, Haithem Barbour, Daniel R. Barnes, Jonathan Beesley, Otto Sanchez, Hal K. Berman, Grant W. Brown, El Bachir Affar, Georgia Chenevix-Trench, Antonis C. Antoniou, Cheryl H. Arrowsmith, Brian Raught, Miquel Angel Pujana, Karim Mekhail, Anne Hakem, Razqallah Hakem
The development of ascites correlates with advanced stage disease and poor prognosis in ovarian cancer. Vascular permeability is the key pathophysiological change involved in ascites development. Previously, we provided evidence that perivascular M2-like macrophages protect the vascular barrier through direct contact with endothelial cells (ECs). Here, we investigated the molecular mechanism and its clinical significance in the ovarian cancer setting. We found that upon direct coculture with the endothelium, M2 macrophages tuned down their VLA4 and reduced the levels of VCAM1 in ECs. On the other hand, ectopically overexpressing VLA4 in macrophages or VCAM1 in ECs induced hyperpermeability. Mechanistically, downregulation of VLA4 or VCAM1 led to reduced levels of RAC1 and ROS, which resulted in decreased phosphorylation of PYK2 (p-PYK2) and VE-cadherin (p–VE-cad), hence enhancing cell adhesion. Furthermore, targeting the VLA4/VCAM1 axis augmented vascular integrity and abrogated ascites formation in vivo. Finally, VLA4 expression on the macrophages isolated from ascites dictated permeability ex vivo. Importantly, VLA4 antibody acted synergistically with bevacizumab to further enhance the vascular barrier. Taking these data together, we reveal here that M2 macrophages regulate the vascular barrier though the VCAM1/RAC1/ROS/p-PYK2/p–VE-cad cascade, which provides specific therapeutic targets for the treatment of malignant ascites.
Shibo Zhang, Bingfan Xie, Lijie Wang, Hua Yang, Haopei Zhang, Yuming Chen, Feng Wang, Changqing Liu, Huanhuan He
The coat protein I (COPI) complex mediates retrograde trafficking from the Golgi to the endoplasmic reticulum (ER). Five siblings with persistent bacterial and viral infections and defective humoral and cellular immunity had a homozygous p.K652E mutation in the γ1 subunit of COPI (γ1-COP). The mutation disrupts COPI binding to the KDEL receptor and impairs the retrieval of KDEL-bearing chaperones from the Golgi to the ER. Homozygous Copg1K652E mice had increased ER stress in activated T and B cells, poor antibody responses, and normal numbers of T cells that proliferated normally, but underwent increased apoptosis upon activation. Exposure of the mutants to pet store mice caused weight loss, lymphopenia, and defective T cell proliferation that recapitulated the findings in the patients. The ER stress-relieving agent tauroursodeoxycholic acid corrected the immune defects of the mutants and reversed the phenotype they acquired following exposure to pet store mice. This study establishes the role of γ1-COP in the ER retrieval of KDEL-bearing chaperones and thereby the importance of ER homeostasis in adaptive immunity.
Wayne Bainter, Craig D. Platt, Seung-Yeol Park, Kelsey Stafstrom, Jacqueline G. Wallace, Zachary T. Peters, Michel J. Massaad, Michel Becuwe, Sandra Andrea Salinas, Jennifer Jones, Sarah Beaussant-Cohen, Faris Jaber, Jia-Shu Yang, Tobias C. Walther, Jordan S. Orange, Chitong Rao, Seth Rakoff-Nahoum, Maria Tsokos, Shafiq Ur Rehman Naseem, Salem Al-Tamemi, Janet Chou, Victor W. Hsu, Raif S. Geha
Neutrophil infiltration around lipotoxic hepatocytes is a hallmark of nonalcoholic steatohepatitis (NASH); however, how these 2 types of cells communicate remains obscure. We have previously demonstrated that neutrophil-specific microRNA-223 (miR-223) is elevated in hepatocytes to limit NASH progression in obese mice. Here, we demonstrated that this elevation of miR-223 in hepatocytes was due to preferential uptake of miR-223–enriched extracellular vesicles (EVs) derived from neutrophils as well other types of cells, albeit to a lesser extent. This selective uptake was dependent on the expression of low-density lipoprotein receptor (LDLR) on hepatocytes and apolipoprotein E (APOE) on neutrophil-derived EVs, which was enhanced by free fatty acids. Once internalized by hepatocytes, the EV-derived miR-223 acted to inhibit hepatic inflammatory and fibrogenic gene expression. In the absence of this LDLR- and APOE-dependent uptake of miR-223–enriched EVs, the progression of steatosis to NASH was accelerated. In contrast, augmentation of this transfer by treatment with an inhibitor of proprotein convertase subtilisin/kexin type 9, a drug used to lower blood cholesterol by upregulating LDLR, ameliorated NASH in mice. This specific role of LDLR and APOE in the selective control of miR-223–enriched EV transfer from neutrophils to hepatocytes may serve as a potential therapeutic target for NASH.
Yong He, Robim M. Rodrigues, Xiaolin Wang, Wonhyo Seo, Jing Ma, Seonghwan Hwang, Yaojie Fu, Eszter Trojnár, Csaba Mátyás, Suxian Zhao, Ruixue Ren, Dechun Feng, Pal Pacher, George Kunos, Bin Gao
Inborn errors of immunity cause monogenic immune dysregulatory conditions such as severe and recurrent pathogen infection, inflammation, allergy, and malignancy. Somatic reversion refers to the spontaneous repair of a pathogenic germline genetic variant and has been reported to occur in a number of inborn errors of immunity, with a range of impacts on clinical outcomes of these conditions. DOCK8 deficiency due to biallelic inactivating mutations in DOCK8 causes a combined immunodeficiency characterized by severe bacterial, viral, and fungal infections, as well as allergic disease and some cancers. Here, we describe the clinical, genetic, and cellular features of 3 patients with biallelic DOCK8 variants who, following somatic reversion in multiple lymphocyte subsets, exhibited improved clinical features, including complete resolution of infection and allergic disease, and cure over time. Acquisition of DOCK8 expression restored defective lymphocyte signalling, survival and proliferation, as well as CD8+ T cell cytotoxicity, CD4+ T cell cytokine production, and memory B cell generation compared with typical DOCK8-deficient patients. Our temporal analysis of DOCK8-revertant and DOCK8-deficient cells within the same individual established mechanisms of clinical improvement in these patients following somatic reversion and revealed further nonredundant functions of DOCK8 in human lymphocyte biology. Last, our findings have significant implications for future therapeutic options for the treatment of DOCK8 deficiency.
Bethany A. Pillay, Mathieu Fusaro, Paul E. Gray, Aaron L. Statham, Leslie Burnett, Liliana Bezrodnik, Alisa Kane, Winnie Tong, Chrystelle Abdo, Sarah Winter, Samuel Chevalier, Romain Levy, Cécile Masson, Yohann Schmitt, Christine Bole, Marion Malphettes, Elizabeth Macintyre, Jean-Pierre De Villartay, John B. Ziegler, Joanne M. Smart, Jane Peake, Asghar Aghamohammadi, Lennart Hammarström, Hassan Abolhassani, Capucine Picard, Alain Fischer, Sylvain Latour, Benedicte Neven, Stuart G. Tangye, Cindy S. Ma
Identification of neoepitopes that are effective in cancer therapy is a major challenge in creating cancer vaccines. Here, using an entirely unbiased approach, we queried all possible neoepitopes in a mouse cancer model and asked which of those are effective in mediating tumor rejection and, independently, in eliciting a measurable CD8 response. This analysis uncovered a large trove of effective anticancer neoepitopes that have strikingly different properties from conventional epitopes and suggested an algorithm to predict them. It also revealed that our current methods of prediction discard the overwhelming majority of true anticancer neoepitopes. These results from a single mouse model were validated in another antigenically distinct mouse cancer model and are consistent with data reported in human studies. Structural modeling showed how the MHC I–presented neoepitopes had an altered conformation, higher stability, or increased exposure to T cell receptors as compared with the unmutated counterparts. T cells elicited by the active neoepitopes identified here demonstrated a stem-like early dysfunctional phenotype associated with effective responses against viruses and tumors of transgenic mice. These abundant anticancer neoepitopes, which have not been tested in human studies thus far, can be exploited for generation of personalized human cancer vaccines.
Cory A. Brennick, Mariam M. George, Marmar M. Moussa, Adam T. Hagymasi, Sahar Al Seesi, Tatiana V. Shcheglova, Ryan P. Englander, Grant L.J. Keller, Jeremy L. Balsbaugh, Brian M. Baker, Andrea Schietinger, Ion I. Mandoiu, Pramod K. Srivastava
BACKGROUND We investigated residual β cell function in Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) study participants with an average 35-year duration of type 1 diabetes mellitus (T1DM).METHODS Serum C-peptide was measured during a 4-hour mixed-meal tolerance test. Associations with metabolic outcomes and complications were explored among nonresponders (all C-peptide values after meal <0.003 nmol/L) and 3 categories of responders, classified by peak C-peptide concentration (nmol/L) as high (>0.2), intermediate (>0.03 to ≤0.2), and low (≥ 0.003 to ≤0.03).RESULTS Of the 944 participants, 117 (12.4%) were classified as responders. Residual C-peptide concentrations were associated with higher DCCT baseline concentrations of stimulated C-peptide (P value for trend = 0.0001). Residual C-peptide secretion was not associated with current or mean HbA1c, HLA high-risk haplotypes for T1DM, or the current presence of T1DM autoantibodies. The proportion of subjects with a history of severe hypoglycemia was lower with high (27%) and intermediate (48%) residual C-peptide concentrations than with low (74%) and no (70%) residual C-peptide concentrations (P value for trend = 0.0001). Responders and nonresponders demonstrated similar rates of advanced microvascular complications.CONCLUSION β Cell function can persist in long-duration T1DM. With a peak C-peptide concentration of >0.03 nmol/L, we observed clinically meaningful reductions in the prevalence of severe hypoglycemia.TRIAL REGISTRATION ClinicalTrials.gov NCT00360815 and NCT00360893.FUNDING Division of Diabetes Endocrinology and Metabolic Diseases of the National Institute of Diabetes and Digestive and Kidney Diseases (DP3-DK104438, U01 DK094176, and U01 DK094157).
Rose A. Gubitosi-Klug, Barbara H. Braffett, Susan Hitt, Valerie Arends, Diane Uschner, Kimberly Jones, Lisa Diminick, Amy B. Karger, Andrew D. Paterson, Delnaz Roshandel, Santica Marcovina, John M. Lachin, Michael Steffes, Jerry P. Palmer, the DCCT/EDIC Research Group
Chronic pancreatitis affects over 250,000 people in the US and millions worldwide. It is associated with chronic debilitating pain, pancreatic exocrine failure, and high risk of pancreatic cancer and usually progresses to diabetes. Treatment options are limited and ineffective. We developed a new potential therapy, wherein a pancreatic ductal infusion of 1%–2% acetic acid in mice and nonhuman primates resulted in a nonregenerative, near-complete ablation of the exocrine pancreas, with complete preservation of the islets. Pancreatic ductal infusion of acetic acid in a mouse model of chronic pancreatitis led to resolution of chronic inflammation and pancreatitis-associated pain. Furthermore, acetic acid–treated animals showed improved glucose tolerance and insulin secretion. The loss of exocrine tissue in this procedure would not typically require further management in patients with chronic pancreatitis because they usually have pancreatic exocrine failure requiring dietary enzyme supplements. Thus, this procedure, which should be readily translatable to humans through an endoscopic retrograde cholangiopancreatography (ERCP), may offer a potential innovative nonsurgical therapy for chronic pancreatitis that relieves pain and prevents the progression of pancreatic diabetes.
Mohamed Saleh, Kartikeya Sharma, Ranjeet Kalsi, Joseph Fusco, Anuradha Sehrawat, Jami L. Saloman, Ping Guo, Ting Zhang, Nada Mohamed, Yan Wang, Krishna Prasadan, George K. Gittes
BACKGROUND Despite a rapidly growing body of literature on coronavirus disease 2019 (COVID-19), our understanding of the immune correlates of disease severity, course, and outcome remains poor.METHODS Using mass cytometry, we assessed the immune landscape in longitudinal whole-blood specimens from 59 patients presenting with acute COVID-19 and classified based on maximal disease severity. Hospitalized patients negative for SARS-CoV-2 were used as controls.RESULTS We found that the immune landscape in COVID-19 formed 3 dominant clusters, which correlated with disease severity. Longitudinal analysis identified a pattern of productive innate and adaptive immune responses in individuals who had a moderate disease course, whereas those with severe disease had features suggestive of a protracted and dysregulated immune response. Further, we identified coordinate immune alterations accompanying clinical improvement and decline that were also seen in patients who received IL-6 pathway blockade.CONCLUSION The hospitalized COVID-19 negative cohort allowed us to identify immune alterations that were shared between severe COVID-19 and other critically ill patients. Collectively, our findings indicate that selection of immune interventions should be based in part on disease presentation and early disease trajectory due to the profound differences in the immune response in those with mild to moderate disease and those with the most severe disease.FUNDING Benaroya Family Foundation, the Leonard and Norma Klorfine Foundation, Glenn and Mary Lynn Mounger, and the National Institutes of Health.
Hamid Bolouri, Cate Speake, David Skibinski, S. Alice Long, Anne M. Hocking, Daniel J. Campbell, Jessica A. Hamerman, Uma Malhotra, Jane H. Buckner, the Benaroya Research Institute COVID-19 Research Team
Propranolol, a pleiotropic β-adrenergic blocker, has been anecdotally reported to reduce cerebral cavernous malformations (CCMs) in humans. However, propranolol has not been rigorously evaluated in animal models, nor has its mechanism of action in CCM been defined. We report that propranolol or its S(-) enantiomer dramatically reduced embryonic venous cavernomas in ccm2 mosaic zebrafish, whereas R-(+)-propranolol, lacking β antagonism, had no effect. Silencing of the β1, but not β2, adrenergic receptor mimicked the beneficial effects of propranolol in a zebrafish CCM model, as did the β1-selective antagonist metoprolol. Thus, propranolol ameliorated cavernous malformations by β1 adrenergic antagonism in zebrafish. Oral propranolol significantly reduced lesion burden in 2 chronic murine models of the exceptionally aggressive Pdcd10/Ccm3 form of CCM. Propranolol or other β1-selective antagonists may be beneficial in CCM disease.
Wenqing Li, Robert Shenkar, Mathew R. Detter, Thomas Moore, Christian Benavides, Rhonda Lightle, Romuald Girard, Nicholas Hobson, Ying Cao, Yan Li, Erin Griffin, Carol Gallione, Joseph M. Zabramski, Mark H. Ginsberg, Douglas A. Marchuk, Issam A. Awad
BACKGROUND SARS-CoV-2–specific antibodies may protect from reinfection and disease, providing rationale for administration of plasma containing SARS-CoV-2–neutralizing antibodies (nAbs) as a treatment for COVID-19. Clinical factors and laboratory assays to streamline plasma donor selection, and the durability of nAb responses, are incompletely understood.METHODS Potential convalescent plasma donors with virologically documented SARS-CoV-2 infection were tested for serum IgG against SARS-CoV-2 spike protein S1 domain and against nucleoprotein (NP), and for nAb.RESULTS Among 250 consecutive persons, including 27 (11%) requiring hospitalization, who were studied a median of 67 days since symptom onset, 97% were seropositive on 1 or more assays. Sixty percent of donors had nAb titers ≥1:80. Correlates of higher nAb titers included older age (adjusted OR [AOR] 1.03 per year of age, 95% CI 1.00–1.06), male sex (AOR 2.08, 95% CI 1.13–3.82), fever during illness (AOR 2.73, 95% CI 1.25–5.97), and disease severity represented by hospitalization (AOR 6.59, 95% CI 1.32–32.96). Receiver operating characteristic analyses of anti-S1 and anti-NP antibody results yielded cutoffs that corresponded well with nAb titers, with the anti-S1 assay being slightly more predictive. nAb titers declined in 37 of 41 paired specimens collected a median of 98 days (range 77–120) apart (P < 0.001). Seven individuals (2.8%) were persistently seronegative and lacked T cell responses.CONCLUSION nAb titers correlated with COVID-19 severity, age, and sex. SARS-CoV-2 IgG results can serve as useful surrogates for nAb testing. Functional nAb levels declined, and a small proportion of convalescent individuals lacked adaptive immune responses.FUNDING The project was supported by the Frederick National Laboratory for Cancer Research with support from the NIAID under contract number 75N91019D00024, and was supported by the Fred Hutchinson Joel Meyers Endowment, Fast-Grants, a New Investigator award from the American Society for Transplantation and Cellular Therapy, and NIH contracts 75N93019C0063, 75N91019D00024, and HHSN272201800013C, and NIH grants T32-AI118690, T32-AI007044, K08-AI119142, and K23-AI140918.
Jim Boonyaratanakornkit, Chihiro Morishima, Stacy Selke, Danniel Zamora, Sarah McGuffin, Adrienne E. Shapiro, Victoria L. Campbell, Christopher L. McClurkan, Lichen Jing, Robin Gross, Janie Liang, Elena Postnikova, Steven Mazur, Vladimir V. Lukin, Anu Chaudhary, Marie K. Das, Susan L. Fink, Andrew Bryan, Alex L. Greninger, Keith R. Jerome, Michael R. Holbrook, Terry B. Gernsheimer, Mark H. Wener, Anna Wald, David M. Koelle
Clonal expansion of infected CD4+ T cells is a major mechanism of HIV-1 persistence and a barrier to achieving a cure. Potential causes are homeostatic proliferation, effects of HIV-1 integration, and interaction with antigens. Here, we show that it is possible to link antigen responsiveness, the full proviral sequence, the integration site, and the T cell receptor β-chain (TCRβ) sequence to examine the role of recurrent antigenic exposure in maintaining the HIV-1 reservoir. We isolated CMV- and Gag-responding CD4+ T cells from 10 treated individuals. Proviral populations in CMV-responding cells were dominated by large clones, including clones harboring replication-competent proviruses. TCRβ repertoires showed high clonality driven by converging adaptive responses. Although some proviruses were in genes linked to HIV-1 persistence (BACH2, STAT5B, MKL1), the proliferation of infected cells under antigenic stimulation occurred regardless of the site of integration. Paired TCRβ and integration site analysis showed that infection could occur early or late in the course of a clone’s response to antigen and could generate infected cell populations too large to be explained solely by homeostatic proliferation. Together, these findings implicate antigen-driven clonal selection as a major factor in HIV-1 persistence, a finding that will be a difficult challenge to eradication efforts.
Francesco R. Simonetti, Hao Zhang, Garshasb P. Soroosh, Jiayi Duan, Kyle Rhodehouse, Alison L. Hill, Subul A. Beg, Kevin McCormick, Hayley E. Raymond, Christopher L. Nobles, John K. Everett, Kyungyoon J. Kwon, Jennifer A. White, Jun Lai, Joseph B. Margolick, Rebecca Hoh, Steven G. Deeks, Frederic D. Bushman, Janet D. Siliciano, Robert F. Siliciano