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Review

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The intersection of COVID-19 and autoimmunity
Jason S. Knight, … , Julia Y. Wang, W. Joseph McCune
Jason S. Knight, … , Julia Y. Wang, W. Joseph McCune
Published October 28, 2021
Citation Information: J Clin Invest. 2021. https://doi.org/10.1172/JCI154886.
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The intersection of COVID-19 and autoimmunity

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Abstract

Acute coronavirus disease 2019 (COVID-19), caused by SARS-CoV-2, is characterized by diverse clinical presentations, ranging from asymptomatic infection to fatal respiratory failure, and often associated with varied longer-term sequelae. Over the past 18 months, it has become apparent that inappropriate immune responses contribute to the pathogenesis of severe COVID-19. Researchers working at the intersection of COVID-19 and autoimmunity recently gathered at an American Autoimmune Related Disease Association (AARDA) Noel R. Rose Colloquium to address the current state of knowledge regarding two important questions: Does established autoimmunity predispose to severe COVID-19? And, at the same time, can SARS-CoV-2 infection trigger de novo autoimmunity? Indeed, work to date has demonstrated that 10 to 15% of patients with critical COVID-19 pneumonia exhibit autoantibodies against type I interferons, suggesting that preexisting autoimmunity underlies severe disease in some patients. Other studies have identified functional autoantibodies following infection with SARS-CoV-2, such as those that promote thrombosis or antagonize cytokine signaling. These autoantibodies may arise from a predominantly extrafollicular B cell response that is more prone to generating autoantibody-secreting B cells. This review highlights the current understanding, evolving concepts, and unanswered questions provided by this unique opportunity to determine mechanisms by which a viral infection can be exacerbated by, and even trigger, autoimmunity. The potential role of autoimmunity in post-acute sequelae of COVID-19 is also discussed.

Authors

Jason S. Knight, Roberto Caricchio, Jean Laurent Casanova, Alexis J. Combes, Betty Diamond, Sharon E. Fox, David A. Hanauer, Judith A. James, Yogendra Kanthi, Virginia Ladd, Puja Mehta, Aaron M. Ring, Ignacio Sanz, Carlo Selmi, Russell P. Tracy, Paul J. Utz, Catriona A. Wagner, Julia Y. Wang, W. Joseph McCune

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Fibroblast pathology in inflammatory diseases
Kevin Wei, … , Hung N. Nguyen, Michael B. Brenner
Kevin Wei, … , Hung N. Nguyen, Michael B. Brenner
Published October 15, 2021
Citation Information: J Clin Invest. 2021;131(20):e149538. https://doi.org/10.1172/JCI149538.
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Fibroblast pathology in inflammatory diseases

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Abstract

Fibroblasts are important cells for the support of homeostatic tissue function. In inflammatory diseases such as rheumatoid arthritis and inflammatory bowel disease, fibroblasts take on different roles (a) as inflammatory cells themselves and (b) in recruiting leukocytes, driving angiogenesis, and enabling chronic inflammation in tissues. Recent advances in single-cell profiling techniques have transformed the ability to examine fibroblast states and populations in inflamed tissues, providing evidence of previously underappreciated heterogeneity and disease-associated fibroblast populations. These studies challenge the preconceived notion that fibroblasts are homogeneous and provide new insights into the role of fibroblasts in inflammatory pathology. In addition, new molecular insights into the mechanisms of fibroblast activation reveal powerful cell-intrinsic amplification loops that synergize with primary fibroblast stimuli to result in striking responses. In this Review, we focus on recent developments in our understanding of fibroblast heterogeneity and fibroblast pathology across tissues and diseases in rheumatoid arthritis and inflammatory bowel diseases. We highlight new approaches to, and applications of, single-cell profiling techniques and what they teach us about fibroblast biology. Finally, we address how these insights could lead to the development of novel therapeutic approaches to targeting fibroblasts in disease.

Authors

Kevin Wei, Hung N. Nguyen, Michael B. Brenner

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RNA-binding proteins of COSMIC importance in cancer
Peter S. Choi, Andrei Thomas-Tikhonenko
Peter S. Choi, Andrei Thomas-Tikhonenko
Published September 15, 2021
Citation Information: J Clin Invest. 2021;131(18):e151627. https://doi.org/10.1172/JCI151627.
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RNA-binding proteins of COSMIC importance in cancer

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Abstract

Herculean efforts by the Wellcome Sanger Institute, the National Cancer Institute, and the National Human Genome Research Institute to sequence thousands of tumors representing all major cancer types have yielded more than 700 genes that contribute to neoplastic growth when mutated, amplified, or deleted. While some of these genes (now included in the COSMIC Cancer Gene Census) encode proteins previously identified in hypothesis-driven experiments (oncogenic transcription factors, protein kinases, etc.), additional classes of cancer drivers have emerged, perhaps none more surprisingly than RNA-binding proteins (RBPs). Over 40 RBPs responsible for virtually all aspects of RNA metabolism, from synthesis to degradation, are recurrently mutated in cancer, and just over a dozen are considered major cancer drivers. This Review investigates whether and how their RNA-binding activities pertain to their oncogenic functions. Focusing on several well-characterized steps in RNA metabolism, we demonstrate that for virtually all cancer-driving RBPs, RNA processing activities are either abolished (the loss-of-function phenotype) or carried out with low fidelity (the LoFi phenotype). Conceptually, this suggests that in normal cells, RBPs act as gatekeepers maintaining proper RNA metabolism and the “balanced” proteome. From the practical standpoint, at least some LoFi phenotypes create therapeutic vulnerabilities, which are beginning to be exploited in the clinic.

Authors

Peter S. Choi, Andrei Thomas-Tikhonenko

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HIF in the heart: development, metabolism, ischemia, and atherosclerosis
Andrew Kekūpaʻa Knutson, … , William A. Boisvert, Ralph V. Shohet
Andrew Kekūpaʻa Knutson, … , William A. Boisvert, Ralph V. Shohet
Published September 1, 2021
Citation Information: J Clin Invest. 2021;131(17):e137557. https://doi.org/10.1172/JCI137557.
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HIF in the heart: development, metabolism, ischemia, and atherosclerosis

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Abstract

The heart forms early in development and delivers oxygenated blood to the rest of the embryo. After birth, the heart requires kilograms of ATP each day to support contractility for the circulation. Cardiac metabolism is omnivorous, utilizing multiple substrates and metabolic pathways to produce this energy. Cardiac development, metabolic tuning, and the response to ischemia are all regulated in part by the hypoxia-inducible factors (HIFs), central components of essential signaling pathways that respond to hypoxia. Here we review the actions of HIF1, HIF2, and HIF3 in the heart, from their roles in development and metabolism to their activity in regeneration and preconditioning strategies. We also discuss recent work on the role of HIFs in atherosclerosis, the precipitating cause of myocardial ischemia and the leading cause of death in the developed world.

Authors

Andrew Kekūpaʻa Knutson, Allison L. Williams, William A. Boisvert, Ralph V. Shohet

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Therapeutic targeting of BAG3: considering its complexity in cancer and heart disease
Jonathan A. Kirk, … , Joseph Y. Cheung, Arthur M. Feldman
Jonathan A. Kirk, … , Joseph Y. Cheung, Arthur M. Feldman
Published August 16, 2021
Citation Information: J Clin Invest. 2021;131(16):e149415. https://doi.org/10.1172/JCI149415.
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Therapeutic targeting of BAG3: considering its complexity in cancer and heart disease

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Abstract

Bcl2-associated athanogene-3 (BAG3) is expressed ubiquitously in humans, but its levels are highest in the heart, the skeletal muscle, and the central nervous system; it is also elevated in many cancers. BAG3’s diverse functions are supported by its multiple protein-protein binding domains, which couple with small and large heat shock proteins, members of the Bcl2 family, other antiapoptotic proteins, and various sarcomere proteins. In the heart, BAG3 inhibits apoptosis, promotes autophagy, couples the β-adrenergic receptor with the L-type Ca2+ channel, and maintains the structure of the sarcomere. In cancer cells, BAG3 binds to and supports an identical array of prosurvival proteins, and it may represent a therapeutic target. However, the development of strategies to block BAG3 function in cancer cells may be challenging, as they are likely to interfere with the essential roles of BAG3 in the heart. In this Review, we present the current knowledge regarding the biology of this complex protein in the heart and in cancer and suggest several therapeutic options.

Authors

Jonathan A. Kirk, Joseph Y. Cheung, Arthur M. Feldman

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The lung microbiome: progress and promise
Samantha A. Whiteside, … , John E. McGinniss, Ronald G. Collman
Samantha A. Whiteside, … , John E. McGinniss, Ronald G. Collman
Published August 2, 2021
Citation Information: J Clin Invest. 2021;131(15):e150473. https://doi.org/10.1172/JCI150473.
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The lung microbiome: progress and promise

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Abstract

The healthy lung was long thought of as sterile, but recent advances using molecular sequencing approaches have detected bacteria at low levels. Healthy lung bacteria largely reflect communities present in the upper respiratory tract that enter the lung via microaspiration, which is balanced by mechanical and immune clearance and likely involves limited local replication. The nature and dynamics of the lung microbiome, therefore, differ from those of ecological niches with robust self-sustaining microbial communities. Aberrant populations (dysbiosis) have been demonstrated in many pulmonary diseases not traditionally considered microbial in origin, and potential pathways of microbe-host crosstalk are emerging. The question now is whether and how dysbiotic microbiota contribute to initiation or perpetuation of injury. The fungal microbiome and virome are less well studied. This Review highlights features of the lung microbiome, unique considerations in studying it, examples of dysbiosis in selected disease, emerging concepts in lung microbiome–host interactions, and critical areas for investigation.

Authors

Samantha A. Whiteside, John E. McGinniss, Ronald G. Collman

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Distinctive features of severe SARS-CoV-2 pneumonia
G.R. Scott Budinger, … , Benjamin D. Singer, Richard G. Wunderink
G.R. Scott Budinger, … , Benjamin D. Singer, Richard G. Wunderink
Published July 15, 2021
Citation Information: J Clin Invest. 2021;131(14):e149412. https://doi.org/10.1172/JCI149412.
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Distinctive features of severe SARS-CoV-2 pneumonia

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Abstract

The coronavirus disease 2019 (COVID-19) pandemic is among the most important public health crises of our generation. Despite the promise of prevention offered by effective vaccines, patients with severe COVID-19 will continue to populate hospitals and intensive care units for the foreseeable future. The most common clinical presentation of severe COVID-19 is hypoxemia and respiratory failure, typical of the acute respiratory distress syndrome (ARDS). Whether the clinical features and pathobiology of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pneumonia differ from those of pneumonia secondary to other pathogens is unclear. This uncertainty has created variability in the application of historically proven therapies for ARDS to patients with COVID-19. We review the available literature and find many similarities between patients with ARDS from pneumonia attributable to SARS-CoV-2 versus other respiratory pathogens. A notable exception is the long duration of illness among patients with COVID-19, which could result from its unique pathobiology. Available data support the use of care pathways and therapies proven effective for patients with ARDS, while pointing to unique features that might be therapeutically targeted for patients with severe SARS-CoV-2 pneumonia.

Authors

G.R. Scott Budinger, Alexander V. Misharin, Karen M. Ridge, Benjamin D. Singer, Richard G. Wunderink

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Meant to B: B cells as a therapeutic target in systemic lupus erythematosus
Yemil Atisha-Fregoso, … , Bahtiyar Toz, Betty Diamond
Yemil Atisha-Fregoso, … , Bahtiyar Toz, Betty Diamond
Published June 15, 2021
Citation Information: J Clin Invest. 2021;131(12):e149095. https://doi.org/10.1172/JCI149095.
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Meant to B: B cells as a therapeutic target in systemic lupus erythematosus

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Abstract

B cells have a prominent role in the pathogenesis of systemic lupus erythematosus (SLE). They are mediators of inflammation through the production of pathogenic antibodies that augment inflammation and cause direct tissue and cell damage. Multiple therapeutic agents targeting B cells have been successfully used in mouse models of SLE; however, these preclinical studies have led to approval of only one new agent to treat patients with SLE: belimumab, a monoclonal antibody targeting B cell–activating factor (BAFF). Integrating the experience acquired from previous clinical trials with the knowledge generated by new studies about mechanisms of B cell contributions to SLE in specific groups of patients is critical to the development of new treatment strategies that will help to improve outcomes in patients with SLE. In particular, a sharper focus on B cell differentiation to plasma cells is warranted.

Authors

Yemil Atisha-Fregoso, Bahtiyar Toz, Betty Diamond

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Insights from integrating clinical and preclinical studies advance understanding of graft-versus-host disease
Gérard Socié, … , Robert Zeiser, Bruce R. Blazar
Gérard Socié, … , Robert Zeiser, Bruce R. Blazar
Published June 8, 2021
Citation Information: J Clin Invest. 2021. https://doi.org/10.1172/JCI149296.
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Insights from integrating clinical and preclinical studies advance understanding of graft-versus-host disease

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Abstract

As a result of impressive increases in our knowledge of rodent and human immunology, the pathophysiological mechanisms underlying graft-versus-host disease (GVHD) have dramatically improved in the past 15 years. Despite improved knowledge, translation to clinical care has not proceeded rapidly, with results from experimental models being inconsistent in their ability to predict the clinical utility of new therapeutic agents. In parallel, new tools in immunology have allowed in depth analyses of the human system and have been recently been applied in the field of clinical GVHD. Notwithstanding these advances, there is a relative paucity of mechanistic insights into human translational research, and this remains an area of high unmet need. Here we review selected recent advances both in preclinical experimental transplantation and translational human studies, including new insights into human immunology, the microbiome, and regenerative medicine. We focus on the fact that both approaches can interactively improve our understanding of both acute and chronic GVHD biology and open the door to improved therapeutics and successes.

Authors

Gérard Socié, Leslie S. Kean, Robert Zeiser, Bruce R. Blazar

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How elite controllers and posttreatment controllers inform our search for an HIV-1 cure
Jonathan Z. Li, Joel N. Blankson
Jonathan Z. Li, Joel N. Blankson
Published June 1, 2021
Citation Information: J Clin Invest. 2021;131(11):e149414. https://doi.org/10.1172/JCI149414.
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How elite controllers and posttreatment controllers inform our search for an HIV-1 cure

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Abstract

A small percentage of people living with HIV-1 can control viral replication without antiretroviral therapy (ART). These patients are called elite controllers (ECs) if they are able to maintain viral suppression without initiating ART and posttreatment controllers (PTCs) if they control HIV replication after ART has been discontinued. Both types of controllers may serve as a model of a functional cure for HIV-1 but the mechanisms responsible for viral control have not been fully elucidated. In this review, we highlight key lessons that have been learned so far in the study of ECs and PTCs and their implications for HIV cure research.

Authors

Jonathan Z. Li, Joel N. Blankson

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