COVID-19, the disease caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has resulted in a global pandemic and a disruptive health crisis. COVID-19-related morbidity and mortality has been attributed to an exaggerated immune response. The role of complement activation and its contribution to illness severity is being increasingly recognized. Here, we summarize current knowledge about the interaction of coronaviruses with the complement system. We posit that: (a) coronaviruses activate multiple complement pathways; (b) severe COVID-19 clinical features often resemble complementopathies; (c) the combined effects of complement activation, dysregulated neutrophilia, endothelial injury, and hypercoagulability appear to be intertwined to drive the severe features of COVID-19; (d) a subset of patients with COVID-19 may have a genetic predisposition associated with complement dysregulation; and (e) these observations create a basis for clinical trials of complement inhibitors in life-threatening illness.
Anuja Java, Anthony J. Apicelli, M. Kathryn Liszewski, Ariella Coler-Reilly, John P. Atkinson, Alfred H.J. Kim, Hrishikesh S. Kulkarni
Recent large-scale GWAS and large epidemiologic studies have accelerated the discovery of genes and environmental factors that contribute to the risk of keratinocyte carcinoma (KC), which includes basal cell carcinoma (BCC) and squamous cell carcinoma (SCC). This Review summarizes the genomic regions associated with SCC and BCC risk, examines the genetic overlap between SCC and BCC, and discusses biological pathways involved in SCC and BCC development. Next, we review environmental factors that are associated with KC risk, including those that are shared between SCC and BCC as well as others that associated with only one type of KC. We conclude with a critical appraisal of current research and potential directions for future research.
Hélène Choquet, Sepideh Ashrafzadeh, Yuhree Kim, Maryam M. Asgari, Eric Jorgenson
Protection from relapse after allogeneic hematopoietic cell transplantation (HCT) is partly due to donor T cell–mediated graft-versus-leukemia (GVL) immune responses. Relapse remains common in HCT recipients, but strategies to augment GVL could significantly improve outcomes after HCT. Donor T cells with αβ T cell receptors (TCRs) mediate GVL through recognition of minor histocompatibility antigens and alloantigens in HLA-matched and -mismatched HCT, respectively. αβ T cells specific for other leukemia-associated antigens, including nonpolymorphic antigens and neoantigens, may also deliver an antileukemic effect. γδ T cells may contribute to GVL, although their biology and specificity are less well understood. Vaccination or adoptive transfer of donor-derived T cells with natural or transgenic receptors are strategies with potential to selectively enhance αβ and γδ T cell GVL effects.
Melinda A. Biernacki, Vipul S. Sheth, Marie Bleakley
Chronic inflammatory demyelinating polyneuropathy (CIDP) is an autoimmune disease of the peripheral nerves that presents with either chronic progression or relapsing disease. Recent studies in samples from patients with CIDP and mouse models have delineated how defects in central (thymic) and peripheral (extrathymic) immune tolerance mechanisms can cause PNS autoimmunity. Notably, nerve parenchymal cells actively contribute to local autoimmunity and also control disease outcome. Here, we outline how emerging technologies increasingly enable an integrated view of how immune cells and PNS parenchymal cells communicate in CIDP. We also relate the known heterogeneity of clinical presentation with specific underlying mechanisms. For example, a severe subtype of CIDP with tremor is associated with pathogenic IgG4 autoantibodies against nodal and paranodal proteins. An improved understanding of pathogenic mechanisms in CIDP will form the basis for more effective mechanism-based therapies.
Jolien Wolbert, Mandy I. Cheng, Gerd Meyer zu Horste, Maureen A. Su
Iron is an essential element for multiple fundamental biological processes required for life; yet iron overload can be cytotoxic. Consequently, iron concentrations at the cellular and tissue level must be exquisitely governed by mechanisms that complement and fine-tune systemic control. It is well appreciated that macrophages are vital for systemic iron homeostasis, supplying or sequestering iron as needed for erythropoiesis or bacteriostasis, respectively. Indeed, recycling of iron through erythrophagocytosis by splenic macrophages is a major contributor to systemic iron homeostasis. However, accumulating evidence suggests that tissue-resident macrophages regulate local iron availability and modulate the tissue microenvironment, contributing to cellular and tissue function. Here, we summarize the significance of tissue-specific regulation of iron availability and highlight how resident macrophages are critical for this process. This tissue-dependent regulation has broad implications for understanding both resident macrophage function and tissue iron homeostasis in health and disease.
Nathan C. Winn, Katrina M. Volk, Alyssa H. Hasty
Recent discoveries demonstrate a critical role for circadian rhythms and sleep in immune system homeostasis. Both innate and adaptive immune responses — ranging from leukocyte mobilization, trafficking, and chemotaxis to cytokine release and T cell differentiation —are mediated in a time of day–dependent manner. The National Institutes of Health (NIH) recently sponsored an interdisciplinary workshop, “Sleep Insufficiency, Circadian Misalignment, and the Immune Response,” to highlight new research linking sleep and circadian biology to immune function and to identify areas of high translational potential. This Review summarizes topics discussed and highlights immediate opportunities for delineating clinically relevant connections among biological rhythms, sleep, and immune regulation.
Jeffrey A. Haspel, Ron Anafi, Marishka K. Brown, Nicolas Cermakian, Christopher Depner, Paula Desplats, Andrew E. Gelman, Monika Haack, Sanja Jelic, Brian S. Kim, Aaron D. Laposky, Yvonne C. Lee, Emmanuel Mongodin, Aric A. Prather, Brian Prendergast, Colin Reardon, Albert C. Shaw, Shaon Sengupta, Éva Szentirmai, Mahesh Thakkar, Wendy E. Walker, Laura A. Solt
Necroptosis is a genetically regulated form of necrotic cell death that has emerged as an important pathway in human disease. The necroptosis pathway is induced by a variety of signals, including death receptor ligands, and regulated by receptor-interacting protein kinases 1 and 3 (RIPK1 and RIPK3) and mixed-lineage kinase domain–like pseudokinase (MLKL), which form a regulatory necrosome complex. RIPK3-mediated phosphorylation of MLKL executes necroptosis. Recent studies, using animal models of tissue injury, have revealed that RIPK3 and MLKL are key effectors of injury propagation. This Review explores the functional roles of RIPK3 and MLKL as crucial pathogenic determinants and markers of disease progression and severity in experimental models of human disease, including acute and chronic pulmonary diseases; renal, hepatic, cardiovascular, and neurodegenerative diseases; cancer; and critical illness.
Mary E. Choi, David R. Price, Stefan W. Ryter, Augustine M. K. Choi
Respiratory diseases are among the leading causes of death and disability worldwide. However, the pathogenesis of both acute and chronic lung diseases remains incompletely understood. As a result, therapeutic options for important clinical problems, including acute respiratory distress syndrome and chronic obstructive pulmonary disease, are limited. Research efforts have been held back in part by the difficulty of modeling lung injury in animals. Donor human lungs that have been rejected for transplantation offer a valuable alternative for understanding these diseases. In 2007, our group developed a simple preparation of an ex vivo–perfused single human lung. In this Review, we discuss the availability of donor human lungs for research, describe the ex vivo–perfused lung preparation, and highlight how this preparation can be used to study the mechanisms of lung injury, to isolate primary cells, and to test novel therapeutics.
James T. Ross, Nicolas Nesseler, Jae-Woo Lee, Lorraine B. Ware, Michael A. Matthay
Inflammatory arthritis encompasses a set of common diseases characterized by immune-mediated attack on joint tissues. Most but not all affected patients manifest circulating autoantibodies. Decades of study in human and animal arthritis have identified key roles for autoantibodies in immune complexes and through direct modulation of articular biology. However, joint inflammation can arise because of pathogenic T cells and other pathways that are antibody-independent. Here we review the evidence for these parallel tracks, in animal models and in humans, to explore the range of mechanisms engaged in the pathophysiology of arthritis and to highlight opportunities for targeted therapeutic intervention.
Margaret H. Chang, Peter A. Nigrovic
Small heat shock proteins (sHSPs) comprise an important protein family that is ubiquitously expressed, is highly conserved among species, and has emerged as a critical regulator of protein folding. While these proteins are functionally important for a variety of tissues, an emerging field of cardiovascular research reveals sHSPs are also extremely important for maintaining normal cardiac function and regulating the cardiac stress response. Notably, numerous mutations in genes encoding sHSPs have been associated with multiple cardiac diseases. sHSPs (HSPB5, HSPB6, and HSPB8) have been described as mediating chaperone functions within the heart by interacting with the cochaperone protein BCL-2–associated anthanogene 3 (BAG3); however, recent reports indicate that sHSPs (HSPB7) can perform other BAG3-independent functions. Here, we summarize the cardiac functions of sHSPs and present the notion that cardiac sHSPs function via BAG3-dependent or -independent pathways.
Xi Fang, Julius Bogomolovas, Christa Trexler, Ju Chen
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