Review
Abstract
Stroke is the second leading cause of death worldwide and a leading cause of disability. Most strokes are caused by occlusion of a major cerebral artery, and substantial advances have been made in elucidating how ischemia damages the brain. In particular, increasing evidence points to a double-edged role of the immune system in stroke pathophysiology. In the acute phase, innate immune cells invade brain and meninges and contribute to ischemic damage, but may also be protective. At the same time, danger signals released into the circulation by damaged brain cells lead to activation of systemic immunity, followed by profound immunodepression that promotes life-threatening infections. In the chronic phase, antigen presentation initiates an adaptive immune response targeted to the brain, which may underlie neuropsychiatric sequelae, a considerable cause of poststroke morbidity. Here, we briefly review these pathogenic processes and assess the potential therapeutic value of targeting immunity in human stroke.
Authors
Costantino Iadecola, Marion S. Buckwalter, Josef Anrather
Abstract
The renaissance of complement diagnostics and therapeutics has introduced precision medicine into a widened field of complement-mediated diseases. In particular, complement-mediated diseases (or complementopathies) with ongoing or published clinical trials of complement inhibitors include paroxysmal nocturnal hemoglobinuria, cold agglutinin disease, hemolytic uremic syndrome, nephropathies, HELLP syndrome, transplant-associated thrombotic microangiopathy, antiphospholipid antibody syndrome, myasthenia gravis, and neuromyelitis optica. Recognizing that this field is rapidly expanding, we aim to provide a state-of-the-art review of (a) current understanding of complement biology for the clinician, (b) novel insights into complement with potential applicability to clinical practice, (c) complement in disease across various disciplines (hematology, nephrology, obstetrics, transplantation, rheumatology, and neurology), and (d) the potential future of precision medicine. Better understanding of complement diagnostics and therapeutics will not only facilitate physicians treating patients in clinical practice but also provide the basis for future research toward precision medicine in this field.
Authors
Eleni Gavriilaki, Robert A. Brodsky
Abstract
Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the cause of coronavirus disease (COVID-19), has spurred a global health crisis. To date, there are no proven options for prophylaxis for those who have been exposed to SARS-CoV-2, nor therapy for those who develop COVID-19. Immune (i.e. “convalescent”) plasma refers to plasma that is collected from individuals, following resolution of infection and development of antibodies. Passive antibody administration through transfusion of convalescent plasma may offer the only short-term strategy to confer immediate immunity to susceptible individuals. There are numerous examples, where convalescent plasma has been used successfully as post-exposure prophylaxis and/or treatment of infectious diseases, including other outbreaks of coronaviruses (e.g., SARS-1, Middle East Respiratory Syndrome [MERS]). Convalescent plasma has also been used in the COVID-19 pandemic; limited data from China suggest clinical benefit, including radiological resolution, reduction in viral loads and improved survival. Globally, blood centers have robust infrastructure to undertake collections and construct inventories of convalescent plasma to meet the growing demand. Nonetheless, there are nuanced challenges, both regulatory and logistical, spanning donor eligibility, donor recruitment, collections and transfusion itself. Data from rigorously controlled clinical trials of convalescent plasma are also few, underscoring the need to evaluate its use objectively for a range of indications (e.g., prevention vs treatment) and patient populations (e.g., age, comorbid disease). We provide an overview of convalescent plasma, from evidence of benefit, regulatory considerations, logistical work flow and proposed clinical trials, as scale up is brought underway to mobilize this critical resource.
Authors
Evan M. Bloch, Shmuel Shoham, Arturo Casadevall, Bruce S. Sachais, Beth Shaz, Jeffrey L. Winters, Camille van Buskirk, Brenda J. Grossman, Michael Joyner, Jeffrey P. Henderson, Andrew Pekosz, Bryan Lau, Amy Wesolowski, Louis Katz, Hua Shan, Paul G. Auwaerter, David Thomas, David J. Sullivan, Nigel Paneth, Eric Gehrie, Steven Spitalnik, Eldad Hod, Lewis Pollack, Wayne T. Nicholson, Liise-anne Pirofski, Jeffrey A. Bailey, Aaron A.R. Tobian
Abstract
Regenerative pain medicine, which seeks to harness the body’s own reparative capacity, is rapidly emerging as a field within pain medicine and orthopedics. It is increasingly appreciated that common analgesic mechanisms for these treatments depend on neuroimmune modulation. In this Review, we discuss recent progress in mechanistic understanding of nociceptive sensitization in chronic pain with a focus on neuroimmune modulation. We also examine the spectrum of regenerative outcomes, including preclinical and clinical outcomes. We further distinguish the analgesic mechanisms of regenerative therapies from those of cellular replacement, creating a conceptual and mechanistic framework to evaluate future research on regenerative medicine.
Authors
Thomas Buchheit, Yul Huh, William Maixner, Jianguo Cheng, Ru-Rong Ji
Abstract
The functional state of the preexisting T cells in the tumor microenvironment is a key determinant for effective antitumor immunity and immunotherapy. Increasing evidence suggests that immunosenescence is an important state of T cell dysfunction that is distinct from exhaustion, a key strategy used by malignant tumors to evade immune surveillance and sustain the suppressive tumor microenvironment. Here, we discuss the phenotypic and functional characteristics of senescent T cells and their role in human cancers. We also explore the possible mechanisms and signaling pathways responsible for induction of T cell senescence by malignant tumors, and then discuss potential strategies to prevent and/or reverse senescence in tumor-specific T cells. A better understanding of these critical issues should provide novel strategies to enhance cancer immunotherapy.
Authors
Xia Liu, Daniel F. Hoft, Guangyong Peng
Abstract
Sickle cell anemia is a unique disease dominated by hemolytic anemia and vaso-occlusive events. The latter trigger a version of ischemia/reperfusion (I/R) pathobiology that is singular in its origin, cyclicity, complexity, instability, perpetuity, and breadth of clinical consequences. Specific clinical features are probably attributable to local I/R injury (e.g., stroke syndromes) or remote organ injury (e.g., acute chest syndrome) or the systematization of inflammation (e.g., multifocal arteriopathy). Indeed, by fashioning an underlying template of endothelial dysfunction and vulnerability, the robust inflammatory systematization no doubt contributes to all sickle pathology. In this Review, we highlight I/R–targeting therapeutics shown to improve microvascular blood flow in sickle transgenic mice undergoing I/R, and we suggest how such insights might be translated into human therapeutic strategies.
Authors
Robert P. Hebbel, John D. Belcher, Gregory M. Vercellotti
Abstract
Signaling by the TGF-β superfamily is important in the regulation of hematopoiesis and is dysregulated in myelodysplastic syndromes (MDSs), contributing to ineffective hematopoiesis and clinical cytopenias. TGF-β, activins, and growth differentiation factors exert inhibitory effects on red cell formation by activating canonical SMAD2/3 pathway signaling. In this Review, we summarize evidence that overactivation of SMAD2/3 signaling pathways in MDSs causes anemia due to impaired erythroid maturation. We also describe the basis for biological activity of activin receptor ligand traps, novel fusion proteins such as luspatercept that are promising as erythroid maturation agents to alleviate anemia and related comorbidities in MDSs and other conditions characterized by impaired erythroid maturation.
Authors
Amit Verma, Rajasekhar N.V.S. Suragani, Srinivas Aluri, Nishi Shah, Tushar D. Bhagat, Mark J. Alexander, Rami Komrokji, Ravi Kumar
Abstract
Immunotherapy has transformed the treatment landscape for a wide range of human cancers. Immune checkpoint inhibitors (ICIs), monoclonal antibodies that block the immune-regulatory “checkpoint” receptors CTLA-4, PD-1, or its ligand PD-L1, can produce durable responses in some patients. However, coupled with their success, these treatments commonly evoke a wide range of immune-related adverse events (irAEs) that can affect any organ system and can be treatment-limiting and life-threatening, such as diabetic ketoacidosis, which appears to be more frequent than initially described. The majority of irAEs from checkpoint blockade involve either barrier tissues (e.g., gastrointestinal mucosa or skin) or endocrine organs, although any organ system can be affected. Often, irAEs resemble spontaneous autoimmune diseases, such as inflammatory bowel disease, autoimmune thyroid disease, type 1 diabetes mellitus (T1D), and autoimmune pancreatitis. Yet whether similar molecular or pathologic mechanisms underlie these apparent autoimmune adverse events and classical autoimmune diseases is presently unknown. Interestingly, evidence links HLA alleles associated with high risk for autoimmune disease with ICI-induced T1D and colitis. Understanding the genetic risks and immunologic mechanisms driving ICI-mediated inflammatory toxicities may not only identify therapeutic targets useful for managing irAEs, but may also provide new insights into the pathoetiology and treatment of autoimmune diseases.
Authors
Michael Dougan, Massimo Pietropaolo
Abstract
The discovery of peripheral intracellular clocks revealed circadian oscillations of clock genes and their targets in all cell types, including those in the lung, sparking exploration of clocks in lung disease pathophysiology. While the focus has been on the role of these clocks in adult airway diseases, clock biology is also likely to be important in perinatal lung development, where it has received far less attention. Historically, fetal circadian rhythms have been considered irrelevant owing to lack of external light exposure, but more recent insights into peripheral clock biology raise questions of clock emergence, its concordance with tissue-specific structure/function, the interdependence of clock synchrony and functionality in perinatal lung development, and the possibility of lung clocks in priming the fetus for postnatal life. Understanding the perinatal molecular clock may unravel mechanistic targets for chronic airway disease across the lifespan. With current research providing more questions than answers, it is about time to investigate clocks in the developing lung.
Authors
Colleen M. Bartman, Aleksey Matveyenko, Y.S. Prakash
Abstract
Vaccine development against tuberculosis (TB) is based on the induction of adaptive immune responses endowed with long-term memory against mycobacterial antigens. Memory B and T cells initiate a rapid and robust immune response upon encounter with Mycobacterium tuberculosis, thus achieving long-lasting protection against infection. Recent studies have shown, however, that innate immune cell populations such as myeloid cells and NK cells also undergo functional adaptation after infection or vaccination, a de facto innate immune memory that is also termed trained immunity. Experimental and epidemiological data have shown that induction of trained immunity contributes to the beneficial heterologous effects of vaccines such as bacille Calmette-Guérin (BCG), the licensed TB vaccine. Moreover, increasing evidence argues that trained immunity also contributes to the anti-TB effects of BCG vaccination. An interaction among immunological signals, metabolic rewiring, and epigenetic reprogramming underlies the molecular mechanisms mediating trained immunity in myeloid cells and their bone marrow progenitors. Future studies are warranted to explore the untapped potential of trained immunity to develop a future generation of TB vaccines that would combine innate and adaptive immune memory induction.
Authors
Shabaana A. Khader, Maziar Divangahi, Willem Hanekom, Philip C. Hill, Markus Maeurer, Karen W. Makar, Katrin D. Mayer-Barber, Musa M. Mhlanga, Elisa Nemes, Larry S. Schlesinger, Reinout van Crevel, Ramakrishna Vankalayapati, Ramnik J. Xavier, Mihai G. Netea, on behalf of the Bill and Melinda Gates Foundation Collaboration for TB Vaccine Discovery Innate Immunity Working Group18
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