Annu Rev Pathol
· 2022 Jan · PMID 34637338
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Recent years have seen growing attention to inflammatory and infectious disorders of the spinal cord, not only due to the discovery of autoantibody-mediated disorders of the spinal cord [e.g., aquaporin-4 immunoglobulin...Recent years have seen growing attention to inflammatory and infectious disorders of the spinal cord, not only due to the discovery of autoantibody-mediated disorders of the spinal cord [e.g., aquaporin-4 immunoglobulin G (IgG) antibodies and myelin oligodendrocyte glycoprotein IgG antibodies], but also due to the emergence of clusters of infection-related myelopathy, now known as acute flaccid myelitis. We review the spectrum of infection-related myelopathies and outline a nosological classification system based on association with infection. We describe the epidemiology and definitions of myelopathies, with a discussion of clinical presentation and neuroimaging features, and then turn to specific discussion of myelopathies due to direct pathogen invasion and those considered to be post- or parainfectious.
Annu Rev Pathol
· 2022 Jan · PMID 34606377
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Multiple sclerosis (MS) is a chronic autoimmune, inflammatory, and neurodegenerative disease that affects the central nervous system (CNS). MS is characterized by immune dysregulation, which results in the infiltration o...Multiple sclerosis (MS) is a chronic autoimmune, inflammatory, and neurodegenerative disease that affects the central nervous system (CNS). MS is characterized by immune dysregulation, which results in the infiltration of the CNS by immune cells, triggering demyelination, axonal damage, and neurodegeneration. Although the exact causes of MS are not fully understood, genetic and environmental factors are thought to control MS onset and progression. In this article, we review the main immunological mechanisms involved in MS pathogenesis.
Koutsodendris N, Nelson MR, Rao A
… +1 more, Huang Y
Annu Rev Pathol
· 2022 Jan · PMID 34460318
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Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder that involves dysregulation of many cellular and molecular processes. It is notoriously difficult to develop therapeutics for AD due to its complex...Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder that involves dysregulation of many cellular and molecular processes. It is notoriously difficult to develop therapeutics for AD due to its complex nature. Nevertheless, recent advancements in imaging technology and the development of innovative experimental techniques have allowed researchers to perform in-depth analyses to uncover the pathogenic mechanisms of AD. An important consideration when studying late-onset AD is its major genetic risk factor, apolipoprotein E4 (apoE4). Although the exact mechanisms underlying apoE4 effects on AD initiation and progression are not fully understood, recent studies have revealed critical insights into the apoE4-induced deficits that occur in AD. In this review, we highlight notable studies that detail apoE4 effects on prominent AD pathologies, including amyloid-β, tau pathology, neuroinflammation, and neural network dysfunction. We also discuss evidence that defines the physiological functions of apoE and outlines how these functions are disrupted in apoE4-related AD.
Shah VS, Chivukula RR, Lin B
… +2 more, Waghray A, Rajagopal J
Annu Rev Pathol
· 2022 Jan · PMID 34437820
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Cystic fibrosis (CF) is caused by defects in an anion channel, the cystic fibrosis transmembrane conductance regulator (CFTR). Recently, a new airway epithelial cell type has been discovered and dubbed the pulmonary iono...Cystic fibrosis (CF) is caused by defects in an anion channel, the cystic fibrosis transmembrane conductance regulator (CFTR). Recently, a new airway epithelial cell type has been discovered and dubbed the pulmonary ionocyte. Unexpectedly, these ionocytes express higher levels of CFTR than any other airway epithelial cell type. However, ionocytes are not the sole CFTR-expressing airway epithelial cells, and CF-associated disease genes are in fact expressed in multiple airway epithelial cell types. The experimental depletion of ionocytes perturbs epithelial physiology in the mouse trachea, but the role of these rare cells in the pathogenesis of human CF remains mysterious. Ionocytes have been described in diverse tissues(kidney and inner ear) and species (frog and fish). We draw on these prior studies to suggest potential roles of airway ionocytes in health and disease. A complete understanding of ionocytes in the mammalian airway will ultimately depend on cell type-specific genetic manipulation.
Annu Rev Pathol
· 2022 Jan · PMID 34425055
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Desmosomal cadherins are a recent evolutionary innovation that make up the adhesive core of highly specialized intercellular junctions called desmosomes. Desmosomal cadherins, which are grouped into desmogleins and desmo...Desmosomal cadherins are a recent evolutionary innovation that make up the adhesive core of highly specialized intercellular junctions called desmosomes. Desmosomal cadherins, which are grouped into desmogleins and desmocollins, are related to the classical cadherins, but their cytoplasmic domains are tailored for anchoring intermediate filaments instead of actin to sites of cell-cell adhesion. The resulting junctions are critical for resisting mechanical stress in tissues such as the skin and heart. Desmosomal cadherins also act as signaling hubs that promote differentiation and facilitate morphogenesis, creating more complex and effective tissue barriers in vertebrate tissues. Interference with desmosomal cadherin adhesive and supra-adhesive functions leads to a variety of autoimmune, hereditary, toxin-mediated, and malignant diseases. We review our current understanding of how desmosomal cadherins contribute to human health and disease, highlight gaps in our knowledge about their regulation and function, and introduce promising new directions toward combatting desmosome-related diseases.
Annu Rev Pathol
· 2022 Jan · PMID 34416820
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Long noncoding RNAs (lncRNAs) are pervasively transcribed in the genome, exhibit a diverse range of biological functions, and exert effects through a variety of mechanisms. The sheer number of lncRNAs in the human genome...Long noncoding RNAs (lncRNAs) are pervasively transcribed in the genome, exhibit a diverse range of biological functions, and exert effects through a variety of mechanisms. The sheer number of lncRNAs in the human genome has raised important questions about their potential biological significance and roles in human health and disease. Technological and computational advances have enabled functional annotation of a large number of lncRNAs. Though the number of publications related to lncRNAs has escalated in recent years, relatively few have focused on those involved in hepatic physiology and pathology. We provide an overview of evolving lncRNA classification systems and characteristics and highlight important advances in our understanding of the contribution of lncRNAs to liver disease, with a focus on nonalcoholic steatohepatitis, hepatocellular carcinoma, and cholestatic liver disease.
Annu Rev Pathol
· 2021 Jan · PMID 33497264
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The life expectancy of cystic fibrosis (CF) patients has greatly increased over the past decade, and researchers and clinicians must now navigate complex disease manifestations that were not a concern prior to the develo...The life expectancy of cystic fibrosis (CF) patients has greatly increased over the past decade, and researchers and clinicians must now navigate complex disease manifestations that were not a concern prior to the development of modern therapies. Explosive growth in the number of CF animal models has also occurred over this time span, clarifying CF disease pathophysiology and creating opportunities to understand more complex disease processes associated with an aging CF population. This review focuses on the CF-associated pathologies of the gastrointestinal system and how animal models have increased our understanding of this complex multisystemic disease. Although CF is primarily recognized as a pulmonary disease, gastrointestinal pathology occurs very commonly and can affect the quality of life for these patients. Furthermore, we discuss how next-generation genetic engineering of larger animal models will impact the field's understanding of CF disease pathophysiology and the development of novel therapeutic strategies.
Annu Rev Pathol
· 2021 Jan · PMID 33497263
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Alzheimer's disease (AD) is a pervasive, relentlessly progressive neurodegenerative disorder that includes both hereditary and sporadic forms linked by common underlying neuropathologic changes and neuropsychological man...Alzheimer's disease (AD) is a pervasive, relentlessly progressive neurodegenerative disorder that includes both hereditary and sporadic forms linked by common underlying neuropathologic changes and neuropsychological manifestations. While a clinical diagnosis is often made on the basis of initial memory dysfunction that progresses to involve multiple cognitive domains, definitive diagnosis requires autopsy examination of the brain to identify amyloid plaques and neurofibrillary degeneration. Over the past 100 years, there has been remarkable progress in our understanding of the underlying pathophysiologic processes, pathologic changes, and clinical phenotypes of AD, largely because genetic pathways that include but expand beyond amyloid processing have been uncovered. This review discusses the current state of understanding of the genetics of AD with a focus on how these advances are both shaping our understanding of the disease and informing novel avenues and approaches for development of potential therapeutic targets.
Annu Rev Pathol
· 2021 Jan · PMID 33497262
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Immunotherapy has revolutionized cancer treatment over the past decade. Nonetheless, prolonged survival is limited to relatively few patients. Cancers enforce a multifaceted immune-suppressive network whose nature is pro...Immunotherapy has revolutionized cancer treatment over the past decade. Nonetheless, prolonged survival is limited to relatively few patients. Cancers enforce a multifaceted immune-suppressive network whose nature is progressively shaped by systemic and local cues during tumor development. Monocytes bridge innate and adaptive immune responses and can affect the tumor microenvironment through various mechanisms that induce immune tolerance, angiogenesis, and increased dissemination of tumor cells. Yet monocytes can also give rise to antitumor effectors and activate antigen-presenting cells. This yin-yang activity relies on the plasticity of monocytes in response to environmental stimuli. In this review, we summarize current knowledge of the ontogeny, heterogeneity, and functions of monocytes and monocyte-derived cells in cancer, pinpointing the main pathways that are important for modeling the immunosuppressive tumor microenvironment.
Annu Rev Pathol
· 2021 Jan · PMID 33497261
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I have had the singular opportunity to perform research and to participate in medical education. Not unexpectedly, people have asked me which of the two was more important to me. My answer has always been and remains tha...I have had the singular opportunity to perform research and to participate in medical education. Not unexpectedly, people have asked me which of the two was more important to me. My answer has always been and remains that I am equally passionate about research and teaching. My research has been curiosity driven and not purposeful; hence, I was willing to take risks. That my research led to the discovery of natural killer cells and the unraveling of the molecular basis of a human disease was an unexpected reward. By contrast, my interest in medical education was purposeful, with the goal of improving healthcare by teaching pathology as the scientific foundation of medicine. It started with participation in Robbins pathology texts but progressed toward development of technology-based tools for medical education. This was driven by the belief that technology, by providing equal access to knowledge across the world, can be a powerful democratizing force.
Annu Rev Pathol
· 2021 Jan · PMID 33497260
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Genetic diseases cause numerous complex and intractable pathologies. DNA sequences encoding each human's complexity and many disease risks are contained in the mitochondrial genome, nuclear genome, and microbial metageno...Genetic diseases cause numerous complex and intractable pathologies. DNA sequences encoding each human's complexity and many disease risks are contained in the mitochondrial genome, nuclear genome, and microbial metagenome. Diagnosis of these diseases has unified around applications of next-generation DNA sequencing. However, translating specific genetic diagnoses into targeted genetic therapies remains a central goal. To date, genetic therapies have fallen into three broad categories: bulk replacement of affected genetic compartments with a new exogenous genome, nontargeted addition of exogenous genetic material to compensate for genetic errors, and most recently, direct correction of causative genetic alterations using gene editing. Generalized methods of diagnosis, therapy, and reagent delivery into each genetic compartment will accelerate the next generations of curative genetic therapies. We discuss the structure and variability of the mitochondrial, nuclear, and microbial metagenomic compartments, as well as the historical development and current practice of genetic diagnostics and gene therapies targeting each compartment.
Annu Rev Pathol
· 2021 Jan · PMID 33497259
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Specific proteins accumulate in neurodegenerative disease, and human genetics has indicated a causative role for many. In most cases, however, the mechanisms remain poorly understood. Degeneration is thought to involve a...Specific proteins accumulate in neurodegenerative disease, and human genetics has indicated a causative role for many. In most cases, however, the mechanisms remain poorly understood. Degeneration is thought to involve a gain of abnormal function, although we do not know the normal function of many proteins implicated. The protein α-synuclein accumulates in the Lewy pathology of Parkinson's disease and related disorders, and mutations in α-synuclein cause degeneration, but we have not known its normal function or how it triggers disease. α-Synuclein localizes to presynaptic boutons and interacts with membranes in vitro. Overexpression slows synaptic vesicle exocytosis, and recent data suggest a normal role for the endogenous synucleins in dilation of the exocytic fusion pore. Disrupted membranes also appear surprisingly prominent in Lewy pathology. Synuclein thus interacts with membranes under both physiological and pathological conditions, suggesting that the normal function of synuclein may illuminate its role in degeneration.
Kinsella RL, Zhu DX, Harrison GA
… +4 more, Mayer Bridwell AE, Prusa J, Chavez SM, Stallings CL
Annu Rev Pathol
· 2021 Jan · PMID 33497258
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(), the causative agent of tuberculosis (TB), remains a leading cause of death due to infection in humans. To more effectively combat this pandemic, many aspects of TB control must be developed, including better point of...(), the causative agent of tuberculosis (TB), remains a leading cause of death due to infection in humans. To more effectively combat this pandemic, many aspects of TB control must be developed, including better point of care diagnostics, shorter and safer drug regimens, and a protective vaccine. To address all these areas of need, better understanding of the pathogen, host responses, and clinical manifestations of the disease is required. Recently, the application of cutting-edge technologies to the study of pathogenesis has resulted in significant advances in basic biology, vaccine development, and antibiotic discovery. This leaves us in an exciting era of research in which our understanding of this deadly infection is improving at a faster rate than ever, and renews hope in our fight to end TB. In this review, we reflect on what is known regarding pathogenesis, highlighting recent breakthroughs that will provide leverage for the next leaps forward in the field.
Annu Rev Pathol
· 2021 Jan · PMID 33497257
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Hereditary peripheral neuropathy (HPN) is a complex group of neurological disorders caused by mutations in genes expressed by neurons and Schwann cells. The inheritance of a single mutation or multiple mutations in sever...Hereditary peripheral neuropathy (HPN) is a complex group of neurological disorders caused by mutations in genes expressed by neurons and Schwann cells. The inheritance of a single mutation or multiple mutations in several genes leads to disease phenotype. Patients exhibit symptoms during development, at an early age or later in adulthood. Most of the mechanistic understanding about these neuropathies comes from animal models and histopathological analyses of postmortem human tissues. Diagnosis is often very complex due to the heterogeneity and overlap in symptoms and the frequent overlap between various genes and different mutations they possess. Some symptoms in HPN are common through different subtypes such as axonal degeneration, demyelination, and loss of motor and sensory neurons, leading to similar physiologic abnormalities. Recent advances in gene-targeted therapies, genetic engineering, and next-generation sequencing have augmented our understanding of the underlying pathogenetic mechanisms of HPN.
Annu Rev Pathol
· 2021 Jan · PMID 33321055
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Unlike other cell types, B cells undergo multiple rounds of V(D)J recombination and hypermutation to evolve high-affinity antibodies. Reflecting high frequencies of DNA double-strand breaks, adaptive immune protection by...Unlike other cell types, B cells undergo multiple rounds of V(D)J recombination and hypermutation to evolve high-affinity antibodies. Reflecting high frequencies of DNA double-strand breaks, adaptive immune protection by B cells comes with an increased risk of malignant transformation. In addition, the vast majority of newly generated B cells express an autoreactive B cell receptor (BCR). Thus, B cells are under intense selective pressure to remove autoreactive and premalignant clones. Despite stringent negative selection, B cells frequently give rise to autoimmune disease and B cell malignancies. In this review, we discuss mechanisms that we term metabolic gatekeepers to eliminate pathogenic B cell clones on the basis of energy depletion. Chronic activation signals from autoreactive BCRs or transforming oncogenes increase energy demands in autoreactive and premalignant B cells. Thus, metabolic gatekeepers limit energy supply to levels that are insufficient to fuel either a transforming oncogene or hyperactive signaling from an autoreactive BCR.
Annu Rev Pathol
· 2021 Jan · PMID 33276706
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Over the last four decades, the cancer biology field has concentrated on cellular and microenvironmental drivers of metastasis. Despite this focus, mortality rates upon diagnosis of metastatic disease remain essentially...Over the last four decades, the cancer biology field has concentrated on cellular and microenvironmental drivers of metastasis. Despite this focus, mortality rates upon diagnosis of metastatic disease remain essentially unchanged. Would a small change in perspective help? Knowing what constitutes an inhospitable, rather than hospitable, microenvironment could provide the inspiration necessary to develop better therapies and preventative strategies. In this review, we canvas the literature for hints about what characteristics four common antimetastatic niches-skeletal muscle, spleen, thyroid, and yellow bone marrow-have in common. We posit that thorough molecular and mechanistic characterization of antimetastatic tissues may inspire reimagined therapies that inhibit metastatic development and/or progression in an enduring manner.
Rodrigues PM, Olaizola P, Paiva NA
… +6 more, Olaizola I, Agirre-Lizaso A, Landa A, Bujanda L, Perugorria MJ, Banales JM
Annu Rev Pathol
· 2021 Jan · PMID 33264573
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Cholangiocarcinoma (CCA) encompasses a group of malignancies that can arise at any point in the biliary tree. Although considered a rare cancer, the incidence of CCA is increasing globally. The silent and asymptomatic na...Cholangiocarcinoma (CCA) encompasses a group of malignancies that can arise at any point in the biliary tree. Although considered a rare cancer, the incidence of CCA is increasing globally. The silent and asymptomatic nature of these tumors, particularly in their early stages, in combination with their high aggressiveness, intra- and intertumor heterogeneity, and chemoresistance, significantly compromises the efficacy of current therapeutic options, contributing to a dismal prognosis. During the last few years, increasing efforts have been made to unveil the etiologies and pathogenesis of these tumors and to develop more effective therapies. In this review, we summarize current findings in the field of CCA, mainly focusing on the mechanisms of pathogenesis, cells of origin, genomic and epigenetic abnormalities, molecular alterations, chemoresistance, and therapies.
Annu Rev Pathol
· 2021 Jan · PMID 33264572
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The immune system is tasked with identifying malignant cells to eliminate or prevent cancer spread. This involves a complex orchestration of many immune cell types that together recognize different aspects of tumor trans...The immune system is tasked with identifying malignant cells to eliminate or prevent cancer spread. This involves a complex orchestration of many immune cell types that together recognize different aspects of tumor transformation and growth. In response, tumors have developed mechanisms to circumvent immune attack. Type I interferons (IFN-Is) are a class of proinflammatory cytokines produced in response to viruses and other environmental stressors. IFN-Is are also emerging as essential drivers of antitumor immunity, potently stimulating the ability of immune cells to eliminate tumor cells. However, a more complicated role for IFN-Is has arisen, as prolonged stimulation can promote feedback inhibitory mechanisms that contribute to immune exhaustion and other deleterious effects that directly or indirectly permit cancer cells to escape immune clearance. We review the fundamental and opposing functions of IFN-Is that modulate tumor growth and impact immune function and ultimately how these functions can be harnessed for the design of new cancer therapies.
Annu Rev Pathol
· 2021 Jan · PMID 33234023
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Studies of the regenerative capacity of the liver have converged on the Hippo pathway, a serine/threonine kinase cascade discovered in and conserved from unicellular organisms to mammals. Genetic studies of mouse and ra...Studies of the regenerative capacity of the liver have converged on the Hippo pathway, a serine/threonine kinase cascade discovered in and conserved from unicellular organisms to mammals. Genetic studies of mouse and rat livers have revealed that the Hippo pathway is a key regulator of liver size, regeneration, development, metabolism, and homeostasis and that perturbations in the Hippo pathway can lead to the development of common liver diseases, such as fatty liver disease and liver cancer. In turn, pharmacological targeting of the Hippo pathway may be utilized to boost regeneration and to prevent the development and progression of liver diseases. We review current insights provided by the Hippo pathway into liver pathophysiology. Furthermore, we present a path forward for future studies to understand how newly identified components of the Hippo pathway may control liver physiology and how the Hippo pathway is regulated in the liver.
Annu Rev Pathol
· 2021 Jan · PMID 33234022
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It is known that the gut microbiota, the numerically vast and taxonomically diverse microbial communities that thrive in a symbiotic fashion within our alimentary tract, can affect the normal physiology of the gastrointe...It is known that the gut microbiota, the numerically vast and taxonomically diverse microbial communities that thrive in a symbiotic fashion within our alimentary tract, can affect the normal physiology of the gastrointestinal tract and liver. Further, disturbances of the microbiota community structure from both endogenous and exogenous influences as well as the failure of host responsive mechanisms have been implicated in a variety of disease processes. Mechanistically, alterations in intestinal permeability and dysbiosis of the microbiota can result in inflammation, immune activation, and exposure to xenobiotic influences. Additionally, the gut and liver are continually exposed to small molecule products of the microbiota with proinflammatory, gene regulatory, and oxidative properties. Long-term coevolution has led to tolerance and incorporation of these influences into normal physiology and homeostasis; conversely, changes in this equilibrium from either the host or the microbial side can result in a wide variety of immune, inflammatory, metabolic, and neoplastic intestinal and hepatic disorders.