Annual Review of Pathology: Mechanisms of Disease - Volume 14, 2019

Among the age-dependent protein aggregation disorders, nine neurodegenerative diseases are caused by expansions of CAG repeats encoding polyglutamine (polyQ) tracts. We review the clinical, pathological, and biological features of these inherited disorders. We discuss insights into pathogenesis gleaned from studies of model systems and patients, highlighting work that informs efforts to develop effective therapies. An important conclusion from these analyses is that expanded CAG/polyQ domains are the primary drivers of neurodegeneration, with the biology of carrier proteins influencing disease-specific manifestations. Additionally, it has become apparent that CAG/polyQ repeat expansions produce neurodegeneration via multiple downstream mechanisms, involving both gain- and loss-of-function effects. This conclusion indicates that the likelihood of developing effective therapies targeting single nodes is reduced. The evaluation of treatments for premanifest disease will likely require new investigational approaches. We highlight the opportunities and challenges underlying ongoing work and provide recommendations related to the development of symptomatic and disease-modifying therapies and biomarkers that could inform future research.

Epstein–Barr virus (EBV) contributes to about 1.5% of all cases of human cancer worldwide, and viral genes are expressed in the malignant cells. EBV also very efficiently causes the proliferation of infected human B lymphocytes. The functions of the viral proteins and small RNAs that may contribute to EBV-associated cancers are becoming increasingly clear, and a broader understanding of the sequence variation of the virus genome has helped to interpret their roles. The improved understanding of the mechanisms of these cancers means that there are great opportunities for the early diagnosis of treatable stages of EBV-associated cancers and the use of immunotherapy to target EBV-infected cells or overcome immune evasion. There is also scope for preventing disease by immunization and for developing therapeutic agents that target the EBV gene products expressed in the cancers.

This review focuses primarily on the beneficial effects for human health of exposure to ultraviolet radiation (UVR). UVR stimulates anti-inflammatory and immunosuppressive pathways in skin that modulate psoriasis, atopic dermatitis, and vitiligo; suppresses cutaneous lesions of graft-versus-host disease; and regulates some infection and vaccination outcomes. While polymorphic light eruption and the cutaneous photosensitivity of systemic lupus erythematosus are triggered by UVR, polymorphic light eruption also frequently benefits from UVR-induced immunomodulation. For systemic diseases such as multiple sclerosis, type 1 diabetes, asthma, schizophrenia, autism, and cardiovascular disease, any positive consequences of UVR exposure are more speculative, but could occur through the actions of UVR-induced regulatory cells and mediators, including 1,25-dihydroxy vitamin D3, interleukin-10, and nitric oxide. Reduced UVR exposure is a risk factor for the development of several inflammatory, allergic, and autoimmune conditions, including diseases initiated in early life. This suggests that UVR-induced molecules can regulate cell maturation in developing organs.

Evidence indicates that diet, nutrition, lifestyle, the environment, the microbiome, and other exogenous factors have pathogenic roles and also influence the genome, epigenome, transcriptome, proteome, and metabolome of tumor and nonneoplastic cells, including immune cells. With the need for big-data research, pathology must transform to integrate data science fields, including epidemiology, biostatistics, and bioinformatics. The research framework of molecular pathological epidemiology (MPE) demonstrates the strengths of such an interdisciplinary integration, having been used to study breast, lung, prostate, and colorectal cancers. The MPE research paradigm not only can provide novel insights into interactions among environment, tumor, and host but also opens new research frontiers. New developments—such as computational digital pathology, systems biology, artificial intelligence, and in vivo pathology technologies—will further transform pathology and MPE. Although it is necessary to address the rarity of transdisciplinary education and training programs, MPE provides an exemplary model of integrative scientific approaches and contributes to advancements in precision medicine, therapy, and prevention.

Dystrophinopathy is a class of genetic skeletal muscle disease characterized by myofiber degeneration and regeneration due to insufficient levels or functioning of dystrophin. Pathological evaluation for dystrophinopathy includes the identification of dystrophic skeletal muscle pathology and the immunohistochemical evaluation of dystrophin epitopes, but biopsies have become rare in recent years. However, the evaluation of dystrophin expression in the research setting has become critically important due to recent advances in genetic therapies, including exon skipping and gene therapy. Given the number of these therapies under evaluation in patients, it is likely that the traditional methods of evaluating dystrophinopathy will need to evolve in the near future. This review discusses current muscle biopsy diagnostic practices in dystrophinopathy and further focuses on how these practices have evolved in the context of therapeutic interventions for dystrophinopathy.

Obligately intracytosolic rickettsiae that cycle between arthropod and vertebrate hosts cause human diseases with a spectrum of severity, primarily by targeting microvascular endothelial cells, resulting in endothelial dysfunction. Endothelial cells and mononuclear phagocytes have important roles in the intracellular killing of rickettsiae upon activation by the effector molecules of innate and adaptive immunity. In overwhelming infection, immunosuppressive effects contribute to the severity of illness. Rickettsia–host cell interactions involve host cell receptors for rickettsial ligands that mediate cell adhesion and, in some instances, trigger induced phagocytosis. Rickettsiae interact with host cell actin to effect both cellular entry and intracellular actin-based mobility. The interaction of rickettsiae with the host cell also involves rickettsial evasion of host defense mechanisms and exploitation of the intracellular environment. Signal transduction events exemplify these effects. An intriguing frontier is the array of rickettsial noncoding RNA molecules and their potential effects on the pathogenesis and transmission of rickettsial diseases.

The physiological significance of innate immune signaling lies primarily in its role in host defense against invading pathogens. It is becoming increasingly clear that innate immune signaling also modulates the development of metabolic diseases, especially nonalcoholic fatty liver disease and cardiovascular diseases, which are characterized by chronic, low-grade inflammation due to a disarrangement of innate immune signaling. Notably, recent studies indicate that in addition to regulating canonical innate immune-mediated inflammatory responses (or immune-dependent signaling-induced responses), molecules of the innate immune system regulate pathophysiological responses in multiple organs during metabolic disturbances (termed immune-independent signaling-induced responses), including the disruption of metabolic homeostasis, tissue repair, and cell survival. In addition, emerging evidence from the study of immunometabolism indicates that the systemic metabolic status may have profound effects on cellular immune function and phenotypes through the alteration of cell-intrinsic metabolism. We summarize how the innate immune system interacts with metabolic disturbances to trigger immune-dependent and immune-independent pathogenesis in the context of nonalcoholic fatty liver disease, as representative of metabolic diseases, and cardiovascular diseases.

Pregnancy stimulates an elaborate assortment of dynamic changes, allowing intimate approximation of genetically discordant maternal and fetal tissues. Although the cellular and molecular details about how this works remain largely undefined, important clues arise from evaluating how a prior pregnancy influences the outcome of a future pregnancy. The risk of complications is consistently increased when complications occurred in a prior pregnancy. Reciprocally, a prior successful pregnancy protects against complications in a future pregnancy. Here, we summarize immunological perturbations associated with fetal loss, with particular focus on how both harmful and protective adaptations may persist in mothers. Immunological aberrancy as a root cause of pregnancy complications is also considered, given their shared overlapping risk factors and the sustained requirement for averting maternal–fetal conflict throughout pregnancy. Understanding pregnancy-induced immunological changes may expose not only new therapeutic strategies for improving pregnancy outcomes but also new facets of how immune tolerance works that may be applicable to other physiological and pathological contexts.

Cardiovascular diseases exist across all developed countries. Biomarkers that can predict or diagnose diseases early in their pathogeneses can reduce their morbidity and mortality in afflicted individuals. microRNAs are small regulatory RNAs that modulate translation and have been identified as potential fluid-based biomarkers across numerous maladies. We describe the current state of cardiovascular disease biomarkers across a range of diseases, including myocardial infarction, acute coronary syndrome, myocarditis, hypertension, heart failure, heart transplantation, aortic stenosis, diabetic cardiomyopathy, atrial fibrillation, and sepsis. We present the current understanding of microRNAs as possible biomarkers in these categories and where their best opportunities exist to enter clinical practice.

The tauopathies constitute a group of diseases that have Tau inclusions in neurons or glia as their common denominator. In this review, we describe the biochemical and histological differences in Tau pathology that are characteristic of the spectrum of frontotemporal lobar degeneration as primary tauopathies and of Alzheimer's disease as a secondary tauopathy, as well as the commonalities and differences between the familial and sporadic forms. Furthermore, we discuss selected advances in transgenic animal models in delineating the different pathomechanisms of Tau.

Since the discovery of sickle cell disease (SCD) in 1910, enormous strides have been made in the elucidation of the pathogenesis of its protean complications, which has inspired recent advances in targeted molecular therapies. In SCD, a single amino acid substitution in the β-globin chain leads to polymerization of mutant hemoglobin S, impairing erythrocyte rheology and survival. Clinically, erythrocyte abnormalities in SCD manifest in hemolytic anemia and cycles of microvascular vaso-occlusion leading to end-organ ischemia-reperfusion injury and infarction. Vaso-occlusive events and intravascular hemolysis promote inflammation and redox instability that lead to progressive small- and large-vessel vasculopathy. Based on current evidence, the pathobiology of SCD is considered to be a vicious cycle of four major processes, all the subject of active study and novel therapeutic targeting: (a) hemoglobin S polymerization, (b) impaired biorheology and increased adhesion-mediated vaso-occlusion, (c) hemolysis-mediated endothelial dysfunction, and (d) concerted activation of sterile inflammation (Toll-like receptor 4– and inflammasome-dependent innate immune pathways). These molecular, cellular, and biophysical processes synergize to promote acute and chronic pain and end-organ injury and failure in SCD. This review provides an exhaustive overview of the current understanding of the molecular pathophysiology of SCD, how this pathophysiology contributes to complications of the central nervous and cardiopulmonary systems, and how this knowledge is being harnessed to develop current and potential therapies.

Malformations of cortical development encompass heterogeneous groups of structural brain anomalies associated with complex neurodevelopmental disorders and diverse genetic and nongenetic etiologies. Recent progress in understanding the genetic basis of brain malformations has been driven by extraordinary advances in DNA sequencing technologies. For example, somatic mosaic mutations that activate mammalian target of rapamycin signaling in cortical progenitor cells during development are now recognized as the cause of hemimegalencephaly and some types of focal cortical dysplasia. In addition, research on brain development has begun to reveal the cellular and molecular bases of cortical gyrification and axon pathway formation, providing better understanding of disorders involving these processes. New neuroimaging techniques with improved resolution have enhanced our ability to characterize subtle malformations, such as those associated with intellectual disability and autism. In this review, we broadly discuss cortical malformations and focus on several for which genetic etiologies have elucidated pathogenesis.

Nearly all infectious agents contain DNA or RNA genomes, making sequencing an attractive approach for pathogen detection. The cost of high-throughput or next-generation sequencing has been reduced by several orders of magnitude since its advent in 2004, and it has emerged as an enabling technological platform for the detection and taxonomic characterization of microorganisms in clinical samples from patients. This review focuses on the application of untargeted metagenomic next-generation sequencing to the clinical diagnosis of infectious diseases, particularly in areas in which conventional diagnostic approaches have limitations. The review covers (a) next-generation sequencing technologies and common platforms, (b) next-generation sequencing assay workflows in the clinical microbiology laboratory, (c) bioinformatics analysis of metagenomic next-generation sequencing data, (d) validation and use of metagenomic next-generation sequencing for diagnosing infectious diseases, and (e) significant case reports and studies in this area. Next-generation sequencing is a new technology that has the promise to enhance our ability to diagnose, interrogate, and track infectious diseases.

Endometrial cancer is the most commonly diagnosed gynecologic malignancy in the United States. Endometrioid endometrial carcinomas constitute approximately 85% of newly diagnosed cases; serous carcinomas represent approximately 3–10% of diagnoses; clear cell carcinoma accounts for <5% of diagnoses; and uterine carcinosarcomas are rare, biphasic tumors. Longstanding molecular observations implicate PTEN inactivation as a major driver of endometrioid carcinomas; TP53 inactivation as a major driver of most serous carcinomas, some high-grade endometrioid carcinomas, and many uterine carcinosarcomas; and inactivation of either gene as drivers of some clear cell carcinomas. In the past decade, targeted gene and exome sequencing have uncovered additional pathogenic aberrations in each histotype. Moreover, an integrated genomic analysis by The Cancer Genome Atlas (TCGA) resulted in the molecular classification of endometrioid and serous carcinomas into four distinct subgroups, POLE (ultramutated), microsatellite instability (hypermutated), copy number low (endometrioid), and copy number high (serous-like). In this review, we provide an overview of the major molecular features of the aforementioned histopathological subtypes and TCGA subgroups and discuss potential prognostic and therapeutic implications for endometrial carcinoma.

Type I interferons, which make up the first cytokine family to be described and are the essential mediators of antivirus host defense, have emerged as central elements in the immunopathology of systemic autoimmune diseases, with systemic lupus erythematosus as the prototype. Lessons from investigation of interferon regulation following virus infection can be applied to lupus, with the conclusion that sustained production of type I interferon shifts nearly all components of the immune system toward pathologic functions that result in tissue damage and disease. We review recent data, mainly from studies of patients with systemic lupus erythematosus, that provide new insights into the mechanisms of induction and the immunologic consequences of chronic activation of the type I interferon pathway. Current concepts implicate endogenous nucleic acids, driving both cytosolic sensors and endosomal Toll-like receptors, in interferon pathway activation and suggest targets for development of novel therapeutics that may restore the immune system to health.

Human induced pluripotent stem cells (iPSCs) provide a renewable supply of patient-specific and tissue-specific cells for cellular and molecular studies of disease mechanisms. Combined with advances in various omics technologies, iPSC models can be used to profile the expression of genes, transcripts, proteins, and metabolites in relevant tissues. In the past 2 years, large panels of iPSC lines have been derived from hundreds of genetically heterogeneous individuals, further enabling genome-wide mapping to identify coexpression networks and elucidate gene regulatory networks. Here, we review recent developments in omics profiling of various molecular phenotypes and the emergence of human iPSCs as a systems biology model of human diseases.

Chagas heart disease is an inflammatory cardiomyopathy that develops in approximately one-third of people infected with the protozoan parasite Trypanosoma cruzi. One way T. cruzi is transmitted to people is through contact with infected kissing bugs, which are found in much of the Western Hemisphere, including in vast areas of the United States. The epidemiology of T. cruzi and Chagas heart disease and the varied mechanisms leading to myocyte destruction, mononuclear cell infiltration, fibrosis, and edema in the heart have been extensively studied by hundreds of scientists for more than 100 years. Despite this wealth of knowledge, it is still impossible to predict what will happen in an individual infected with T. cruzi because of the tremendous variability in clonal parasite virulence and human susceptibility to infection and the lack of definitive molecular predictors of outcome from either side of the host–parasite equation. Further, while several distinct mechanisms of pathogenesis have been studied in isolation, it is certain that multiple coincident mechanisms combine to determine the ultimate outcome. For these reasons, Chagas disease is best considered a collection of related but distinct illnesses. This review highlights the pathology and pathogenesis of the most common adverse sequela of T. cruzi infection—Chagas heart disease—and concludes with a discussion of key unanswered questions and a view to the future.

Understanding the physiopathology of disease remains an essential step in developing novel therapeutics. Although animal models have certainly contributed to advancing this enterprise, their limitation in modeling all the aspects of complex human disorders is one of the major challenges faced by the biomedical research field. Human induced pluripotent stem cells (hiPSCs) derived from patients represent a great opportunity to overcome this deficiency because these cells cover the genetic diversity needed to fully model human diseases. Here, we provide an overview of the history of hiPSC technology and discuss common challenges and approaches that we and others have faced when using hiPSCs to model disease. Our emphasis is on liver disease, and consequently, we review the progress made using this technology to produce functional liver cells in vitro and how these systems are being used to recapitulate a diversity of developmental, metabolic, genetic, and infectious liver disorders.

Frontotemporal dementia is a group of early onset dementia syndromes linked to underlying frontotemporal lobar degeneration (FTLD) pathology that can be classified based on the formation of abnormal protein aggregates involving tau and two RNA binding proteins, TDP-43 and FUS. Although elucidation of the mechanisms leading to FTLD pathology is in progress, recent advances in genetics and neuropathology indicate that a majority of FTLD cases with proteinopathy involving RNA binding proteins show highly congruent genotype–phenotype correlations. Specifically, recent studies have uncovered the unique properties of the low-complexity domains in RNA binding proteins that can facilitate liquid–liquid phase separation in the formation of membraneless organelles. Furthermore, there is compelling evidence that mutations in FTLD genes lead to dysfunction in diverse cellular pathways that converge on the endolysosomal pathway, autophagy, and neuroinflammation. Together, these results provide key mechanistic insights into the pathogenesis and potential therapeutic targets of FTLD.

Prion diseases are rapidly progressive, incurable neurodegenerative disorders caused by misfolded, aggregated proteins known as prions, which are uniquely infectious. Remarkably, these infectious proteins have been responsible for widespread disease epidemics, including kuru in humans, bovine spongiform encephalopathy in cattle, and chronic wasting disease in cervids, the latter of which has spread across North America and recently appeared in Norway and Finland. The hallmark histopathological features include widespread spongiform encephalopathy, neuronal loss, gliosis, and deposits of variably sized aggregated prion protein, ranging from small, soluble oligomers to long, thin, unbranched fibrils, depending on the disease. Here, we explore recent advances in prion disease research, from the function of the cellular prion protein to the dysfunction triggering neurotoxicity, as well as mechanisms underlying prion spread between cells. We also highlight key findings that have revealed new therapeutic targets and consider unanswered questions for future research.