Pathogenic Mechanisms Underlying Idiopathic Pulmonary Fibrosis

The pathogenesis of idiopathic pulmonary fibrosis (IPF) involves a complex interplay of cell types and signaling pathways. Recurrent alveolar epithelial cell (AEC) injury may occur in the context of predisposing factors (e.g., genetic, environmental, epigenetic, immunologic, and gerontologic), leading to metabolic dysfunction, senescence, aberrant epithelial cell activation, and dysregulated epithelial repair. The dysregulated epithelial cell interacts with mesenchymal, immune, and endothelial cells via multiple signaling mechanisms to trigger fibroblast and myofibroblast activation. Recent single-cell RNA sequencing studies of IPF lungs support the epithelial injury model. These studies have uncovered a novel type of AEC with characteristics of an aberrant basal cell, which may disrupt normal epithelial repair and propagate a profibrotic phenotype. Here, we review the pathogenesis of IPF in the context of novel bioinformatics tools as strategies to discover pathways of disease, cell-specific mechanisms, and cell-cell interactions that propagate the profibrotic niche. Expected final online publication date for the Annual Review of Pathology: Mechanisms of Disease, Volume 17 is January 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

Engineering β Cell Replacement Therapies for Type 1 Diabetes: Biomaterial Advances and Considerations for Macroscale Constructs

While significant progress has been made in treatments for type 1 diabetes (T1D) based on exogenous insulin, transplantation of insulin-producing cells (islets or stem cell–derived β cells) remains a promising curative strategy. The current paradigm for T1D cell therapy is clinical islet transplantation (CIT)—the infusion of islets into the liver—although this therapeutic modality comes with its own limitations that deteriorate islet health. Biomaterials can be leveraged to actively address the limitations of CIT, including undesired host inflammatory and immune responses, lack of vascularization, hypoxia, and the absence of native islet extracellular matrix cues. Moreover, in efforts toward a clinically translatable T1D cell therapy, much research now focuses on developing biomaterial platforms at the macroscale, at which implanted platforms can be easily retrieved and monitored. In this review, we discuss how biomaterials have recently been harnessed for macroscale T1D β cell replacement therapies. Expected final online publication date for the Annual Review of Pathology: Mechanisms of Disease, Volume 17 is January 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

Lysophospholipid Mediators in Health and Disease

Lysophospholipids, exemplified by lysophosphatidic acid (LPA) and sphingosine 1-phosphate (S1P), are produced by the metabolism and perturbation of biological membranes. Both molecules are established extracellular lipid mediators that signal via specific G protein–coupled receptors in vertebrates. This widespread signaling axis regulates the development, physiological functions, and pathological processes of all organ systems. Indeed, recent research into LPA and S1P has revealed their important roles in cellular stress signaling, inflammation, resolution, and host defense responses. In this review, we focus on how LPA regulates fibrosis, neuropathic pain, abnormal angiogenesis, endometriosis, and disorders of neuroectodermal development such as hydrocephalus and alopecia. In addition, we discuss how S1P controls collective behavior, apoptotic cell clearance, and immunosurveillance of cancers. Advances in lysophospholipid research have led to new therapeutics in autoimmune diseases, with many more in earlier stages of development for a wide variety of diseases, such as fibrotic disorders, vascular diseases, and cancer. Expected final online publication date for the Annual Review of Pathology: Mechanisms of Disease, Volume 17 is January 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

Innate Immunity and Cancer Pathophysiology

Chronic inflammation increases the risk of several cancers, including gastric, colon, and hepatic cancers. Conversely, tumors, similar to tissue injury, trigger an inflammatory response coordinated by the innate immune system. Cellular and molecular mediators of inflammation modulate tumor growth directly and by influencing the adaptive immune response. Depending on the balance of immune cell types and signals within the tumor microenvironment, inflammation can support or restrain the tumor. Adding to the complexity, research from the past two decades has revealed that innate immune cells are highly heterogeneous and plastic, with variable phenotypes depending on tumor type, stage, and treatment. The field is now on the cusp of being able to harness this wealth of data to ( a) classify tumors on the basis of their immune makeup, with implications for prognosis, treatment choice, and clinical outcome, and ( b) design therapeutic strategies that activate antitumor immune responses by targeting innate immune cells. Expected final online publication date for the Annual Review of Pathology: Mechanisms of Disease, Volume 17 is January 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

Role of the Inflammasome in Liver Disease

The involvement of inflammasomes in the proinflammatory response observed in chronic liver diseases, such as alcohol-associated liver disease (ALD) and nonalcoholic fatty liver disease (NAFLD), is widely recognized. Although there are different types of inflammasomes, most studies to date have given attention to NLRP3 (nucleotide-binding oligomerization domain-like receptor family, pyrin domain containing 3) in the pathogenesis of ALD, NAFLD/nonalcoholic steatohepatitis, and fibrosis. Canonical inflammasomes are intracellular multiprotein complexes that are assembled after the sensing of danger signals and activate caspase-1, which matures interleukin (IL)-1β, IL-18, and IL-37 and also induces a form of cell death called pyroptosis. Noncanonical inflammasomes activate caspase-11 to induce pyroptosis. We discuss the different types of inflammasomes involved in liver diseases with a focus on ( a) signals and mechanisms of inflammasome activation, ( b) the role of different types of inflammasomes and their products in the pathogenesis of liver diseases, and ( c) potential therapeutic strategies targeting components of the inflammasomes or cytokines produced upon inflammasome activation. Expected final online publication date for the Annual Review of Pathology: Mechanisms of Disease, Volume 17 is January 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

Extrachromosomal DNA: An Emerging Hallmark in Human Cancer

Human genes are arranged on 23 pairs of chromosomes, but in cancer, tumor-promoting genes and regulatory elements can free themselves from chromosomes and relocate to circular, extrachromosomal pieces of DNA (ecDNA). ecDNA, because of its nonchromosomal inheritance, drives high-copy-number oncogene amplification and enables tumors to evolve their genomes rapidly. Furthermore, the circular ecDNA architecture fundamentally alters gene regulation and transcription, and the higher-order organization of ecDNA contributes to tumor pathogenesis. Consequently, patients whose cancers harbor ecDNA have significantly shorter survival. Although ecDNA was first observed more than 50 years ago, its critical importance has only recently come to light. In this review, we discuss the current state of understanding of how ecDNAs form and function as well as how they contribute to drug resistance and accelerated cancer evolution. Expected final online publication date for the Annual Review of Pathology: Mechanisms of Disease, Volume 17 is January 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

Multiplexed Ion Beam Imaging: Insights into Pathobiology

Next-generation tools for multiplexed imaging have driven a new wave of innovation in understanding how single-cell function and tissue structure are interrelated. In previous work, we developed multiplexed ion beam imaging by time of flight, a highly multiplexed platform that uses secondary ion mass spectrometry to image dozens of antibodies tagged with metal reporters. As instrument throughput has increased, the breadth and depth of imaging data have increased as well. To extract meaningful information from these data, we have developed tools for cell identification, cell classification, and spatial analysis. In this review, we discuss these tools and provide examples of their application in various contexts, including ductal carcinoma in situ, tuberculosis, and Alzheimer's disease. We hope the synergy between multiplexed imaging and automated image analysis will drive a new era in anatomic pathology and personalized medicine wherein quantitative spatial signatures are used routinely for more accurate diagnosis, prognosis, and therapeutic selection. Expected final online publication date for the Annual Review of Pathology: Mechanisms of Disease, Volume 17 is January 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

In Vivo Dynamics of the Latent Reservoir for HIV-1: New Insights and Implications for Cure

Although antiretroviral therapy (ART) can reduce viremia to below the limit of detection and allow persons living with HIV-1 (PLWH) to lead relatively normal lives, viremia rebounds when treatment is interrupted. Rebound reflects viral persistence in a stable latent reservoir in resting CD4+ T cells. This reservoir is now recognized as the major barrier to cure and is the focus of intense international research efforts. Strategies to cure HIV-1 infection include interventions to eliminate this reservoir, to prevent viral rebound from the reservoir, or to enhance immune responses such that viral replication is effectively controlled. Here we consider recent developments in understanding the composition of the reservoir and how it can be measured in clinical studies. We also discuss exciting new insights into the in vivo dynamics of the reservoir and the reasons for its remarkable stability. Finally we discuss recent discoveries on the complex processes that govern viral rebound. Expected final online publication date for the Annual Review of Pathology: Mechanisms of Disease, Volume 17 is January 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

DNA Methylation Profiling: An Emerging Paradigm for Cancer Diagnosis

Histomorphology has been a mainstay of cancer diagnosis in anatomic pathology for many years. DNA methylation profiling is an additional emerging tool that will serve as an adjunct to increase accuracy of pathological diagnosis. Genome-wide interrogation of DNA methylation signatures, in conjunction with machine learning methods, has allowed for the creation of clinical-grade classifiers, most prominently in central nervous system and soft tissue tumors. Tumor DNA methylation profiling has led to the identification of new entities and the consolidation of morphologically disparate cancers into biologically coherent entities, and it will progressively become mainstream in the future. In addition, DNA methylation patterns in circulating tumor DNA hold great promise for minimally invasive cancer detection and classification. Despite practical challenges that accompany any new technology, methylation profiling is here to stay and will become increasingly utilized as a cancer diagnostic tool across a range of tumor types. Expected final online publication date for the Annual Review of Pathology: Mechanisms of Disease, Volume 17 is January 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

Molecular Pathogenesis of Gastrointestinal Stromal Tumor: A Paradigm for Personalized Medicine

Over the past three to four decades, the molecular pathogenesis of gastrointestinal stromal tumors (GISTs) has been elucidated in great detail. In this review, we discuss the biological genesis of GISTs, identification of the various primary activating driver mutations (focusing on KIT and PDGFRA), oncogene addiction and targeted therapies with imatinib and other tyrosine kinase inhibitors, and the subsequent characterization of the various mechanisms of drug resistance. We illustrate how GIST has become a quintessential paradigm for personalized medicine. Expected final online publication date for the Annual Review of Pathology: Mechanisms of Disease, Volume 17 is January 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.