Annual Review of Pathology: Mechanisms of Disease - Volume 3, 2008

Molecular analysis in the service of research on human disease has finally come of age, as the chapters within this volume testify. Many technical advances, among them the development of recombinant DNA and its many applications, opened the way to study cells and processes that were unapproachable in the 1960s, when I first began my research career. The state of molecular biological studies at that time limited studies of human cell membrane proteins to experimental material most available and accessible, making the human erythrocyte membrane the favored target. I describe here how studies of red blood cell membrane proteins evolved and how results from those studies still inform present-day research.

Prion diseases are infectious neurodegenerative diseases occurring in humans and animals with an invariably lethal outcome. One fundamental mechanistic event in prion diseases is the aggregation of aberrantly folded prion protein into large amyloid plaques and fibrous structures associated with neurodegeneration. The cellular prion protein (PrP^C) is absolutely required for disease development, and prion knockout mice are not susceptible to prion disease. Prions accumulate not only in the central nervous system but also in lymphoid organs, as shown for new variant and sporadic Creutzfeldt-Jakob patients and for some animals. To date it is largely accepted that prions consist primarily of PrP^Sc, a misfolded and aggregated β-sheet-rich isoform of PrP^C. However, PrP^Sc may or may not be completely congruent with the infectious moiety. Here, we discuss the molecular mechanisms leading to neurodegeneration, the role of the immune system in prion pathogenesis, and the existence of prion strains that appear to have different tropisms and biochemical characteristics.

Aging is accompanied by cognitive decline in a major segment of the population and is the primary risk factor for Alzheimer's disease and other prevalent neurodegenerative disorders. Despite this central role in disease pathogenesis and morbidity, the aging of the brain has not been well understood at a molecular level. This review seeks to integrate what is known about age-related cognitive and neuroanatomical changes with recent advances in understanding basic molecular mechanisms that underlie aging. An important issue is how normal brain aging transitions to pathological aging, giving rise to neurodegenerative disorders. Toxic protein aggregates have been identified as potential contributory factors, including amyloid β-protein in Alzheimer's disease, tau in frontotemporal dementia, and α-synuclein in Parkinson's disease. However, current models of pathogenesis do not explain the origin of the common sporadic forms of these diseases or address the critical nexus between aging and disease. This review discusses potential approaches to unifying the systems biology of the aging brain with the pathogenesis of neurodegeneration.

DNA microarray platforms for gene expression profiling were invented relatively recently, and breast cancer has been among the earliest and most intensely studied diseases using this technology. The molecular signatures so identified help reveal the biologic spectrum of breast cancers, provide diagnostic tools as well as prognostic and predictive gene signatures, and may identify new therapeutic targets. Data are best presented in an open access format to facilitate external validation, the most crucial step in identifying robust, reproducible gene signatures suitable for clinical translation. Clinically practical applications derived from full expression profile studies already in use include reduced versions of microarrays representing key discriminatory genes and therapeutic targets, quantitative polymerase chain reaction assays, or immunohistochemical surrogate panels (suitable for application to standard pathology blocks). Prospective trials are now underway to determine the value of such tools for clinical decision making in breast cancer; these efforts may serve as a model for using such approaches in other tumor types.

When cells die in vivo, they trigger an inflammatory response. The ensuing hyperemia, leak of plasma proteins, and recruitment of leukocytes serve a number of useful functions in host defense and tissue repair. However, this response can also cause tissue damage and contribute to the pathogenesis of a number of diseases. Given the key role of inflammation in these processes, it is important to understand the underlying mechanisms that drive this response. Injured cells release danger signals that alert the host to cell death. Some of these molecules are recognized by cellular receptors that stimulate the generation of proinflammatory mediators. Other molecules released by dead cells stimulate the generation of mediators from extracellular sources. The resulting mediators then orchestrate the inflammatory response, eliciting its various vascular and cellular components. Dead cells also release danger signals that activate dendritic cells and promote the generation of immune responses to antigens. Here we review what is presently known about the sterile inflammatory response and its underlying mechanisms.

Myocarditis is a cardiac disease associated with inflammation and injury of the myocardium. Several viruses have been associated with myocarditis in humans. However, coxsackievirus B3 is still considered the dominant etiological agent. The observed pathology in viral myocarditis is a result of cooperation or teamwork between viral processes and host immune responses at various stages of disease. Both innate and adaptive immune responses are crucial determinants of the severity of myocardial damage, and contribute to the development of chronic myocarditis and dilated cardiomyopathy following acute viral myocarditis. Advances in genomics and proteomics, and in the use of informatics and biostatistics, are allowing unbiased initial evaluations that can be the basis for testable hypotheses about virus pathogenesis and new therapies.

The past two decades have witnessed an explosion in our understanding of pancreatic cancer, and it is now clear that pancreatic cancer is a disease of inherited (germ-line) and somatic gene mutations. The genes mutated in pancreatic cancer include KRAS2, p16/CDKN2A, TP53, and SMAD4/DPC4, and these are accompanied by a substantial compendium of genomic and transcriptomic alterations that facilitate cell cycle deregulation, cell survival, invasion, and metastases. Pancreatic cancers do not arise de novo, and three distinct precursor lesions have been identified. Experimental models of pancreatic cancer have been developed in genetically engineered mice, which recapitulate the multistep progression of the cognate human disease. Although the putative cell of origin for pancreatic cancer remains elusive, minor populations of cells with stem-like properties have been identified that appear responsible for tumor initiation, metastases, and resistance of pancreatic cancer to conventional therapies.

We describe the molecular and cellular mechanisms believed to be responsible for the rejection of renal allografts, including acute T cell–mediated rejection, acute antibody-mediated (humoral) rejection, rejection mediated by the innate immune system, and chronic rejection. We present mechanisms of graft acceptance, including accommodation, regulation, and tolerance. Studies in animals have replicated many pathologic features of acute and chronic rejection. We illuminate the pathogenesis of human pathology by reflection from experimental models.

Metastasis is the result of cancer cell adaptation to a tissue microenvironment at a distance from the primary tumor. Metastatic cancer cells require properties that allow them not only to adapt to a foreign microenvironment but to subvert it in a way that is conducive to their continued proliferation and survival. Recent conceptual and technological advances have contributed to our understanding of the role of the host tissue stroma in promoting tumor cell growth and dissemination and have provided new insight into the genetic makeup of cancers with high metastatic proclivity.

Profound thrombocytopenia and microangiopathic hemolytic anemia characterize thrombotic microangiopathy, which includes two major disorders: thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS). TTP has at least three types: congenital or familial, idiopathic, and nonidiopathic. The congenital and idiopathic TTP syndromes are caused primarily by deficiency of ADAMTS13, owing to mutations in the ADAMTS13 gene or autoantibodies that inhibit ADAMTS13 activity. HUS is similar to TTP, but is associated with acute renal failure. Diarrhea-associated HUS accounts for more than 90% of cases and is usually caused by infection with Shiga-toxin-producing Escherichia coli (O157:H7). Diarrhea-negative HUS is associated with complement dysregulation in up to 50% of cases, caused by mutations in complement factor H, membrane cofactor protein, factor I or factor B, or by autoantibodies against factor H. The incomplete penetrance of mutations in either ADAMTS13 or complement regulatory genes suggests that precipitating events or triggers may be required to cause thrombotic microangiopathy in many patients.

The popular view that all lipid mediators are pro-inflammatory arises largely from the finding that nonsteroidal anti-inflammatory drugs block the biosynthesis of prostaglandins. The resolution of inflammation was widely held as a passive event until recently, with the characterization of novel biochemical pathways and lipid-derived mediators that are actively turned on in resolution and that possess potent anti-inflammatory and proresolving actions. A lipid-mediator informatics approach was employed to systematically identify new families of endogenous local-acting mediators from omega-3 polyunsaturated fatty acids (eicosapentaenoic acid and docosahexaenoic acid) in resolving exudates, which also contain lipoxins and aspirin-triggered lipoxins generated from arachidonic acid. Given their potent bioactions, these new chemical mediator families were termed resolvins and protectins. Here, we review the recent advances in our understanding of the biosynthesis and stereospecific actions of these new proresolving mediators, which have also proven to be organ protective and antifibrotic.

Three-dimensional (3D) epithelial culture systems recreate the cardinal features of glandular epithelium in vivo and represent a valuable tool for modeling breast cancer initiation and progression in a structurally appropriate context. 3D models have emerged as a powerful method to interrogate the biological activities of cancer genes and oncogenic pathways, and recent studies have poignantly illustrated their utility in dissecting the emerging role of tensional force in regulating epithelial tissue homeostasis. We review how 3D models are being used to investigate fundamental cellular and biophysical mechanisms associated with breast cancer progression that have not been readily amenable to traditional genetic or biochemical analysis.

Childhood tumors containing cells that are morphologically and functionally similar to normal progenitor cells provide fertile ground for investigating the links between development and cancer. In this respect, integrated studies of normal cerebellar development and the medulloblastoma, a malignant embryonal tumor of the cerebellum, have proven especially fruitful. Emerging evidence indicates that the different precursor cell populations that form the cerebellum and the cell signaling pathways that regulate its development likely represent distinct compartments from which the various subtypes of medulloblastoma arise. Definitive characterization of each medulloblastoma subtype will undoubtedly improve treatment of this disease and provide important insights to the origins of cancer.

The lymphatic vasculature is essential for the maintenance of tissue fluid balance, immune surveillance, and adsorption fatty acids in the gut. The lymphatic vessels are also crucially involved in the pathogenesis of diseases such as tumor metastasis, lymphedema, and various inflammatory conditions. Attempts to control or treat these diseases have drawn a lot of interest to lymphatic vascular research during the past few years. Recently, several markers specific for lymphatic endothelium and models for lymphatic vascular research have been characterized, enabling great technical progress in lymphatic vascular biology, and many critical regulators of lymphatic vessel growth have been identified. Despite these significant achievements, our understanding of the lymphatic vessel development and pathogenesis is still rather limited. Several key questions remain to be resolved, including the relative contributions of different pathways targeting lymphatic vasculature, the molecular and cellular processes of lymphatic maturation, and the detailed mechanisms of tumor metastasis via the lymphatic system.

The endoplasmic reticulum (ER) is the site of synthesis and folding of membrane and secretory proteins, which, collectively, represent a large fraction of the total protein output of a mammalian cell. Therefore, the protein flux through the ER must be carefully monitored for abnormalities, including the buildup of misfolded proteins. Mammalian cells have evolved an intricate set of signaling pathways from the ER to the cytosol and nucleus, to allow the cell to respond to the presence of misfolded proteins within the ER. These pathways, known collectively as the unfolded protein response, are important for normal cellular homeostasis and organismal development and may also play key roles in the pathogenesis of many diseases. This review provides background information on the unfolded protein response and discusses a selection of diseases whose pathogenesis involves ER stress.

Autophagy is a process by which cytoplasmic components are sequestered in double membrane vesicles and degraded upon fusion with lysosomal compartments. In yeast, autophagy is activated in response to changes in the extracellular milieu. Depending upon the stimulus, autophagy can degrade cytoplasmic contents nonspecifically or can target the degradation of specific cellular components. Both of these have been adopted in higher eukaryotes and account for the expanding role of autophagy in various cellular processes, as well as contribute to the variation in cellular outcomes after induction of autophagy. In some cases, autophagy appears to be an adaptive response, whereas under other circumstances it is involved in cell death. In mammals, autophagy has been implicated in either the pathogenesis or response to a wide variety of diseases, including neurodegenerative disease, chronic bacterial and viral infections, atherosclerosis, and cancer. As the basic molecular pathways that regulate autophagy are elucidated, the relationship of autophagy to the pathogenesis of various disease states emerges.

Bone is a dynamic organ constantly remodeled to support calcium homeostasis and structural needs. The osteoclast is the cell responsible for removing both the organic and inorganic components of bone. It is derived from hematopoietic progenitors in the macrophage lineage and differentiates in response to the tumor necrosis factor family cytokine receptor activator of NFκB ligand. αvβ3 integrin mediates cell adhesion necessary for polarization and formation of an isolated, acidified resorptive microenvironment. Defects in osteoclast function, whether genetic or iatrogenic, may increase bone mass but lead to poor bone quality and a high fracture risk. Pathological stimulation of osteoclast formation and resorption occurs in postmenopausal osteoporosis, inflammatory arthritis, and metastasis of tumors to bone. In these diseases, osteoclast activity causes bone loss that leads to pain, deformity, and fracture. Thus, osteoclasts are critical for normal bone function, but their activity must be controlled.

Detailed and comprehensive characterization of proteins is a major goal of proteomics. This goal has become more realistic today with the latest high-resolution mass spectrometers capable of faster sequencing in a high-throughput fashion and with the emergence of new techniques such as protein and peptide microarrays. A promising area for discovery is the application of these advanced mass spectrometric and other quantitative proteomic methodologies to laboratory diagnosis. This review focuses on the role of proteomics in the development of new laboratory diagnostics and the implications for routine diagnosis and monitoring of diseases.

Influenza viruses are significant human respiratory pathogens that cause both seasonal, endemic infections and periodic, unpredictable pandemics. The worst pandemic on record, in 1918, killed approximately 50 million people worldwide. Human infections caused by H5N1 highly pathogenic avian influenza viruses have raised concern about the emergence of another pandemic. The histopathology of fatal influenza virus pneumonias as documented over the past 120 years is reviewed here. Strikingly, the spectrum of pathologic changes described in the 1918 influenza pandemic is not significantly different from the histopathology observed in other less lethal pandemics or even in deaths occurring during seasonal influenza outbreaks.

Airway smooth muscle plays a multifaceted role in the pathogenesis of asthma. We review the current understanding of the contribution of airway myocytes to airway inflammation, airway wall remodeling, and airflow obstruction in this prevalent disease syndrome. Together, these roles make airway smooth muscle an attractive target for asthma therapy.