Environmental exposures interplay with human host factors to promote the development and progression of allergic diseases. The worldwide prevalence of allergic disease is rising as a result of complex gene-environment interactions that shape the immune system and host response. Research shows an association between the rise of allergic diseases and increasingly modern Westernized lifestyles, which are characterized by increased urbanization, time spent indoors, and antibiotic usage. These environmental changes result in increased exposure to air and traffic pollution, fungi, infectious agents, tobacco smoke, and other early-life and lifelong risk factors for the development and exacerbation of asthma and allergic diseases. It is increasingly recognized that the timing, load, and route of allergen exposure affect allergic disease phenotypes and development. Still, our ability to prevent allergic diseases is hindered by gaps in understanding of the underlying mechanisms and interaction of environmental, viral, and allergen exposures with immune pathways that impact disease development. This Review highlights epidemiologic and mechanistic evidence linking environmental exposures to the development and exacerbation of allergic airway responses.
Liza Bronner Murrison, Eric B. Brandt, Jocelyn Biagini Myers, Gurjit K. Khurana Hershey
The rapid expansion in the number of encephalitis disorders associated with autoantibodies against neuronal proteins has led to an incremental increase in use of the term “autoimmune epilepsy,” yet has occurred with limited attention to the physiopathology of each disease and genuine propensity to develop epilepsy. Indeed, most autoimmune encephalitides present with seizures, but the probability of evolving to epilepsy is relatively small. The risk of epilepsy is higher for disorders in which the antigens are intracellular (often T cell–mediated) compared with disorders in which the antigens are on the cell surface (antibody-mediated). Most autoantibodies against neuronal surface antigens show robust effects on the target proteins, resulting in hyperexcitability and impairment of synaptic function and plasticity. Here, we trace the evolution of the concept of autoimmune epilepsy and examine common inflammatory pathways that might lead to epilepsy. Then, we focus on several antibody-mediated encephalitis disorders that associate with seizures and review the synaptic alterations caused by patients’ antibodies, with emphasis on those that have been modeled in animals (e.g., antibodies against NMDA, AMPA receptors, LGI1 protein) or in cultured neurons (e.g., antibodies against the GABAb receptor).
Christian Geis, Jesus Planagumà, Mar Carreño, Francesc Graus, Josep Dalmau
The Hedgehog pathway is critical for the development of diverse organs. Misactivation of the Hedgehog pathway can cause developmental abnormalities and cancers, including medulloblastoma, the most common pediatric brain tumor, and basal cell carcinoma, the most common cancer in the United States. Here, we review how basic, translational, and clinical studies of the Hedgehog pathway have helped reveal how cells communicate, how intercellular communication controls development, how signaling goes awry to cause cancer, and how to use targeted molecular agents to treat both inherited and sporadic cancers.
David R. Raleigh, Jeremy F. Reiter
The initiation and evolution of myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) are driven by genomic events that disrupt multiple genes controlling hematopoiesis. Human genetic studies have discovered germline mutations in single genes that instigate familial MDS/AML. The best understood of these genes encode transcription factors, such as GATA-2, RUNX1, ETV6, and C/EBPα, which establish and maintain genetic networks governing the genesis and function of blood stem and progenitor cells. Many questions remain unanswered regarding how genes and circuits within these networks function in physiology and disease and whether network integrity is exquisitely sensitive to or efficiently buffered from perturbations. In familial MDS/AML, mutations change the coding sequence of a gene to generate a mutant protein with altered activity or introduce frameshifts or stop codons or disrupt regulatory elements to alter protein expression. Each mutation has the potential to exert quantitatively and qualitatively distinct influences on networks. Consistent with this mechanistic diversity, disease onset is unpredictable and phenotypic variability can be considerable. Efforts to elucidate mechanisms and forge prognostic and therapeutic strategies must therefore contend with a spectrum of patient-specific leukemogenic scenarios. Here we illustrate mechanistic advances in our understanding of familial MDS/AML syndromes caused by germline mutations of hematopoietic transcription factors.
Jane E. Churpek, Emery H. Bresnick
Antisense oligonucleotides (ASOs) are chemically synthesized nucleic acid analogs designed to bind to RNA by Watson-Crick base pairing. Following binding to the targeted RNA, the ASO perturbs RNA function by promoting selective degradation of the targeted RNA, altering RNA intermediary metabolism, or disrupting function of the RNA. Most antisense drugs are chemically modified to enhance their pharmacological properties and for passive targeting of the tissues of therapeutic interest. Recent advances in selective tissue targeting have resulted in a newer generation of ASO drugs that are more potent and better tolerated than previous generations, spawning renewed interest in identifying selective ligands that enhance targeted delivery of ASOs to tissues.
Punit P. Seth, Michael Tanowitz, C. Frank Bennett
The tumor suppressor phosphatase and tensin homolog (PTEN) classically counteracts the PI3K/AKT/mTOR signaling cascade. Germline pathogenic PTEN mutations cause PTEN hamartoma tumor syndrome (PHTS), featuring various benign and malignant tumors, as well as neurodevelopmental disorders such as autism spectrum disorder. Germline and somatic mosaic mutations in genes encoding components of the PI3K/AKT/mTOR pathway downstream of PTEN predispose to syndromes with partially overlapping clinical features, termed the “PTEN-opathies.” Experimental models of PTEN pathway disruption uncover the molecular and cellular processes influencing clinical phenotypic manifestations. Such insights not only teach us about biological mechanisms in states of health and disease, but also enable more accurate gene-informed cancer risk assessment, medical management, and targeted therapeutics. Hence, the PTEN-opathies serve as a prototype for bedside to bench, and back to the bedside, practice of evidence-based precision medicine.
Lamis Yehia, Joanne Ngeow, Charis Eng
The field of hereditary kidney cancer has begun to mature following the identification of several germline syndromes that define genetic and molecular features of this cancer. Molecular defects within these hereditary syndromes demonstrate consistent deficits in angiogenesis and metabolic signaling, largely driven by altered hypoxia signaling. The classical mutation, loss of function of the von Hippel-Lindau (VHL) tumor suppressor, provides a human pathogenesis model for critical aspects of pseudohypoxia. These features are mimicked in a less common hereditary renal tumor syndrome, known as hereditary leiomyomatosis and renal cell carcinoma. Here, we review renal tumor angiogenesis and metabolism from a HIF-centric perspective, considering alterations in the hypoxic landscape, and molecular deviations resulting from high levels of HIF family members. Mutations underlying HIF deregulation drive multifactorial aberrations in angiogenic signals and metabolism. The mechanisms by which these defects drive tumor growth are still emerging. However, the distinctive patterns of angiogenesis and glycolysis-/glutamine-dependent bioenergetics provide insight into the cellular environment of these cancers. The result is a scenario permissive for aggressive tumorigenesis especially within the proximal renal tubule. These features of tumorigenesis have been highly actionable in kidney cancer treatments, and will likely continue as central tenets of kidney cancer therapeutics.
John C. Chappell, Laura Beth Payne, W. Kimryn Rathmell
Although platelets are best known for their role in hemostasis, they are also crucial in development, host defense, inflammation, and tissue repair. Many of these roles are regulated by the immune-like receptors glycoprotein VI (GPVI) and C-type lectin receptor 2 (CLEC-2), which signal through an immunoreceptor tyrosine–based activation motif (ITAM). GPVI is activated by collagen in the subendothelial matrix, by fibrin and fibrinogen in the thrombus, and by a remarkable number of other ligands. CLEC-2 is activated by the transmembrane protein podoplanin, which is found outside of the vasculature and is upregulated in development, inflammation, and cancer, but there is also evidence for additional ligands. In this Review, we discuss the physiological and pathological roles of CLEC-2 and GPVI and their potential as targets in thrombosis and thrombo-inflammatory disorders (i.e., disorders in which inflammation plays a critical role in the ensuing thrombosis) relative to current antiplatelet drugs.
Julie Rayes, Steve P. Watson, Bernhard Nieswandt
Donor age and recipient age are factors that influence transplantation outcomes. Aside from age-associated differences in intrinsic graft function and alloimmune responses, the ability of young and old cells to exert either rejuvenating or aging effects extrinsically may also apply to the transplantation of hematopoietic stem cells or solid organ transplants. While the potential for rejuvenation mediated by the transfer of youthful cells is currently being explored for therapeutic applications, aspects that relate to accelerating aging are no less clinically significant. Those effects may be particularly relevant in transplantation with an age discrepancy between donor and recipient. Here, we review recent advances in understanding the mechanisms by which young and old cells modify their environments to promote rejuvenation- or aging-associated phenotypes. We discuss their relevance to clinical transplantation and highlight potential opportunities for therapeutic intervention.
Ashley Lau, Brian K. Kennedy, James L. Kirkland, Stefan G. Tullius
Fibrosis, the progressive accumulation of connective tissue that occurs in response to injury, causes irreparable organ damage and may result in organ failure. The few available antifibrotic treatments modify the rate of fibrosis progression, but there are no available treatments to reverse established fibrosis. Thus, more effective therapies are urgently needed. Molecular imaging is a promising biomedical methodology that enables noninvasive visualization of cellular and subcellular processes. It provides a unique means to monitor and quantify dysregulated molecular fibrotic pathways in a noninvasive manner. Molecular imaging could be used for early detection, disease staging, and prognostication, as well as for assessing disease activity and treatment response. As fibrotic diseases are often molecularly heterogeneous, molecular imaging of a specific pathway could be used for patient stratification and cohort enrichment with the goal of improving clinical trial design and feasibility and increasing the ability to detect a definitive outcome for new therapies. Here we review currently available molecular imaging probes for detecting fibrosis and fibrogenesis, the active formation of new fibrous tissue, and their application to models of fibrosis across organ systems and fibrotic processes. We provide our opinion as to the potential roles of molecular imaging in human fibrotic diseases.
Sydney B. Montesi, Pauline Désogère, Bryan C. Fuchs, Peter Caravan
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