{"title":"Genetics and Epigenetics of Type 1 Diabetes Self-Reactive T Cells","authors":"Tae Gun Kang, Benjamin Youngblood","doi":"10.1101/cshperspect.a041586","DOIUrl":"https://doi.org/10.1101/cshperspect.a041586","url":null,"abstract":"Type 1 diabetes (T1D) serves as an exemplar of chronic autoimmune disease characterized by insulin deficiency due to pancreatic β-cell destruction, leading to hyperglycemia and progressive organ failure. Until recently, therapeutic efforts to mitigate the root cause of disease have been limited by the challenges in studying mechanisms involved in immune tolerance in humans. The current clinical advances, and existing challenges, highlight a need to incorporate new insights into mechanisms into correlative studies that assess immune tolerance in the setting of delayed β-cell destruction. Among several factors known to promote T1D, autoreactive T cells play a critical role in initiating and sustaining disease through their direct recognition and destruction of β cells. Emerging research defining the genetic and epigenetic etiology of long-lived β-cell-specific T cells is providing new insight into mechanisms that promote lifelong disease and future opportunities for targeted therapeutic intervention. This article will provide an overview of recent progress toward understanding the development of autoreactive T cells and epigenetic mechanisms stabilizing their developmental state during T1D pathogenesis.","PeriodicalId":10452,"journal":{"name":"Cold Spring Harbor perspectives in medicine","volume":"78 1","pages":""},"PeriodicalIF":5.4,"publicationDate":"2024-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141935076","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Ana Westenberger, Norbert Brüggemann, Christine Klein
{"title":"Genetics of Parkinson's Disease: From Causes to Treatment","authors":"Ana Westenberger, Norbert Brüggemann, Christine Klein","doi":"10.1101/cshperspect.a041774","DOIUrl":"https://doi.org/10.1101/cshperspect.a041774","url":null,"abstract":"The genetic architecture of Parkinson's disease (PD) comprises five autosomal dominantly inherited forms with a clinical picture overall resembling idiopathic disease (PARK-<em>SNCA</em>, PARK-<em>LRRK2</em>, PARK-<em>VPS35</em>, PARK-<em>CHCHD2</em>, and PARK-<em>RAB32</em>) and three recessive types (PARK-<em>PRKN</em>, PARK-<em>PINK1</em>, and PARK-<em>PARK7</em>), several monogenic forms causing atypical parkinsonism, as well as a plethora of known genetic risk factors, most notably <em>SNCA</em> and <em>GBA1</em> including a recently discovered risk variant unique to individuals of African descent, as well as polygenic scores. The Movement Disorder Society Genetic mutation database (MDSGene) (www.mdsgene.org) provides PD genotype–phenotype relationships, whereas global PD genetics networks, such as the Global Parkinson's Genetics Program (www.gp2.org) elucidate PD genetic factors at an unprecedented scale. Two large studies in relatively unselected, multicenter PD samples estimate the frequency of genetic forms, including PARK-<em>GBA1</em>, at ∼15%. PD genetics are becoming increasingly actionable, with the first gene-targeted clinical trials underway. Furthermore, PD genetics has recently been incorporated into a new biological classification of PD.","PeriodicalId":10452,"journal":{"name":"Cold Spring Harbor perspectives in medicine","volume":"1 1","pages":""},"PeriodicalIF":5.4,"publicationDate":"2024-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141934986","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"The Role of B Lymphocytes in Type 1 Diabetes","authors":"Mia J. Smith, Joanne Boldison, F. Susan Wong","doi":"10.1101/cshperspect.a041593","DOIUrl":"https://doi.org/10.1101/cshperspect.a041593","url":null,"abstract":"While autoreactive T cells are known to induce β-cell death in type 1 diabetes (T1D), self-reactive B cells also play an important role in the pathogenesis of T1D. Studies have shown that individuals living with T1D have an increased frequency of self-reactive B cells that escape from the bone marrow and populate peripheral organs, become activated, and participate in disease. These failed tolerance mechanisms may be attributed to genetic risk alleles that are associated with the development of T1D. Once in the periphery, these self-reactive B cells act as important antigen-presenting cells to autoreactive T cells and produce autoantibodies that are used to predict individuals at risk for or diagnosed with T1D. Here, we discuss the evidence that B cells are important in the pathogenesis of T1D, how these cells escape normal tolerance mechanisms, their role in disease progression, and how targeting these cells and/or monitoring them as biomarkers for response to therapy will be of clinical benefit.","PeriodicalId":10452,"journal":{"name":"Cold Spring Harbor perspectives in medicine","volume":"195 1","pages":""},"PeriodicalIF":5.4,"publicationDate":"2024-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141934988","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Mouse Models of Metastasis and Dormancy.","authors":"Ahmed Mahmoud, Karuna Ganesh","doi":"10.1101/cshperspect.a041386","DOIUrl":"10.1101/cshperspect.a041386","url":null,"abstract":"<p><p>Metastasis is the ultimate and often lethal stage of cancer. Metastasis occurs in three phases that may vary across individuals: First, dissemination from the primary tumor. Second, tumor dormancy at the metastatic site where micrometastatic cancer cells remain quiescent or, in dynamic cycles of proliferation and elimination, remaining clinically undetectable. Finally, cancer cells are able to overcome microenvironmental constraints for outgrowth, or the formation of clinically detectable macrometastases that colonize distant organs and are largely incurable. A variety of approaches have been used to model metastasis to elucidate molecular mechanisms and identify putative therapeutic targets. In particular, metastatic dormancy has been challenging to model in vivo due to the sparse numbers of cancer cells in micrometastasis nodules and the long latency times required for tumor outgrowth. Here, we review state-of-the art genetically engineered mouse, syngeneic, and patient-derived xenograft approaches for modeling metastasis and dormancy. We describe the advantages and limitations of various metastasis models, novel findings enabled by such approaches, and highlight opportunities for future improvement.</p>","PeriodicalId":10452,"journal":{"name":"Cold Spring Harbor perspectives in medicine","volume":" ","pages":""},"PeriodicalIF":7.8,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10925556/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10213389","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Germline Genetic Testing for Hereditary Breast and Ovarian Cancer: Current Concepts in Risk Evaluation.","authors":"Siddhartha Yadav, Fergus J Couch, Susan M Domchek","doi":"10.1101/cshperspect.a041318","DOIUrl":"10.1101/cshperspect.a041318","url":null,"abstract":"<p><p>Our understanding of hereditary breast and ovarian cancer has significantly improved over the past two decades. In addition to <i>BRCA1/2</i>, pathogenic variants in several other DNA-repair genes have been shown to increase the risks of breast and ovarian cancer. The magnitude of cancer risk is impacted not only by the gene involved, but also by family history of cancer, polygenic risk scores, and, in certain genes, pathogenic variant type or location. While estimates of breast and ovarian cancer risk associated with pathogenic variants are available, these are predominantly based on studies of high-risk populations with young age at diagnosis of cancer, multiple primary cancers, or family history of cancer. More recently, breast cancer risk for germline pathogenic variant carriers has been estimated from population-based studies. Here, we provide a review of the field of germline genetic testing and risk evaluation for hereditary breast and ovarian cancers in high-risk and population-based settings.</p>","PeriodicalId":10452,"journal":{"name":"Cold Spring Harbor perspectives in medicine","volume":" ","pages":""},"PeriodicalIF":7.8,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11293548/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139048374","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Caitlin S Latimer, Katherine E Prater, Nadia Postupna, C Dirk Keene
{"title":"Resistance and Resilience to Alzheimer's Disease.","authors":"Caitlin S Latimer, Katherine E Prater, Nadia Postupna, C Dirk Keene","doi":"10.1101/cshperspect.a041201","DOIUrl":"10.1101/cshperspect.a041201","url":null,"abstract":"<p><p>Dementia is a significant public health crisis; the most common underlying cause of age-related cognitive decline and dementia is Alzheimer's disease neuropathologic change (ADNC). As such, there is an urgent need to identify novel therapeutic targets for the treatment and prevention of the underlying pathologic processes that contribute to the development of AD dementia. Although age is the top risk factor for dementia in general and AD specifically, these are not inevitable consequences of advanced age. Some individuals are able to live to advanced age without accumulating significant pathology (resistance to ADNC), whereas others are able to maintain cognitive function despite the presence of significant pathology (resilience to ADNC). Understanding mechanisms of resistance and resilience will inform therapeutic strategies to promote these processes to prevent or delay AD dementia. This article will highlight what is currently known about resistance and resilience to AD, including our current understanding of possible underlying mechanisms that may lead to candidate preventive and treatment interventions for this devastating neurodegenerative disease.</p>","PeriodicalId":10452,"journal":{"name":"Cold Spring Harbor perspectives in medicine","volume":" ","pages":""},"PeriodicalIF":7.8,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11293546/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139048375","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Optogenetic Vision Restoration.","authors":"Volker Busskamp, Botond Roska, Jose-Alain Sahel","doi":"10.1101/cshperspect.a041660","DOIUrl":"10.1101/cshperspect.a041660","url":null,"abstract":"<p><p>Optogenetics has emerged over the past 20 years as a powerful tool to investigate the various circuits underlying numerous functions, especially in neuroscience. The ability to control by light the activity of neurons has enabled the development of therapeutic strategies aimed at restoring some level of vision in blinding retinal conditions. Promising preclinical and initial clinical data support such expectations. Numerous challenges remain to be tackled (e.g., confirmation of safety, cell and circuit specificity, patterns, intensity and mode of stimulation, rehabilitation programs) on the path toward useful vision restoration.</p>","PeriodicalId":10452,"journal":{"name":"Cold Spring Harbor perspectives in medicine","volume":" ","pages":""},"PeriodicalIF":7.8,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11293536/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41112602","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Léo Bertrand, Alexander V Chervonsky, Agnès Lehuen
{"title":"Innate Immunity in Type 1 Diabetes.","authors":"Léo Bertrand, Alexander V Chervonsky, Agnès Lehuen","doi":"10.1101/cshperspect.a041595","DOIUrl":"https://doi.org/10.1101/cshperspect.a041595","url":null,"abstract":"<p><p>Type 1 diabetes (T1D) results from the destruction of pancreatic β cells by the immune system, to which both pancreatic β-cell dysfunction and pathological activation of the immune system contribute. This paper is focused on understanding the modalities of this activation, and the genetic and environmental factors increasing its risk. Innate immunity has a critical role in the loss of self-tolerance and promotion of inflammation either directly using innate effector mechanisms or by providing activation signals to anti-islet adaptive autoimmunity. We provide an overview of various deleterious and protective roles of innate immunity in T1D inside pancreatic islets, regional lymph nodes, and distant locations such as the gut.</p>","PeriodicalId":10452,"journal":{"name":"Cold Spring Harbor perspectives in medicine","volume":" ","pages":""},"PeriodicalIF":7.8,"publicationDate":"2024-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141792096","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Angiogenesis: Biology and Pathology, Second Edition.","authors":"Diane R Bielenberg, Patricia A D'Amore","doi":"10.1101/cshperspect.a041779","DOIUrl":"https://doi.org/10.1101/cshperspect.a041779","url":null,"abstract":"<p><p>During development, the first blood vessels are formed by the de novo assembly of angioblasts, endothelial cell precursors, in a process called vasculogenesis. All subsequent sprouting of blood vessels from pre-existing vessels is termed angiogenesis and is a process that continues throughout our lifespan during physiological processes such as wound healing as well as in number of pathological conditions, such as tumor growth and age-related macular degeneration. The circulatory system pumps blood from the heart out to the organs through arteries and deliveries oxygen and nutrients via capillaries to tissues and cells and returns carbon dioxide and waste products back through veins. Each organ varies in its blood vessel patterning, reflecting specialization to accomplish diverse functions including vascular permeability, filtration, immune trafficking, and hormone regulation. Approximately 90% of the fluid extravasated into the interstitium is recycled back to the circulatory system via the unidirectional lymphatic system. Lymphatic capillaries drain fluid, proteins, and cells from tissues and transport this lymph fluid through collecting lymphatic ducts toward lymph nodes. Eventually lymphatic fluid from the right and left lymphatic ducts joins the subclavian veins and recirculates throughout the circulatory system. These two intricate vascular systems, working in cooperation, help to maintain essential bodily functions such as fluid dynamics, tissue homeostasis, blood pressure, metabolism, and immunity. However, dysfunction of these systems is associated with a host of pathological conditions, including cardiovascular diseases, obesity, retinopathy, hypoxia, necrosis, and vascular malformations.</p>","PeriodicalId":10452,"journal":{"name":"Cold Spring Harbor perspectives in medicine","volume":" ","pages":""},"PeriodicalIF":7.8,"publicationDate":"2024-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141792095","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Timothy J Kieffer, Corinne A Hoesli, A M James Shapiro
{"title":"Advances in Islet Transplantation and the Future of Stem Cell-Derived Islets to Treat Diabetes.","authors":"Timothy J Kieffer, Corinne A Hoesli, A M James Shapiro","doi":"10.1101/cshperspect.a041624","DOIUrl":"https://doi.org/10.1101/cshperspect.a041624","url":null,"abstract":"<p><p>β-Cell replacement for type 1 diabetes (T1D) can restore normal glucose homeostasis, thereby eliminating the need for exogenous insulin and halting the progression of diabetes complications. Success in achieving insulin independence following transplantation of cadaveric islets fueled academic and industry efforts to develop techniques to mass produce β cells from human pluripotent stem cells, and these have now been clinically validated as an alternative source of regulated insulin production. Various encapsulation strategies are being pursued to contain implanted cells in a retrievable format, and different implant sites are being explored with some strategies reaching clinical studies. Stem cell lines, whether derived from embryonic sources or reprogrammed somatic cells, are being genetically modified for designer features, including immune evasiveness to enable implant without the use of chronic immunosuppression. Although hurdles remain in optimizing large-scale manufacturing, demonstrating efficacy, durability, and safety, products containing stem cell-derived β cells promise to provide a potent treatment for insulin-dependent diabetes.</p>","PeriodicalId":10452,"journal":{"name":"Cold Spring Harbor perspectives in medicine","volume":" ","pages":""},"PeriodicalIF":7.8,"publicationDate":"2024-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141792094","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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