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1.
Annu Rev Immunol ; 40: 1-14, 2022 04 26.
Artigo em Inglês | MEDLINE | ID: mdl-34871102

RESUMO

I've had serious misgivings about writing this article, because from living the experience day by day, it's hard to believe my accomplishments merit the attention. To skirt this roadblock, I forced myself to pretend I was in a conversation with my trainees, trying to distill the central driving forces of my career in science. The below chronicles my evolution from would-be astronaut/ballerina to budding developmental biologist to devoted T cell immunologist. It traces my work from a focus on intrathymic events that mold developing T cells into self-major histocompatibility complex (MHC)-restricted lymphocytes to extrathymic events that fine-tune the T cell receptor (TCR) repertoire and impose the finishing touches on T cell maturation. It is a story of a few personal attributes multiplied by generous mentors, good luck, hard work, perseverance, and knowing when to step down.


Assuntos
Complexo Principal de Histocompatibilidade , Linfócitos T , Animais , Diferenciação Celular , Humanos , Timo
2.
Annu Rev Immunol ; 40: 615-649, 2022 04 26.
Artigo em Inglês | MEDLINE | ID: mdl-35134315

RESUMO

Alphaviruses are emerging and reemerging viruses that cause disease syndromes ranging from incapacitating arthritis to potentially fatal encephalitis. While infection by arthritogenic and encephalitic alphaviruses results in distinct clinical manifestations, both virus groups induce robust innate and adaptive immune responses. However, differences in cellular tropism, type I interferon induction, immune cell recruitment, and B and T cell responses result in differential disease progression and outcome. In this review, we discuss aspects of immune responses that contribute to protective or pathogenic outcomes after alphavirus infection.


Assuntos
Infecções por Alphavirus , Alphavirus , Interferon Tipo I , Infecções por Alphavirus/patologia , Animais , Humanos , Imunidade , Tropismo
3.
Annu Rev Immunol ; 39: 611-637, 2021 04 26.
Artigo em Inglês | MEDLINE | ID: mdl-33637017

RESUMO

Infection with Mycobacterium tuberculosis causes >1.5 million deaths worldwide annually. Innate immune cells are the first to encounter M. tuberculosis, and their response dictates the course of infection. Dendritic cells (DCs) activate the adaptive response and determine its characteristics. Macrophages are responsible both for exerting cell-intrinsic antimicrobial control and for initiating and maintaining inflammation. The inflammatory response to M. tuberculosis infection is a double-edged sword. While cytokines such as TNF-α and IL-1 are important for protection, either excessive or insufficient cytokine production results in progressive disease. Furthermore, neutrophils-cells normally associated with control of bacterial infection-are emerging as key drivers of a hyperinflammatory response that results in host mortality. The roles of other innate cells, including natural killer cells and innate-like T cells, remain enigmatic. Understanding the nuances of both cell-intrinsic control of infection and regulation of inflammation will be crucial for the successful development of host-targeted therapeutics and vaccines.


Assuntos
Mycobacterium tuberculosis , Tuberculose , Animais , Citocinas , Humanos , Imunidade Inata , Macrófagos
4.
Annu Rev Immunol ; 39: 791-817, 2021 04 26.
Artigo em Inglês | MEDLINE | ID: mdl-33902311

RESUMO

Programmed cell death (PCD) is a requisite feature of development and homeostasis but can also be indicative of infections, injuries, and pathologies. In concordance with these heterogeneous contexts, an array of disparate effector responses occur downstream of cell death and its clearance-spanning tissue morphogenesis, homeostatic turnover, host defense, active dampening of inflammation, and tissue repair. This raises a fundamental question of how a single contextually appropriate response ensues after an event of PCD. To explore how complex inputs may together tailor the specificity of the resulting effector response, here we consider (a) the varying contexts during which different cell death modalities are observed, (b) the nature of the information that can be passed on by cell corpses, and (c) the ways by which efferocyte populations synthesize signals from dying cells with those from the surrounding microenvironment.


Assuntos
Apoptose , Animais , Morte Celular , Homeostase , Humanos
5.
Annu Rev Immunol ; 39: 103-129, 2021 04 26.
Artigo em Inglês | MEDLINE | ID: mdl-33472004

RESUMO

B cell subsets differ in development, tissue distribution, and mechanisms of activation. In response to infections, however, all can differentiate into extrafollicular plasmablasts that rapidly provide highly protective antibodies, indicating that these plasmablasts are the main humoral immune response effectors. Yet, the effectiveness of this response type depends on the presence of antigen-specific precursors in the circulating mature B cell pool, a pool that is generated initially through the stochastic processes of B cell receptor assembly. Importantly, germinal centers then mold the repertoire of this B cell pool to be increasingly responsive to pathogens by generating a broad array of antimicrobial memory B cells that act as highly effective precursors of extrafollicular plasmablasts. Such B cell repertoire molding occurs in two ways: continuously via the chronic germinal centers of mucosal lymphoid tissues, driven by the presence of the microbiome, and via de novo generated germinal centers following acute infections. For effectively evaluating humoral immunity as a correlate of immune protection, it might be critical to measure memory B cell pools in addition to antibody titers.


Assuntos
Subpopulações de Linfócitos B , Linfócitos B , Animais , Centro Germinativo , Humanos , Imunidade Humoral , Receptores de Antígenos de Linfócitos B
6.
Annu Rev Immunol ; 38: 365-395, 2020 04 26.
Artigo em Inglês | MEDLINE | ID: mdl-31986070

RESUMO

Sialic acid-binding immunoglobulin-type lectins (Siglecs) are expressed on the majority of white blood cells of the immune system and play critical roles in immune cell signaling. Through recognition of sialic acid-containing glycans as ligands, they help the immune system distinguish between self and nonself. Because of their restricted cell type expression and roles as checkpoints in immune cell responses in human diseases such as cancer, asthma, allergy, neurodegeneration, and autoimmune diseases they have gained attention as targets for therapeutic interventions. In this review we describe the Siglec family, its roles in regulation of immune cell signaling, current efforts to define its roles in disease processes, and approaches to target Siglecs for treatment of human disease.


Assuntos
Suscetibilidade a Doenças , Proteínas de Checkpoint Imunológico/genética , Proteínas de Checkpoint Imunológico/metabolismo , Imunomodulação , Lectinas Semelhantes a Imunoglobulina de Ligação ao Ácido Siálico/genética , Lectinas Semelhantes a Imunoglobulina de Ligação ao Ácido Siálico/metabolismo , Transdução de Sinais , Animais , Biomarcadores , Humanos , Sistema Imunitário/imunologia , Sistema Imunitário/metabolismo , Linfócitos/imunologia , Linfócitos/metabolismo
7.
Annu Rev Immunol ; 37: 173-200, 2019 04 26.
Artigo em Inglês | MEDLINE | ID: mdl-30550719

RESUMO

Malignant transformation of cells depends on accumulation of DNA damage. Over the past years we have learned that the T cell-based immune system frequently responds to the neoantigens that arise as a consequence of this DNA damage. Furthermore, recognition of neoantigens appears an important driver of the clinical activity of both T cell checkpoint blockade and adoptive T cell therapy as cancer immunotherapies. Here we review the evidence for the relevance of cancer neoantigens in tumor control and the biological properties of these antigens. We discuss recent technological advances utilized to identify neoantigens, and the T cells that recognize them, in individual patients. Finally, we discuss strategies that can be employed to exploit cancer neoantigens in clinical interventions.


Assuntos
Antígenos de Neoplasias/imunologia , Autoantígenos/imunologia , Vacinas Anticâncer/imunologia , Epitopos de Linfócito T/imunologia , Imunoterapia Adotiva/métodos , Neoplasias/imunologia , Linfócitos T/imunologia , Animais , Antígenos de Neoplasias/genética , Autoantígenos/genética , Epitopos de Linfócito T/genética , Humanos , Imunidade Celular , Ativação Linfocitária , Medicina de Precisão , Linfócitos T/transplante
8.
Annu Rev Immunol ; 37: 73-95, 2019 04 26.
Artigo em Inglês | MEDLINE | ID: mdl-31026414

RESUMO

Neurotropic RNA viruses continue to emerge and are increasingly linked to diseases of the central nervous system (CNS) despite viral clearance. Indeed, the overall mortality of viral encephalitis in immunocompetent individuals is low, suggesting efficient mechanisms of virologic control within the CNS. Both immune and neural cells participate in this process, which requires extensive innate immune signaling between resident and infiltrating cells, including microglia and monocytes, that regulate the effector functions of antiviral T and B cells as they gain access to CNS compartments. While these interactions promote viral clearance via mainly neuroprotective mechanisms, they may also promote neuropathology and, in some cases, induce persistent alterations in CNS physiology and function that manifest as neurologic and psychiatric diseases. This review discusses mechanisms of RNA virus clearance and neurotoxicity during viral encephalitis with a focus on the cytokines essential for immune and neural cell inflammatory responses and interactions. Understanding neuroimmune communications in the setting of viral infections is essential for the development of treatments that augment neuroprotective processes while limiting ongoing immunopathological processes that cause ongoing CNS disease.


Assuntos
Encéfalo/imunologia , Imunidade Inata , Microglia/fisiologia , Infecções por Vírus de RNA/imunologia , Vírus de RNA/fisiologia , Animais , Barreira Hematoencefálica , Encéfalo/virologia , Humanos , Inflamação Neurogênica , Neuroimunomodulação
9.
Annu Rev Immunol ; 36: 19-42, 2018 04 26.
Artigo em Inglês | MEDLINE | ID: mdl-29144837

RESUMO

Adaptive immunity in jawless fishes is based on antigen recognition by three types of variable lymphocyte receptors (VLRs) composed of variable leucine-rich repeats, which are differentially expressed by two T-like lymphocyte lineages and one B-like lymphocyte lineage. The T-like cells express either VLRAs or VLRCs of yet undefined antigen specificity, whereas the VLRB antibodies secreted by B-like cells bind proteinaceous and carbohydrate antigens. The incomplete VLR germline genes are assembled into functional units by a gene conversion-like mechanism that employs flanking variable leucine-rich repeat sequences as templates in association with lineage-specific expression of cytidine deaminases. B-like cells develop in the hematopoietic typhlosole and kidneys, whereas T-like cells develop in the thymoid, a thymus-equivalent region at the gill fold tips. Thus, the dichotomy between T-like and B-like cells and the presence of dedicated lymphopoietic tissues emerge as ancestral vertebrate features, whereas the somatic diversification of structurally distinct antigen receptor genes evolved independently in jawless and jawed vertebrates.


Assuntos
Imunidade Adaptativa , Evolução Biológica , Vertebrados/imunologia , Animais , Linfócitos B/imunologia , Linfócitos B/metabolismo , Linhagem da Célula , Citidina Desaminase/genética , Citidina Desaminase/metabolismo , Humanos , Imunidade Inata , Família Multigênica , Receptores de Antígenos de Linfócitos B/química , Receptores de Antígenos de Linfócitos B/genética , Receptores de Antígenos de Linfócitos B/metabolismo , Receptores de Antígenos de Linfócitos T/química , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos de Linfócitos T/metabolismo , Relação Estrutura-Atividade , Linfócitos T/imunologia , Linfócitos T/metabolismo , Vertebrados/metabolismo
10.
Cell ; 187(8): 1823-1827, 2024 Apr 11.
Artigo em Inglês | MEDLINE | ID: mdl-38608650

RESUMO

"Helicopter research" refers to a practice where researchers from wealthier countries conduct studies in lower-income countries with little involvement of local researchers or community members. This practice also occurs domestically. In this Commentary, we outline strategies to curb domestic helicopter research and to foster equity-centered collaborations.


Assuntos
Pesquisa Biomédica , Participação da Comunidade , Humanos , Pesquisadores , Saúde Global , National Institutes of Health (U.S.) , Estados Unidos , Minorias Desiguais em Saúde e Populações Vulneráveis , Desigualdades de Saúde
11.
Cell ; 187(6): 1347-1349, 2024 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-38490177

RESUMO

Dr. Shirin Heidari is the lead author of the Sex and Gender Equity in Research (SAGER) guidelines. In this interview with Dr. Isabel Goldman at Cell, she discusses her research, GENDRO, the SAGER guidelines and importance of considering sex- and gender-related variables in research, and her work on sexual and reproductive health in forced displacement.


Assuntos
Identidade de Gênero , Equidade em Saúde , Feminino , Humanos , Masculino , Guias como Assunto , Sexo
12.
Cell ; 187(6): 1316-1326, 2024 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-38490173

RESUMO

Understanding sex-related variation in health and illness requires rigorous and precise approaches to revealing underlying mechanisms. A first step is to recognize that sex is not in and of itself a causal mechanism; rather, it is a classification system comprising a set of categories, usually assigned according to a range of varying traits. Moving beyond sex as a system of classification to working with concrete and measurable sex-related variables is necessary for precision. Whether and how these sex-related variables matter-and what patterns of difference they contribute to-will vary in context-specific ways. Second, when researchers incorporate these sex-related variables into research designs, rigorous analytical methods are needed to allow strongly supported conclusions. Third, the interpretation and reporting of sex-related variation require care to ensure that basic and preclinical research advance health equity for all.


Assuntos
Pesquisa Biomédica , Equidade em Saúde , Sexo , Humanos
13.
Cell ; 187(6): 1335-1342, 2024 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-38490175

RESUMO

Gender inequality in STEM fields remains pervasive and undermines the ability for talented individuals to excel. Despite advances, women still encounter obstacles in pursuing academic careers and reaching leadership positions. This commentary discusses the "scissor-shaped curve" and examines effective strategies to fix it, including data-driven initiatives that we have implemented at our university.


Assuntos
Academia , Equidade de Gênero , Humanos , Feminino , Liderança , Universidades
14.
Cell ; 187(6): 1374-1386.e13, 2024 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-38428425

RESUMO

The World Health Organization declared mpox a public health emergency of international concern in July 2022. To investigate global mpox transmission and population-level changes associated with controlling spread, we built phylogeographic and phylodynamic models to analyze MPXV genomes from five global regions together with air traffic and epidemiological data. Our models reveal community transmission prior to detection, changes in case reporting throughout the epidemic, and a large degree of transmission heterogeneity. We find that viral introductions played a limited role in prolonging spread after initial dissemination, suggesting that travel bans would have had only a minor impact. We find that mpox transmission in North America began declining before more than 10% of high-risk individuals in the USA had vaccine-induced immunity. Our findings highlight the importance of broader routine specimen screening surveillance for emerging infectious diseases and of joint integration of genomic and epidemiological information for early outbreak control.


Assuntos
Doenças Transmissíveis Emergentes , Epidemias , Mpox , Humanos , Surtos de Doenças , Mpox/epidemiologia , Mpox/transmissão , Mpox/virologia , Saúde Pública , Monkeypox virus/fisiologia
15.
Cell ; 187(18): 4819-4823, 2024 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-39121858

RESUMO

More globally diverse perspectives are needed in genomic studies and precision medicine practices on non-Europeans. Here, we illustrate this by discussing the distribution of clinically actionable genetic variants involved in drug response in Andean highlanders and Amazonians, considering their environment, history, genetic structure, and historical biases in the perception of biological diversity of Native Americans.


Assuntos
Genômica , Humanos , Variação Genética , Indígenas Sul-Americanos/genética , Genoma Humano , América do Sul , Medicina de Precisão
16.
Cell ; 187(18): 4833-4858, 2024 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-39241746

RESUMO

The dysfunction of blood-vessel-lining endothelial cells is a major cause of mortality. Although endothelial cells, being present in all organs as a single-cell layer, are often conceived as a rather inert cell population, the vascular endothelium as a whole should be considered a highly dynamic and interactive systemically disseminated organ. We present here a holistic view of the field of vascular research and review the diverse functions of blood-vessel-lining endothelial cells during the life cycle of the vasculature, namely responsive and relaying functions of the vascular endothelium and the responsive roles as instructive gatekeepers of organ function. Emerging translational perspectives in regenerative medicine, preventive medicine, and aging research are developed. Collectively, this review is aimed at promoting disciplinary coherence in the field of angioscience for a broader appreciation of the importance of the vasculature for organ function, systemic health, and healthy aging.


Assuntos
Células Endoteliais , Endotélio Vascular , Humanos , Endotélio Vascular/metabolismo , Animais , Células Endoteliais/metabolismo , Envelhecimento/fisiologia , Medicina Regenerativa , Saúde
17.
Cell ; 187(7): 1617-1635, 2024 Mar 28.
Artigo em Inglês | MEDLINE | ID: mdl-38552610

RESUMO

The integration of cancer biomarkers into oncology has revolutionized cancer treatment, yielding remarkable advancements in cancer therapeutics and the prognosis of cancer patients. The development of personalized medicine represents a turning point and a new paradigm in cancer management, as biomarkers enable oncologists to tailor treatments based on the unique molecular profile of each patient's tumor. In this review, we discuss the scientific milestones of cancer biomarkers and explore future possibilities to improve the management of patients with solid tumors. This progress is primarily attributed to the biological characterization of cancers, advancements in testing methodologies, elucidation of the immune microenvironment, and the ability to profile circulating tumor fractions. Integrating these insights promises to continually advance the precision oncology field, fostering better patient outcomes.


Assuntos
Biomarcadores Tumorais , Neoplasias , Medicina de Precisão , Humanos , Oncologia/métodos , Neoplasias/terapia , Neoplasias/tratamento farmacológico , Medicina de Precisão/métodos , Microambiente Tumoral
18.
Cell ; 187(7): 1636-1650, 2024 Mar 28.
Artigo em Inglês | MEDLINE | ID: mdl-38552611

RESUMO

The precision oncology paradigm challenges the feasibility and data generalizability of traditional clinical trials. Consequently, an unmet need exists for practical approaches to test many subgroups, evaluate real-world drug value, and gather comprehensive, accessible datasets to validate novel biomarkers. Real-world data (RWD) are increasingly recognized to have the potential to fill this gap in research methodology. Established applications of RWD include informing disease epidemiology, pharmacovigilance, and healthcare quality assessment. Currently, concerns regarding RWD quality and comprehensiveness, privacy, and biases hamper their broader application. Nonetheless, RWD may play a pivotal role in supplementing clinical trials, enabling conditional reimbursement and accelerated drug access, and innovating trial conduct. Moreover, purpose-built RWD repositories may support the extension or refinement of drug indications and facilitate the discovery and validation of new biomarkers. This perspective explores the potential of leveraging RWD to advance oncology, highlights its benefits and challenges, and suggests a path forward in this evolving field.


Assuntos
Neoplasias , Humanos , Medicina de Precisão , Oncologia , Projetos de Pesquisa , Biomarcadores
19.
Cell ; 187(9): 2095-2116, 2024 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-38670067

RESUMO

Plant diseases cause famines, drive human migration, and present challenges to agricultural sustainability as pathogen ranges shift under climate change. Plant breeders discovered Mendelian genetic loci conferring disease resistance to specific pathogen isolates over 100 years ago. Subsequent breeding for disease resistance underpins modern agriculture and, along with the emergence and focus on model plants for genetics and genomics research, has provided rich resources for molecular biological exploration over the last 50 years. These studies led to the identification of extracellular and intracellular receptors that convert recognition of extracellular microbe-encoded molecular patterns or intracellular pathogen-delivered virulence effectors into defense activation. These receptor systems, and downstream responses, define plant immune systems that have evolved since the migration of plants to land ∼500 million years ago. Our current understanding of plant immune systems provides the platform for development of rational resistance enhancement to control the many diseases that continue to plague crop production.


Assuntos
Resistência à Doença , Doenças das Plantas , Imunidade Vegetal , Plantas , Doenças das Plantas/imunologia , Doenças das Plantas/microbiologia , Imunidade Vegetal/genética , Plantas/imunologia , Plantas/genética , Resistência à Doença/genética , Humanos
20.
Cell ; 187(13): 3373-3389.e16, 2024 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-38906102

RESUMO

The gut microbiota influences the clinical responses of cancer patients to immunecheckpoint inhibitors (ICIs). However, there is no consensus definition of detrimental dysbiosis. Based on metagenomics (MG) sequencing of 245 non-small cell lung cancer (NSCLC) patient feces, we constructed species-level co-abundance networks that were clustered into species-interacting groups (SIGs) correlating with overall survival. Thirty-seven and forty-five MG species (MGSs) were associated with resistance (SIG1) and response (SIG2) to ICIs, respectively. When combined with the quantification of Akkermansia species, this procedure allowed a person-based calculation of a topological score (TOPOSCORE) that was validated in an additional 254 NSCLC patients and in 216 genitourinary cancer patients. Finally, this TOPOSCORE was translated into a 21-bacterial probe set-based qPCR scoring that was validated in a prospective cohort of NSCLC patients as well as in colorectal and melanoma patients. This approach could represent a dynamic diagnosis tool for intestinal dysbiosis to guide personalized microbiota-centered interventions.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Microbioma Gastrointestinal , Imunoterapia , Neoplasias Pulmonares , Neoplasias , Feminino , Humanos , Masculino , Akkermansia , Carcinoma Pulmonar de Células não Pequenas/microbiologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/imunologia , Disbiose/microbiologia , Fezes/microbiologia , Microbioma Gastrointestinal/efeitos dos fármacos , Inibidores de Checkpoint Imunológico/uso terapêutico , Inibidores de Checkpoint Imunológico/farmacologia , Imunoterapia/métodos , Neoplasias Pulmonares/microbiologia , Neoplasias Pulmonares/tratamento farmacológico , Metagenômica/métodos , Neoplasias/microbiologia , Resultado do Tratamento
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