RESUMO
Pathogenic organisms exert a negative impact on host health, revealed by the clinical signs of infectious diseases. Immunity limits the severity of infectious diseases through resistance mechanisms that sense and target pathogens for containment, killing, or expulsion. These resistance mechanisms are viewed as the prevailing function of immunity. Under pathophysiologic conditions, however, immunity arises in response to infections that carry health and fitness costs to the host. Therefore, additional defense mechanisms are required to limit these costs, before immunity becomes operational as well as thereafter to avoid immunopathology. These are tissue damage control mechanisms that adjust the metabolic output of host tissues to different forms of stress and damage associated with infection. Disease tolerance is the term used to define this defense strategy, which does not exert a direct impact on pathogens but is essential to limit the health and fitness costs of infection. Under this argument, we propose that disease tolerance is an inherent component of immunity.
Assuntos
Resistência à Doença/imunologia , Imunidade Inata , Infecções/imunologia , Microbiota/imunologia , Animais , Interações Hospedeiro-Patógeno , Humanos , Tolerância Imunológica , ImunomodulaçãoRESUMO
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 â¼500 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 , HumanosRESUMO
In the 40 years since their discovery, dendritic cells (DCs) have been recognized as central players in immune regulation. DCs sense microbial stimuli through pathogen-recognition receptors (PRRs) and decode, integrate, and present information derived from such stimuli to T cells, thus stimulating immune responses. DCs can also regulate the quality of immune responses. Several functionally specialized subsets of DCs exist, but DCs also display functional plasticity in response to diverse stimuli. In addition to sensing pathogens via PRRs, emerging evidence suggests that DCs can also sense stress signals, such as amino acid starvation, through ancient stress and nutrient sensing pathways, to stimulate adaptive immunity. Here, I discuss these exciting advances in the context of a historic perspective on the discovery of DCs and their role in immune regulation. I conclude with a discussion of emerging areas in DC biology in the systems immunology era and suggest that the impact of DCs on immunity can be usefully contextualized in a hierarchy-of-organization model in which DCs, their receptors and signaling networks, cell-cell interactions, tissue microenvironment, and the host macroenvironment represent different levels of the hierarchy. Immunity or tolerance can then be represented as a complex function of each of these hierarchies.
Assuntos
Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Animais , Comunicação Celular/imunologia , Diferenciação Celular/imunologia , Seleção Clonal Mediada por Antígeno , Resistência à Doença , Suscetibilidade a Doenças , Interações Hospedeiro-Patógeno/imunologia , Humanos , Linfócitos/citologia , Linfócitos/imunologia , Linfócitos/metabolismo , Estresse FisiológicoRESUMO
The diverse microbial populations constituting the intestinal microbiota promote immune development and differentiation, but because of their complex metabolic requirements and the consequent difficulty culturing them, they remained, until recently, largely uncharacterized and mysterious. In the last decade, deep nucleic acid sequencing platforms, new computational and bioinformatics tools, and full-genome characterization of several hundred commensal bacterial species facilitated studies of the microbiota and revealed that differences in microbiota composition can be associated with inflammatory, metabolic, and infectious diseases, that each human is colonized by a distinct bacterial flora, and that the microbiota can be manipulated to reduce and even cure some diseases. Different bacterial species induce distinct immune cell populations that can play pro- and anti-inflammatory roles, and thus the composition of the microbiota determines, in part, the level of resistance to infection and susceptibility to inflammatory diseases. This review summarizes recent work characterizing commensal microbes that contribute to the antimicrobial defense/inflammation axis.
Assuntos
Resistência à Doença/imunologia , Gastroenterite/imunologia , Gastroenterite/microbiologia , Microbioma Gastrointestinal/imunologia , Mucosa Intestinal/imunologia , Mucosa Intestinal/microbiologia , Imunidade Adaptativa , Animais , Doenças Autoimunes/imunologia , Doenças Autoimunes/metabolismo , Doenças Autoimunes/microbiologia , Biologia Computacional , Dieta , Suscetibilidade a Doenças , Gastroenterite/metabolismo , Interações Hospedeiro-Patógeno/imunologia , Humanos , Imunidade Inata , Imunidade nas Mucosas , Mucosa Intestinal/metabolismo , Metaboloma , Neoplasias/etiologia , Vitaminas/metabolismoRESUMO
Helminth parasites are a highly successful group of pathogens that challenge the immune system in a manner distinct from rapidly replicating infectious agents. Of this group, roundworms (nematodes) that dwell in the intestines of humans and other animals are prevalent worldwide. Currently, more than one billion people are infected by at least one species, often for extended periods of time. Thus, host-protective immunity is rarely complete. The reasons for this are complex, but laboratory investigation of tractable model systems in which protective immunity is effective has provided a mechanistic understanding of resistance that is characterized almost universally by a type 2/T helper 2 response. Greater understanding of the mechanisms of susceptibility has also provided the basis for defining host immunoregulation and parasite-evasion strategies, helping place in context the changing patterns of immunological disease observed worldwide.
Assuntos
Helmintíase/imunologia , Helmintíase/parasitologia , Helmintos/imunologia , Interações Hospedeiro-Patógeno/imunologia , Imunidade Adaptativa , Animais , Antígenos de Helmintos/imunologia , Resistência à Doença , Suscetibilidade a Doenças , Gastroenteropatias/imunologia , Gastroenteropatias/microbiologia , Gastroenteropatias/parasitologia , Microbioma Gastrointestinal , Humanos , Imunidade Inata , Nematoides/imunologia , Infecções por Nematoides/imunologia , Infecções por Nematoides/microbiologia , Infecções por Nematoides/parasitologiaRESUMO
Plant immunity is activated upon pathogen perception and often affects growth and yield when it is constitutively active. How plants fine-tune immune homeostasis in their natural habitats remains elusive. Here, we discover a conserved immune suppression network in cereals that orchestrates immune homeostasis, centering on a Ca2+-sensor, RESISTANCE OF RICE TO DISEASES1 (ROD1). ROD1 promotes reactive oxygen species (ROS) scavenging by stimulating catalase activity, and its protein stability is regulated by ubiquitination. ROD1 disruption confers resistance to multiple pathogens, whereas a natural ROD1 allele prevalent in indica rice with agroecology-specific distribution enhances resistance without yield penalty. The fungal effector AvrPiz-t structurally mimics ROD1 and activates the same ROS-scavenging cascade to suppress host immunity and promote virulence. We thus reveal a molecular framework adopted by both host and pathogen that integrates Ca2+ sensing and ROS homeostasis to suppress plant immunity, suggesting a principle for breeding disease-resistant, high-yield crops.
Assuntos
Cálcio/metabolismo , Sequestradores de Radicais Livres/metabolismo , Proteínas Fúngicas/metabolismo , Oryza/imunologia , Imunidade Vegetal , Proteínas de Plantas/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Sistemas CRISPR-Cas/genética , Membrana Celular/metabolismo , Resistência à Doença/genética , Modelos Biológicos , Oryza/genética , Doenças das Plantas/imunologia , Proteínas de Plantas/genética , Ligação Proteica , Estabilidade Proteica , Reprodução , Especificidade da Espécie , Ubiquitina-Proteína Ligases/metabolismo , Ubiquitinação , Zea mays/imunologiaRESUMO
Nucleotide-binding, leucine-rich repeat receptors (NLRs) are major immune receptors in plants and animals. Upon activation, the Arabidopsis NLR protein ZAR1 forms a pentameric resistosome in vitro and triggers immune responses and cell death in plants. In this study, we employed single-molecule imaging to show that the activated ZAR1 protein can form pentameric complexes in the plasma membrane. The ZAR1 resistosome displayed ion channel activity in Xenopus oocytes in a manner dependent on a conserved acidic residue Glu11 situated in the channel pore. Pre-assembled ZAR1 resistosome was readily incorporated into planar lipid-bilayers and displayed calcium-permeable cation-selective channel activity. Furthermore, we show that activation of ZAR1 in the plant cell led to Glu11-dependent Ca2+ influx, perturbation of subcellular structures, production of reactive oxygen species, and cell death. The results thus support that the ZAR1 resistosome acts as a calcium-permeable cation channel to trigger immunity and cell death.
Assuntos
Proteínas de Arabidopsis/metabolismo , Arabidopsis/imunologia , Arabidopsis/metabolismo , Cálcio/metabolismo , Proteínas de Transporte/metabolismo , Resistência à Doença/imunologia , Imunidade Vegetal , Transdução de Sinais , Animais , Morte Celular , Membrana Celular/metabolismo , Permeabilidade da Membrana Celular , Ácido Glutâmico/metabolismo , Bicamadas Lipídicas/metabolismo , Oócitos/metabolismo , Células Vegetais/metabolismo , Multimerização Proteica , Protoplastos/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Imagem Individual de Molécula , Vacúolos/metabolismo , XenopusRESUMO
In response to biotic stress, plants produce suites of highly modified fatty acids that bear unusual chemical functionalities. Despite their chemical complexity and proposed roles in pathogen defense, little is known about the biosynthesis of decorated fatty acids in plants. Falcarindiol is a prototypical acetylenic lipid present in carrot, tomato, and celery that inhibits growth of fungi and human cancer cell lines. Using a combination of untargeted metabolomics and RNA sequencing, we discovered a biosynthetic gene cluster in tomato (Solanum lycopersicum) required for falcarindiol production. By reconstituting initial biosynthetic steps in a heterologous host and generating transgenic pathway mutants in tomato, we demonstrate a direct role of the cluster in falcarindiol biosynthesis and resistance to fungal and bacterial pathogens in tomato leaves. This work reveals a mechanism by which plants sculpt their lipid pool in response to pathogens and provides critical insight into the complex biochemistry of alkynyl lipid production.
Assuntos
Di-Inos/metabolismo , Ácidos Graxos/biossíntese , Álcoois Graxos/metabolismo , Solanum lycopersicum/genética , Resistência à Doença/genética , Di-Inos/química , Ácidos Graxos/metabolismo , Álcoois Graxos/química , Regulação da Expressão Gênica de Plantas/genética , Metabolômica , Família Multigênica/genética , Doenças das Plantas/microbiologia , Folhas de Planta/metabolismo , Proteínas de Plantas/metabolismo , Plantas Geneticamente Modificadas , Estresse Fisiológico/genéticaRESUMO
SARS-CoV-2 infection displays immense inter-individual clinical variability, ranging from silent infection to lethal disease. The role of human genetics in determining clinical response to the virus remains unclear. Studies of outliers-individuals remaining uninfected despite viral exposure and healthy young patients with life-threatening disease-present a unique opportunity to reveal human genetic determinants of infection and disease.
Assuntos
Infecções por Coronavirus/genética , Infecções por Coronavirus/imunologia , Predisposição Genética para Doença , Pneumonia Viral/genética , Pneumonia Viral/imunologia , Fatores Etários , Betacoronavirus/fisiologia , COVID-19 , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/fisiopatologia , Resistência à Doença , Estudos de Associação Genética , Doenças Genéticas Inatas/imunologia , Variação Genética , Genoma Humano , Interações Hospedeiro-Patógeno , Humanos , Infecções/genética , Infecções/imunologia , Infecções/fisiopatologia , Pandemias , Pneumonia Viral/epidemiologia , Pneumonia Viral/fisiopatologia , SARS-CoV-2RESUMO
SARS-CoV-2 infections display tremendous interindividual variability, ranging from asymptomatic infections to life-threatening disease. Inborn errors of, and autoantibodies directed against, type I interferons (IFNs) account for about 20% of critical COVID-19 cases among SARS-CoV-2-infected individuals. By contrast, the genetic and immunological determinants of resistance to infection per se remain unknown. Following the discovery that autosomal recessive deficiency in the DARC chemokine receptor confers resistance to Plasmodium vivax, autosomal recessive deficiencies of chemokine receptor 5 (CCR5) and the enzyme FUT2 were shown to underlie resistance to HIV-1 and noroviruses, respectively. Along the same lines, we propose a strategy for identifying, recruiting, and genetically analyzing individuals who are naturally resistant to SARS-CoV-2 infection.
Assuntos
COVID-19/genética , Resistência à Doença/genética , Predisposição Genética para Doença , SARS-CoV-2/patogenicidade , Animais , COVID-19/imunologia , COVID-19/virologia , Heterogeneidade Genética , Interações Hospedeiro-Patógeno , Humanos , Fenótipo , Fatores de Proteção , Medição de Risco , Fatores de Risco , SARS-CoV-2/imunologiaRESUMO
RNA silencing is a well-established antiviral immunity system in plants, in which small RNAs guide Argonaute proteins to targets in viral RNA or DNA, resulting in virus repression. Virus-encoded suppressors of silencing counteract this defence system. In this Review, we discuss recent findings about antiviral RNA silencing, including the movement of RNA through plasmodesmata and the differentiation between plant self and viral RNAs. We also discuss the emerging role of RNA silencing in plant immunity against non-viral pathogens. This immunity is mediated by transkingdom movement of RNA into and out of the infected plant cells in vesicles or as extracellular nucleoproteins and, like antiviral immunity, is influenced by the silencing suppressors encoded in the pathogens' genomes. Another effect of RNA silencing on general immunity involves host-encoded small RNAs, including microRNAs, that regulate NOD-like receptors and defence signalling pathways in the innate immunity system of plants. These RNA silencing pathways form a network of processes with both positive and negative effects on the immune systems of plants.
Assuntos
MicroRNAs , RNA Viral , Antivirais , Proteínas Argonautas/genética , Proteínas Argonautas/metabolismo , Resistência à Doença/genética , MicroRNAs/genética , Proteínas NLR/genética , Proteínas NLR/metabolismo , Doenças das Plantas/genética , Imunidade Vegetal/genética , Plantas/genética , Interferência de RNA , RNA de Plantas , RNA Interferente Pequeno/metabolismoRESUMO
Infectious disease is both a major force of selection in nature and a prime cause of yield loss in agriculture. In plants, disease resistance is often conferred by nucleotide-binding leucine-rich repeat (NLR) proteins, intracellular immune receptors that recognize pathogen proteins and their effects on the host. Consistent with extensive balancing and positive selection, NLRs are encoded by one of the most variable gene families in plants, but the true extent of intraspecific NLR diversity has been unclear. Here, we define a nearly complete species-wide pan-NLRome in Arabidopsis thaliana based on sequence enrichment and long-read sequencing. The pan-NLRome largely saturates with approximately 40 well-chosen wild strains, with half of the pan-NLRome being present in most accessions. We chart NLR architectural diversity, identify new architectures, and quantify selective forces that act on specific NLRs and NLR domains. Our study provides a blueprint for defining pan-NLRomes.
Assuntos
Proteínas de Arabidopsis/genética , Arabidopsis/genética , Proteínas NLR/genética , Alelos , Proteínas de Arabidopsis/metabolismo , Resistência à Doença/genética , Variação Genética , Genoma de Planta , Proteínas NLR/metabolismo , Doenças das Plantas/genética , Imunidade Vegetal , Especificidade da EspécieRESUMO
Cells have evolved complex mechanisms to maintain protein homeostasis, such as the UPRER, which are strongly associated with several diseases and the aging process. We performed a whole-genome CRISPR-based knockout (KO) screen to identify genes important for cells to survive ER-based protein misfolding stress. We identified the cell-surface hyaluronidase (HAase), Transmembrane Protein 2 (TMEM2), as a potent modulator of ER stress resistance. The breakdown of the glycosaminoglycan, hyaluronan (HA), by TMEM2 within the extracellular matrix (ECM) altered ER stress resistance independent of canonical UPRER pathways but dependent upon the cell-surface receptor, CD44, a putative HA receptor, and the MAPK cell-signaling components, ERK and p38. Last, and most surprisingly, ectopic expression of human TMEM2 in C. elegans protected animals from ER stress and increased both longevity and pathogen resistance independent of canonical UPRER activation but dependent on the ERK ortholog mpk-1 and the p38 ortholog pmk-1.
Assuntos
Caenorhabditis elegans/fisiologia , Retículo Endoplasmático/metabolismo , Hialuronoglucosaminidase/metabolismo , Longevidade/fisiologia , Proteínas de Membrana/metabolismo , Resposta a Proteínas não Dobradas , Animais , Caenorhabditis elegans/imunologia , Linhagem Celular , Proliferação de Células , Resistência à Doença , Estresse do Retículo Endoplasmático , Fibroblastos/metabolismo , Humanos , Imunidade Inata , Modelos Biológicos , Peso Molecular , Transdução de SinaisRESUMO
Neutrophils are a component of the tumor microenvironment and have been predominantly associated with cancer progression. Using a genetic approach complemented by adoptive transfer, we found that neutrophils are essential for resistance against primary 3-methylcholantrene-induced carcinogenesis. Neutrophils were essential for the activation of an interferon-γ-dependent pathway of immune resistance, associated with polarization of a subset of CD4- CD8- unconventional αß T cells (UTCαß). Bulk and single-cell RNA sequencing (scRNA-seq) analyses unveiled the innate-like features and diversity of UTCαß associated with neutrophil-dependent anti-sarcoma immunity. In selected human tumors, including undifferentiated pleomorphic sarcoma, CSF3R expression, a neutrophil signature and neutrophil infiltration were associated with a type 1 immune response and better clinical outcome. Thus, neutrophils driving UTCαß polarization and type 1 immunity are essential for resistance against murine sarcomas and selected human tumors.
Assuntos
Resistência à Doença , Neoplasias/patologia , Neutrófilos/imunologia , Sarcoma/patologia , Linfócitos T/metabolismo , Animais , Cromonas/toxicidade , Resistência à Doença/imunologia , Humanos , Imunidade Inata , Interferon gama/genética , Interferon gama/metabolismo , Interleucina-12/genética , Interleucina-12/metabolismo , Estimativa de Kaplan-Meier , Macrófagos/imunologia , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neoplasias/imunologia , Neoplasias/mortalidade , Infiltração de Neutrófilos , Neutrófilos/citologia , Neutrófilos/metabolismo , Receptores de Fator Estimulador de Colônias/metabolismo , Sarcoma/induzido quimicamente , Sarcoma/imunologia , Linfócitos T/citologia , Linfócitos T/imunologia , Microambiente TumoralRESUMO
Familial Mediterranean fever (FMF) is an autoinflammatory disease caused by homozygous or compound heterozygous gain-of-function mutations in MEFV, which encodes pyrin, an inflammasome protein. Heterozygous carrier frequencies for multiple MEFV mutations are high in several Mediterranean populations, suggesting that they confer selective advantage. Among 2,313 Turkish people, we found extended haplotype homozygosity flanking FMF-associated mutations, indicating evolutionarily recent positive selection of FMF-associated mutations. Two pathogenic pyrin variants independently arose >1,800 years ago. Mutant pyrin interacts less avidly with Yersinia pestis virulence factor YopM than with wild-type human pyrin, thereby attenuating YopM-induced interleukin (IL)-1ß suppression. Relative to healthy controls, leukocytes from patients with FMF harboring homozygous or compound heterozygous mutations and from asymptomatic heterozygous carriers released heightened IL-1ß specifically in response to Y. pestis. Y. pestis-infected MefvM680I/M680I FMF knock-in mice exhibited IL-1-dependent increased survival relative to wild-type knock-in mice. Thus, FMF mutations that were positively selected in Mediterranean populations confer heightened resistance to Y. pestis.
Assuntos
Resistência à Doença/genética , Febre Familiar do Mediterrâneo/genética , Peste , Pirina/genética , Seleção Genética/genética , Animais , Proteínas da Membrana Bacteriana Externa/imunologia , Proteínas da Membrana Bacteriana Externa/metabolismo , Resistência à Doença/imunologia , Haplótipos , Humanos , Inflamassomos/imunologia , Inflamassomos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Mutação , Peste/imunologia , Peste/metabolismo , Pirina/imunologia , Pirina/metabolismo , Turquia , Fatores de Virulência/imunologia , Fatores de Virulência/metabolismo , Yersinia pestisRESUMO
Rice feeds half the world's population, and rice blast is often a destructive disease that results in significant crop loss. Non-race-specific resistance has been more effective in controlling crop diseases than race-specific resistance because of its broad spectrum and durability. Through a genome-wide association study, we report the identification of a natural allele of a C2H2-type transcription factor in rice that confers non-race-specific resistance to blast. A survey of 3,000 sequenced rice genomes reveals that this allele exists in 10% of rice, suggesting that this favorable trait has been selected through breeding. This allele causes a single nucleotide change in the promoter of the bsr-d1 gene, which results in reduced expression of the gene through the binding of the repressive MYB transcription factor and, consequently, an inhibition of H2O2 degradation and enhanced disease resistance. Our discovery highlights this novel allele as a strategy for breeding durable resistance in rice.
Assuntos
Oryza/genética , Proteínas de Plantas/genética , Fatores de Transcrição/genética , Sequência de Bases , Cruzamento , Resistência à Doença , Técnicas de Inativação de Genes , Genoma de Planta , Estudo de Associação Genômica Ampla , Doenças das Plantas , Regiões Promotoras GenéticasRESUMO
Laboratory mice, while paramount for understanding basic biological phenomena, are limited in modeling complex diseases of humans and other free-living mammals. Because the microbiome is a major factor in mammalian physiology, we aimed to identify a naturally evolved reference microbiome to better recapitulate physiological phenomena relevant in the natural world outside the laboratory. Among 21 distinct mouse populations worldwide, we identified a closely related wild relative to standard laboratory mouse strains. Its bacterial gut microbiome differed significantly from its laboratory mouse counterpart and was transferred to and maintained in laboratory mice over several generations. Laboratory mice reconstituted with natural microbiota exhibited reduced inflammation and increased survival following influenza virus infection and improved resistance against mutagen/inflammation-induced colorectal tumorigenesis. By demonstrating the host fitness-promoting traits of natural microbiota, our findings should enable the discovery of protective mechanisms relevant in the natural world and improve the modeling of complex diseases of free-living mammals. VIDEO ABSTRACT.
Assuntos
Microbioma Gastrointestinal , Camundongos/classificação , Camundongos/microbiologia , Animais , Animais de Laboratório , Animais Selvagens , Carcinogênese/imunologia , Resistência à Doença , Feminino , Masculino , Maryland , Camundongos/imunologia , Camundongos Endogâmicos C57BL , Peromyscus , Viroses/imunologiaRESUMO
Neutrophils are essential first-line defense cells against invading pathogens, yet when inappropriately activated, their strong immune response can cause collateral tissue damage and contributes to immunological diseases. However, whether neutrophils can intrinsically titrate their immune response remains unknown. Here we conditionally deleted the Spi1 gene, which encodes the myeloid transcription factor PU.1, from neutrophils of mice undergoing fungal infection and then performed comprehensive epigenomic profiling. We found that as well as providing the transcriptional prerequisite for eradicating pathogens, the predominant function of PU.1 was to restrain the neutrophil defense by broadly inhibiting the accessibility of enhancers via the recruitment of histone deacetylase 1. Such epigenetic modifications impeded the immunostimulatory AP-1 transcription factor JUNB from entering chromatin and activating its targets. Thus, neutrophils rely on a PU.1-installed inhibitor program to safeguard their epigenome from undergoing uncontrolled activation, protecting the host against an exorbitant innate immune response.
Assuntos
Epigênese Genética/imunologia , Epigenômica/métodos , Neutrófilos/imunologia , Proteínas Proto-Oncogênicas/imunologia , Transativadores/imunologia , Animais , Candida albicans/imunologia , Candida albicans/fisiologia , Candidíase/genética , Candidíase/imunologia , Candidíase/microbiologia , Resistência à Doença/genética , Resistência à Doença/imunologia , Perfilação da Expressão Gênica/métodos , Humanos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Neutrófilos/metabolismo , Neutrófilos/microbiologia , Proteínas Proto-Oncogênicas/deficiência , Proteínas Proto-Oncogênicas/genética , Análise de Sobrevida , Transativadores/deficiência , Transativadores/genética , Transcriptoma/genética , Transcriptoma/imunologiaRESUMO
APS1/APECED patients are defined by defects in the autoimmune regulator (AIRE) that mediates central T cell tolerance to many self-antigens. AIRE deficiency also affects B cell tolerance, but this is incompletely understood. Here we show that most APS1/APECED patients displayed B cell autoreactivity toward unique sets of approximately 100 self-proteins. Thereby, autoantibodies from 81 patients collectively detected many thousands of human proteins. The loss of B cell tolerance seemingly occurred during antibody affinity maturation, an obligatorily T cell-dependent step. Consistent with this, many APS1/APECED patients harbored extremely high-affinity, neutralizing autoantibodies, particularly against specific cytokines. Such antibodies were biologically active in vitro and in vivo, and those neutralizing type I interferons (IFNs) showed a striking inverse correlation with type I diabetes, not shown by other anti-cytokine antibodies. Thus, naturally occurring human autoantibodies may actively limit disease and be of therapeutic utility.
Assuntos
Afinidade de Anticorpos , Autoanticorpos/imunologia , Resistência à Doença/imunologia , Poliendocrinopatias Autoimunes/imunologia , Fatores de Transcrição/deficiência , Adolescente , Adulto , Idoso , Animais , Anticorpos Neutralizantes/imunologia , Criança , Pré-Escolar , Citocinas/imunologia , Diabetes Mellitus Tipo 1/imunologia , Humanos , Tolerância Imunológica , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Linfócitos T/imunologia , Adulto Jovem , Proteína AIRERESUMO
The oropharyngeal mucosa serves as a perpetual pathogen entry point and a critical site for viral replication and spread. Here, we demonstrate that type 1 innate lymphoid cells (ILC1s) were the major immune force providing early protection during acute oral mucosal viral infection. Using intravital microscopy, we show that ILC1s populated and patrolled the uninfected labial mucosa. ILC1s produced interferon-γ (IFN-γ) in the absence of infection, leading to the upregulation of key antiviral genes, which were downregulated in uninfected animals upon genetic ablation of ILC1s or antibody-based neutralization of IFN-γ. Thus, tonic IFN-γ production generates increased oral mucosal viral resistance even before infection. Our results demonstrate barrier-tissue protection through tissue surveillance in the absence of rearranged-antigen receptors and the induction of an antiviral state during homeostasis. This aspect of ILC1 biology raises the possibility that these cells do not share true functional redundancy with other tissue-resident lymphocytes.