RESUMO
The Danger Model predicts that there are some molecules that no immune system can ever be fully tolerant of, namely proteins that are only transiently expressed during times of stress, infection, or injury. Among these are the danger/alarm signals themselves. Accordingly, a fleeting autoantibody response to danger signals is expected during times when they are released. Depending on context, these autoantibodies may serve beneficial "housekeeping" functions by removing surplus danger signals from the circulation or, conversely, create an immunodeficiency. Here, we will focus on the Type 1 Interferons as examples of foreseeable targets for a transient autoantibody response, but the principles outlined should hold for other danger-associated molecules as well.
Assuntos
Sistema Imunitário , Interferon Tipo I , AutoanticorposRESUMO
There is growing recognition that regionalization of bacterial colonization and immunity along the intestinal tract has an important role in health and disease. Yet, the mechanisms underlying intestinal regionalization and its dysregulation in disease are not well understood. This study found that regional epithelial expression of the transcription factor GATA4 controls bacterial colonization and inflammatory tissue immunity in the proximal small intestine by regulating retinol metabolism and luminal IgA. Furthermore, in mice without jejunal GATA4 expression, the commensal segmented filamentous bacteria promoted pathogenic inflammatory immune responses that disrupted barrier function and increased mortality upon Citrobacter rodentium infection. In celiac disease patients, low GATA4 expression was associated with metabolic alterations, mucosal Actinobacillus, and increased IL-17 immunity. Taken together, these results reveal broad impacts of GATA4-regulated intestinal regionalization on bacterial colonization and tissue immunity, highlighting an elaborate interdependence of intestinal metabolism, immunity, and microbiota in homeostasis and disease.
Assuntos
Infecções por Enterobacteriaceae , Fator de Transcrição GATA4 , Microbioma Gastrointestinal , Mucosa Intestinal , Animais , Humanos , Camundongos , Actinobacillus , Microbioma Gastrointestinal/imunologia , Fator de Transcrição GATA4/metabolismo , Imunidade nas Mucosas , Interleucina-17/imunologia , Interleucina-17/metabolismo , Mucosa Intestinal/imunologia , Mucosa Intestinal/microbiologia , Intestino Delgado , SimbioseRESUMO
For decades, the main question immunologists have asked about autoimmunity is "what causes a break in self-tolerance?" We have not found good answers to that question, and I believe we are still so ignorant because it's the wrong question. Rather than a break in self-tolerance, I suggest that many autoimmune diseases might be due to defects in normal tissue physiology.
Assuntos
Doenças Autoimunes , Autoimunidade , Humanos , Tolerância a Antígenos Próprios , Tolerância ImunológicaRESUMO
Tumor Associated Macrophages (TAMs) promote tumor survival, angiogenesis and metastases. Although they express MHC Class II molecules, little is known about their ability to present tumor antigens to tumor infiltrating CD4 T cells, nor what are the consequences of such presentation. To answer these questions, we used a C57/BL10 mouse tumor model where we subcutaneously implant a bladder carcinoma cell line naturally expressing the H-Y male antigen into female mice, making the H-Y antigen a de facto neoantigen. We found that TAMs indeed present tumor antigens to effector CD4 T cells and that such presentation is necessary for tumor rejection. As consequence of this interaction TAMs are re-educated to produce lower amounts of tumor promoting proteins and greater amounts of inflammatory proteins. The re-education process of the TAMs is transcriptionally characterized by an IFN-γ signature, including genes of known anti-viral and anti-bacterial functions. CD4 production of IFN-γ, and not TNF-α or CD40L, is required for the re-education process and tumor rejection. Furthermore, IFN-γ signaling on antigen presenting TAMs and not on bystander TAMs, is necessary for the anti-tumor effect. These data identify critical mechanisms of tumor rejection by CD4 T cells and underscores the importance of effector CD4 T cell-tissue macrophage interactions not only at the tumors site but potentially in other tissues.
Assuntos
Linfócitos T CD4-Positivos , Macrófagos Associados a Tumor , Animais , Feminino , Masculino , Camundongos , Antígenos de Neoplasias , Antígenos de Histocompatibilidade Classe II/genética , Proteínas de NeoplasiasRESUMO
Many complex mathematical and epidemiological methods have been used to model the Covid-19 pandemic. Among other results from these models has been the view that closing schools had little impact on infection rates in several countries1. We took a different approach. Making one assumption, we simply plotted cases, hospitalizations and deaths, on a log2 Y axis and a linear date-based X axis, and analyzed them using segmented regression, a powerful method that has largely been overlooked during this pandemic. Here we show that the data fit straight lines with correlation coefficients ranging from 92% - 99%, and that these lines broke at interesting intervals, revealing that school closings dropped infection rates in half, lockdowns dropped the rates 3 to 4 fold, and other actions (such as closing bars and mandating masks) brought the rates even further down. Hospitalizations and deaths paralleled cases, with lags of three to ten days. The graphs, which are easy to read, reveal changes in infection rates that are not obvious using other graphing methods, and have several implications for modeling and policy development during this and future pandemics. Overall, other than full lockdowns, three interventions had the most impact: closing schools, closing bars and wearing masks: a message easily understood by the public.
RESUMO
Dendritic cells (DCs) play a key role in the initiation of an immune response and are known as "professional" APCs because of their ability to activate naive T cells. A widely used method to generate DCs in vitro is to culture bone marrow (BM) cells or blood monocytes in the presence of GM-CSF and IL-4. In this study, we show that a small population of NK cells residing in the BM of RAG-/-, but not RAG-/- γc chain-/- mice, remain in the DC culture and is the source of IFN-γ produced after stimulation with LPS. These cells, which may represent early promoters of LPS-induced responses, have to be taken into account when interpreting experiments using BM-derived DCs.
Assuntos
Células da Medula Óssea/citologia , Células Dendríticas/citologia , Proteínas de Homeodomínio/metabolismo , Interferon gama/metabolismo , Células Matadoras Naturais/imunologia , Animais , Células da Medula Óssea/efeitos dos fármacos , Células da Medula Óssea/imunologia , Diferenciação Celular/efeitos dos fármacos , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/imunologia , Feminino , Fator Estimulador de Colônias de Granulócitos e Macrófagos/farmacologia , Proteínas de Homeodomínio/genética , Interleucina-4/farmacologia , Lipopolissacarídeos/toxicidade , Ativação Linfocitária , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Monócitos/imunologia , Linfócitos T/citologia , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologiaRESUMO
The oral cavity is home to unique resident microbial communities whose interactions with host immunity are less frequently studied than those of the intestinal microbiome. We examined the stimulatory capacity and the interactions of two oral bacteria, Porphyromonas gingivalis (P. gingivalis) and Fusobacterium nucleatum (F. nucleatum), on Dendritic Cell (DC) activation, comparing them to the effects of the well-studied intestinal microbe Escherichia coli (E. coli). Unlike F. nucleatum and E. coli, P. gingivalis failed to activate DCs, and in fact silenced DC responses induced by F. nucleatum or E. coli. We identified a variant strain of P. gingivalis (W50) that lacked this immunomodulatory activity. Using biochemical approaches and whole genome sequencing to compare the two substrains, we found a point mutation in the hagA gene. This protein is though to be involved in the alteration of the PorSS/gingipain pathway, which regulates protein secretion into the extracellular environment. A proteomic comparison of the secreted products of the two substrains revealed enzymatic differences corresponding to this phenotype. We found that P. gingivalis secretes gingipain(s) that inactivate several key proinflammatory mediators made by DCs and/or T cells, but spare Interleukin-1 (IL-1) and GM-CSF, which can cause capillary leaks that serve as a source of the heme that P. gingivalis requires for its survival, and GM-CSF, which can cause epithelial-cell growth. Taken together, our results suggest that P. gingivalis has evolved potent mechanisms to modulate its virulence factors and dampen the innate immune response by selectively inactivating most proinflammatory cytokines.
Assuntos
Proteínas de Bactérias/genética , Interações Hospedeiro-Patógeno/imunologia , Imunidade Inata , Porphyromonas gingivalis/imunologia , Animais , Antibiose , Proteínas de Bactérias/química , Proteínas de Bactérias/metabolismo , Citocinas/análise , Citocinas/metabolismo , DNA Bacteriano/química , DNA Bacteriano/isolamento & purificação , DNA Bacteriano/metabolismo , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Células Dendríticas/microbiologia , Escherichia coli/genética , Feminino , Fusobacterium/fisiologia , Fator Estimulador de Colônias de Granulócitos e Macrófagos/análise , Fator Estimulador de Colônias de Granulócitos e Macrófagos/metabolismo , Humanos , Mediadores da Inflamação/metabolismo , Interleucina-1/análise , Interleucina-1/metabolismo , Lectinas/química , Lectinas/genética , Lectinas/metabolismo , Masculino , Camundongos , Camundongos Transgênicos , Porphyromonas gingivalis/genética , Linfócitos T/imunologia , Linfócitos T/metabolismo , Linfócitos T/microbiologiaRESUMO
Antibiotics, though remarkably useful, can also cause certain adverse effects. We detected that treatment of adult mice with antibiotics decreases hippocampal neurogenesis and memory retention. Reconstitution with normal gut flora (SPF) did not completely reverse the deficits in neurogenesis unless the mice also had access to a running wheel or received probiotics. In parallel to an increase in neurogenesis and memory retention, both SPF-reconstituted mice that ran and mice supplemented with probiotics exhibited higher numbers of Ly6C(hi) monocytes in the brain than antibiotic-treated mice. Elimination of Ly6C(hi) monocytes by antibody depletion or the use of knockout mice resulted in decreased neurogenesis, whereas adoptive transfer of Ly6C(hi) monocytes rescued neurogenesis after antibiotic treatment. We propose that the rescue of neurogenesis and behavior deficits in antibiotic-treated mice by exercise and probiotics is partially mediated by Ly6C(hi) monocytes.
Assuntos
Envelhecimento/fisiologia , Antibacterianos/farmacologia , Antígenos Ly/metabolismo , Microbioma Gastrointestinal/efeitos dos fármacos , Hipocampo/fisiologia , Monócitos/metabolismo , Neurogênese/efeitos dos fármacos , Transferência Adotiva , Animais , Antibiose/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Encéfalo/fisiologia , Contagem de Células , Células Cultivadas , Técnicas de Cocultura , Transplante de Microbiota Fecal , Trato Gastrointestinal/efeitos dos fármacos , Trato Gastrointestinal/fisiologia , Hipocampo/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Células-Tronco Neurais/citologia , Células-Tronco Neurais/efeitos dos fármacos , Células-Tronco Neurais/metabolismo , Condicionamento Físico Animal , Probióticos/farmacologia , Esferoides Celulares/citologia , Esferoides Celulares/efeitos dos fármacosRESUMO
OBJECTIVE: Despite widespread use of antibiotics for the treatment of life-threatening infections and for research on the role of commensal microbiota, our understanding of their effects on the host is still very limited. DESIGN: Using a popular mouse model of microbiota depletion by a cocktail of antibiotics, we analysed the effects of antibiotics by combining intestinal transcriptome together with metagenomic analysis of the gut microbiota. In order to identify specific microbes and microbial genes that influence the host phenotype in antibiotic-treated mice, we developed and applied analysis of the transkingdom network. RESULTS: We found that most antibiotic-induced alterations in the gut can be explained by three factors: depletion of the microbiota; direct effects of antibiotics on host tissues and the effects of remaining antibiotic-resistant microbes. Normal microbiota depletion mostly led to downregulation of different aspects of immunity. The two other factors (antibiotic direct effects on host tissues and antibiotic-resistant microbes) primarily inhibited mitochondrial gene expression and amounts of active mitochondria, increasing epithelial cell death. By reconstructing and analysing the transkingdom network, we discovered that these toxic effects were mediated by virulence/quorum sensing in antibiotic-resistant bacteria, a finding further validated using in vitro experiments. CONCLUSIONS: In addition to revealing mechanisms of antibiotic-induced alterations, this study also describes a new bioinformatics approach that predicts microbial components that regulate host functions and establishes a comprehensive resource on what, why and how antibiotics affect the gut in a widely used mouse model of microbiota depletion by antibiotics.
Assuntos
Antibacterianos/farmacologia , Microbioma Gastrointestinal/efeitos dos fármacos , Microbioma Gastrointestinal/genética , Redes Reguladoras de Genes , Animais , Camundongos , Camundongos Endogâmicos C57BLRESUMO
IL-12p40 partners with the p35 and p19 polypeptides to generate the heterodimeric cytokines IL-12 and IL-23, respectively. These cytokines play critical and distinct roles in host defense. The assembly of these heterodimers is thought to take place within the cell, resulting in the secretion of fully functional cytokines. Although the p40 subunit alone can also be rapidly secreted in response to inflammatory signals, its biological significance remains unclear. In this article, we show that the secreted p40 monomer can generate de novo IL-12-like activities by combining extracellularly with p35 released from other cells. Surprisingly, an unbiased proteomic analysis reveals multiple such extracellular binding partners for p40 in the serum of mice after an endotoxin challenge. We biochemically validate the binding of one of these novel partners, the CD5 Ag-like glycoprotein, to the p40 monomer. Nevertheless, the assembled p40-CD5L heterodimer does not recapitulate the biological activity of IL-12. These findings underscore the plasticity of secreted free p40 monomer, suggesting that p40 functions as an adaptor that is able to generate multiple de novo composites in combination with other locally available polypeptide partners after secretion.
Assuntos
Proteínas Reguladoras de Apoptose/imunologia , Dimerização , Interleucina-12/imunologia , Receptores Imunológicos/imunologia , Animais , Proteínas Reguladoras de Apoptose/genética , Antígenos CD5/genética , Antígenos CD5/imunologia , Interleucina-12/genética , Camundongos , Camundongos Knockout , Proteômica , Receptores Imunológicos/genética , Receptores DepuradoresRESUMO
Although human papillomavirus was identified as an aetiological factor in cervical cancer, the key human gene drivers of this disease remain unknown. Here we apply an unbiased approach integrating gene expression and chromosomal aberration data. In an independent group of patients, we reconstruct and validate a gene regulatory meta-network, and identify cell cycle and antiviral genes that constitute two major subnetworks upregulated in tumour samples. These genes are located within the same regions as chromosomal amplifications, most frequently on 3q. We propose a model in which selected chromosomal gains drive activation of antiviral genes contributing to episomal virus elimination, which synergizes with cell cycle dysregulation. These findings may help to explain the paradox of episomal human papillomavirus decline in women with invasive cancer who were previously unable to clear the virus.
Assuntos
Antivirais/metabolismo , Ciclo Celular/genética , Redes Reguladoras de Genes/genética , Genes Neoplásicos/genética , Papillomaviridae/genética , Neoplasias do Colo do Útero/genética , Neoplasias do Colo do Útero/virologia , Aberrações Cromossômicas , Cromossomos Humanos/genética , Bases de Dados Genéticas , Feminino , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Genoma Humano/genética , Instabilidade Genômica , Humanos , Proteínas de Membrana Lisossomal/metabolismo , Metanálise como Assunto , Proteínas de Neoplasias/metabolismo , Infecções por Papillomavirus/genética , Infecções por Papillomavirus/virologia , Reprodutibilidade dos Testes , Neoplasias do Colo do Útero/patologia , Integração Viral/genéticaRESUMO
LPS-activated dendritic cells (DCs) are thought to follow a set program in which they secrete inflammatory cytokines (such as IL-12) and then become refractory to further stimulation (i.e., "exhausted"). In this study, we show that mouse DCs do indeed lose their responsiveness to LPS, but nevertheless remain perfectly capable of making inflammatory cytokines in response to signals from activated T cells and to CD40-ligand and soluble T cell-derived signals. Furthermore, far from being rigidly programmed by the original activating stimulus, the DCs retained sufficient plasticity to respond differentially to interactions with Th0, Th1, Th2, and Th17 T cells. These data suggest that LPS activation does not exhaust DCs but rather primes them for subsequent signals from T cells.
Assuntos
Comunicação Celular/imunologia , Células Dendríticas/imunologia , Lipopolissacarídeos/imunologia , Linfócitos T/imunologia , Animais , Diferenciação Celular/imunologia , Técnicas de Cocultura , Citocinas/biossíntese , Células Dendríticas/citologia , Ensaio de Imunoadsorção Enzimática , Feminino , Ativação Linfocitária/imunologia , Masculino , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Linfócitos T/citologiaRESUMO
Polly Matzinger, now Chief of the Ghost Laboratory and the section on T-cell Tolerance and Memory at the NIH, has previously worked as a bartender, carpenter, jazz musician, Playboy bunny and dog trainer. She completed her PhD at the University of California, San Diego (USA) and was a postdoctoral fellow at the University of Cambridge (UK). She has worried for years that the dominant model of immunity does not explain a wealth of accumulated data and has recently suggested an alternative, the danger model, which suggests that the immune system is far less concerned with things that are foreign than with those that do damage. This model, whose two major tenets Matzinger admits were thought up in a bath and on a field while herding sheep, has very few assumptions and yet "explains most of what the immune system seems to do right, as well as most of what it appears to do wrong", covering such areas as transplantation, autoimmunity and the immunobiology of tumors. The model has been the subject of a BBC Horizon film and has featured in two other films about immunity and countless articles in both the scientific and the lay press. In her spare time, Matzinger trains border collies for competitive shepherding trials and, in her own words, "composes songs that are not really worth listening to, and worries about the next major question in the immune system", namely "once it decides to respond, how does the immune system know what kind of response to make?"
Assuntos
Sistema Imunitário/imunologia , Sistema Imunitário/fisiopatologia , Modelos Imunológicos , Autobiografias como Assunto , Autoimunidade/imunologia , História do Século XXI , Humanos , Neoplasias/imunologia , Imunologia de TransplantesRESUMO
Using a systems biology approach, we discovered and dissected a three-way interaction between the immune system, the intestinal epithelium and the microbiota. We found that, in the absence of B cells, or of IgA, and in the presence of the microbiota, the intestinal epithelium launches its own protective mechanisms, upregulating interferon-inducible immune response pathways and simultaneously repressing Gata4-related metabolic functions. This shift in intestinal function leads to lipid malabsorption and decreased deposition of body fat. Network analysis revealed the presence of two interconnected epithelial-cell gene networks, one governing lipid metabolism and another regulating immunity, that were inversely expressed. Gene expression patterns in gut biopsies from individuals with common variable immunodeficiency or with HIV infection and intestinal malabsorption were very similar to those of the B cell-deficient mice, providing a possible explanation for a longstanding enigmatic association between immunodeficiency and defective lipid absorption in humans.
Assuntos
Linfócitos B/imunologia , Mucosa Intestinal/imunologia , Mucosa Intestinal/microbiologia , Metabolismo dos Lipídeos , Metagenoma , Animais , Linfócitos B/metabolismo , DNA Bacteriano/isolamento & purificação , Células Epiteliais/imunologia , Células Epiteliais/microbiologia , Fator de Transcrição GATA4/genética , Fator de Transcrição GATA4/metabolismo , Perfilação da Expressão Gênica , Redes Reguladoras de Genes , Humanos , Imunoglobulina A/imunologia , Mucosa Intestinal/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout , Análise em Microsséries , Regulação para CimaRESUMO
In this study, we describe a new population of NK cells that reside in the normal, uninflamed peritoneal cavity. Phenotypically, they share some similarities with the small population of CD49b(-), CD27(+) immature splenic NK cells, as well as liver NK cells, but they differ in their expression of CD62L, TRAIL, and EOMES. Functionally, the peritoneal NK cells resemble the immature splenic NK cells in their production of IFN-γ, GM-CSF, and TNF-α and in the killing of YAC-1 target cells. We also found that the peritoneum induces different behavior in mature and immature splenic NK cells. When transferred i.v. into RAGγc knockout mice, both populations undergo homeostatic proliferation in the spleen, but only the immature splenic NK cells are able to reach the peritoneum. When transferred directly into the peritoneum, the mature NK cells survive but do not divide, whereas the immature NK cells proliferate profusely. These data suggest that the peritoneum is not only home to a new subset of tissue-resident NK cells, but that it differentially regulates the migration and homeostatic proliferation of immature versus mature NK cells.
Assuntos
Células Matadoras Naturais/citologia , Células Matadoras Naturais/imunologia , Peritônio/citologia , Peritônio/imunologia , Animais , Líquido Ascítico/imunologia , Líquido Ascítico/metabolismo , Líquido Ascítico/patologia , Subpopulações de Linfócitos B/citologia , Subpopulações de Linfócitos B/imunologia , Subpopulações de Linfócitos B/metabolismo , Diferenciação Celular/imunologia , Proliferação de Células , Separação Celular , Sobrevivência Celular/imunologia , Homeostase/imunologia , Imunofenotipagem , Células Matadoras Naturais/metabolismo , Macrófagos/citologia , Macrófagos/imunologia , Macrófagos/metabolismo , Camundongos , Camundongos Endogâmicos A , Camundongos Endogâmicos C57BL , Camundongos Knockout , Peritônio/patologia , Baço/citologia , Baço/imunologia , Baço/metabolismoRESUMO
In this Essay, we offer a new perspective on how immune responses are regulated. We do not cover how they are turned on and off, but focus instead on the second major aspect of an immune response: the control of effector class. Although it is generally thought that the class of an immune response is tailored to fit the invading pathogen, we suggest here that it is primarily tailored to fit the tissue in which the response occurs. To this end, we cover such topics as the nature of T helper (T(H)) cell subsets (current and yet to be discovered), the nature of privileged sites, the difference between oral tolerance and oral vaccination, why the route of immunization matters, whether the T(H)1-type response is really the immune system's primary defense, and whether there might be a different role for some regulatory T cells.
Assuntos
Imunidade/imunologia , Modelos Imunológicos , Especificidade de Órgãos/imunologia , Animais , Células Apresentadoras de Antígenos/imunologia , Citocinas/fisiologia , Interações Hospedeiro-Patógeno/imunologia , Humanos , Hipersensibilidade Tardia/imunologia , Tolerância Imunológica/imunologia , Neuroimunomodulação , Receptores Imunológicos/classificação , Receptores Imunológicos/imunologia , Subpopulações de Linfócitos T/classificação , Subpopulações de Linfócitos T/imunologia , Fatores de Tempo , VacinaçãoRESUMO
Complete regeneration of damaged extremities, including both the epithelium and the underlying tissues, is thought to occur mainly in embryos, fetuses, and juvenile mammals, but only very rarely in adult mammals. Surprisingly, we found that common strains of mice are able to regenerate all of the tissues necessary to completely fill experimentally punched ear holes, but only if punched at middle age. Although young postweaning mice regrew the epithelium without typical pre-scar granulation tissue, they showed only minimal regeneration of connective tissues. In contrast, mice punched at 5-11 months of age showed true amphibian-like blastema formation and regrowth of cartilage, fat, and dermis, with blood vessels, sebaceous glands, hair follicles, and, in black mice, melanocytes. These data suggest that at least partial appendage regeneration may be more common in adult mammals than previously thought and call into question the common view that regenerative ability is lost with age. The data suggest that the age at which various inbred mouse strains become capable of epimorphic regeneration may be correlated with adult body weight.