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Biomedical subjects

Bruce Beutler

Publications and source records attributed to Bruce Beutler.

At least 55 records · Page 3Linked to original sources
PubMed2004

The extracellular matrix gene Frem1 is essential for the normal adhesion of the embryonic epidermis.

Fraser syndrome is a rare recessive disorder characterized by cryptophthalmos, syndactyly, renal defects, and a range of other developmental abnormalities. Because of their extensive phenotypic overlap, the mouse blebbing mutants have been considered models of this disorder, and the recent isolation of mutations in Fras1 in both the blebbed mouse and human Fraser patients confirms this hypothesis. Here we report the identification of mutations in an extracellular matrix gene Fras1-related extracellular matrix gene 1 (Frem1) in both the classic head blebs mutant and in an N-ethyl-N-nitrosourea-induced allele. We show that inactivation of the gene results in the formation of in utero epidermal blisters beneath the lamina densa of the basement membrane and also in renal agenesis. Frem1 is expressed widely in the developing embryo in regions of epithelial/mesenchymal interaction and epidermal remodeling. Furthermore, Frem1 appears to act as a dermal mediator of basement membrane adhesion, apparently independently of the other known "blebs" proteins Fras1 and Grip1. Unlike both Fras1 and Grip1 mutants, collagen VI and Fras1 deposition in the basement membrane is normal, indicating that the protein plays an independent role in epidermal differentiation and is required for epidermal adhesion during embryonic development.

Amino Acid Sequence↗
PubMed2004

Inferences, questions and possibilities in Toll-like receptor signalling.

The Toll-like receptors (TLRs) are the key proteins that allow mammals--whether immunologically naive or experienced--to detect microbes. They lie at the core of our inherited resistance to disease, initiating most of the phenomena that occur in the course of infection. Quasi-infectious stimuli that have been used for decades to study inflammatory mechanisms can activate the TLR family of proteins. And it now seems that many inflammatory processes, both sterile and infectious, may depend on TLR signalling. We are in a good position to apply our understanding of TLR signalling to a range of challenges in immunology and medicine.

Animals↗
PubMed2004

Toll-like receptors 9 and 3 as essential components of innate immune defense against mouse cytomegalovirus infection.

Several subsets of dendritic cells have been shown to produce type I IFN in response to viral infections, thereby assisting the natural killer cell-dependent response that eliminates the pathogen. Type I IFN production can be induced both by unmethylated CpG-oligodeoxynucleotide and by double-stranded RNA. Here, we describe a codominant CpG-ODN unresponsive phenotype that results from an N-ethyl-N-nitrosourea-induced missense mutation in the Tlr9 gene (Tlr9(CpG1)). Mice homozygous for the Tlr9(CpG1) allele are highly susceptible to mouse cytomegalovirus infection and show impaired infection-induced secretion of IFN-alpha/beta and natural killer cell activation. We also demonstrate that both the Toll-like receptor (TLR) 9 --> MyD88 and TLR3 --> Trif signaling pathways are activated in vivo on viral inoculation, and that each pathway contributes to innate defense against systemic viral infection. Whereas both pathways lead to type I IFN production, neither pathway offers full protection against mouse cytomegalovirus infection in the absence of the other. The Tlr9(CpG1) mutation alters a leucine-rich repeat motif and lies within a receptor domain that is conserved within the evolutionary cluster encompassing TLRs 7, 8, and 9. In other TLRs, including three mouse-specific TLRs described in this paper, the affected region is not represented. The phenotypic effect of the Tlr9(CpG1) allele thus points to a critical role for TLR9 in viral sensing and identifies a vulnerable amino acid within the ectodomain of three TLR proteins, essential for a ligand response.

Adaptor Proteins, Signal Transducing↗
PubMed2004

Identification of a TLR4- and TRIF-dependent activation program of dendritic cells.

Dendritic cell activation by Toll-like receptors (TLR) is crucial for the generation of protective immune responses. In addition to the common myeloid differentiation factor 88 (MyD88)-dependent signaling pathway, TLR4 engages the adaptor protein Toll/IL-1 receptor (TIR)-domain-containing adaptor inducing IFN-beta (TRIF), leading to interferon regulatory factor 3 (IRF-3) activation and type I interferon production. Using microarray expression profiling we now identify TRIF as a major regulator of the TLR4-triggered activation program of dendritic cells. We show that the expression of 47% of the genes that are responsive to TLR4 stimulation in wild-type dendritic cells is significantly altered in cells carrying a loss-of-function mutation of TRIF. Specifically, expression of IL-12, IL-18, and IL-23 was impaired in the absence of functional TRIF, suggesting that TLR4-promoted Th1 responses are TRIF-dependent. Furthermore, we provide evidence that TRIF regulates TLR4-mediated gene expression both by type I IFN-dependent and -independent mechanisms. Whereas dendritic cell production of CXCL10 and CCL12 was dependent on both TRIF and the type I interferon receptor, expression of IL-6 required TRIF but not type I interferon activity. Functional TRIF was also required for the normal induction of numerous genes considered important for host defense against diverse pathogens.Together, these data therefore identify TRIF as a crucial regulator of TLR4-dependent dendritic cell responses.

Adaptor Proteins, Vesicular Transport↗
PubMed2004

Forward genetic dissection of afferent immunity: the role of TIR adapter proteins in innate and adaptive immune responses.

The innate immune system senses pathogens largely through signals initiated by proteins known as 'Toll-like receptors' (TLRs), of which ten representatives are known to be encoded in the human genome. The understanding of the biochemical circuitry that maintains the innate capacity for immune recognition and response has loomed as a major hurdle in immunology. A total of five adapter proteins with cytoplasmic domain homology to the TLRs are known to exist in mammals. These proteins show preferential association with individual TLR family members, giving a particular character to the signals that distinct microorganisms initiate, and also initiate the adaptive immune response. The adaptive immune response is dependent upon upregulation of costimulatory molecules (UCM) such as CD80 and CD86. Forward genetic analysis has revealed that this upregulation depends upon an adapter encoded by a locus known as Lps2, and upon type I interferon receptor signaling.

Animals↗
PubMed2004

How the mighty have fallen: fatal infectious diseases of divine composers.

Their music is immortal, but famous composers of the last centuries were not. Up to 50 years ago, microbial infections were a major cause of mortality and showed composers no special mercy. They died of various infectious diseases. By application of modern intensive care measurements and effective antibiotics, many of them would have been saved. Disease and painful death brought the work of these divine artists to the level of immortal creations that both inspire and astonish the mortal audience.

Cholera↗
PubMed2004

SHIP, TGF-beta, and endotoxin tolerance.

Research into the biology of endotoxin (aka lipopolysaccharide; LPS) began well over 100 years ago and has had many unexpected turns. The phenomenon of endotoxin tolerance was among these and has engendered immense curiosity over the years. Sly and colleagues (this issue of Immunity) have taken an important step toward understanding the phenomenon of endotoxin tolerance and have enhanced our comprehension of LPS signaling as a whole by demonstrating that the cytosolic phosphatase SHIP is required to permit the development of an LPS-refractory state in macrophages and mice.

Animals↗
PubMed2004

Genetic analysis of innate immunity: TIR adapter proteins in innate and adaptive immune responses.

The innate immune system senses pathogens largely through signals initiated by a collection of phylogenetically related proteins known as "Toll-like receptors" (TLRs), of which 10 representatives are encoded in the human genome. Our understanding of the sensing role played by the TLRs began with the positional cloning of a spontaneous mutation (Lps(d)) in the gene encoding the mammalian lipopolysaccharide (LPS) receptor. Other key innate immunity proteins have been disclosed by germline mutagenesis, and are discussed in the present review.

Animals↗
PubMed2004

Innate immunity: an overview.

Though sometimes portrayed as "new," the science of innate immunity made its start more than 100 years ago. Recent progress has reflected the application of new methods to old problems. In particular, genetic dissection of innate immune pathways has been pursued with great success in model organisms. This has opened the way to an understanding of innate immune sensing. The effector arm of innate immunity has also been tackled, largely though the use of biochemical methods.

Animals↗
PubMed2004

The interface between innate and adaptive immunity.

This focus analyzes some of the ways the innate immune system influences adaptive immune responses. Here the main principles and themes that govern this intricate relationship are discussed.

Adaptation, Physiological↗
PubMed2004

LPS, dsRNA and the interferon bridge to adaptive immune responses: Trif, Tram, and other TIR adaptor proteins.

Toll-like receptors (TLRs) expressed on antigen-presenting cells (APCs), form a critical link between innate and the adaptive immune responses. Activation of TLRs by LPS and dsRNA results in up-regulation of co-stimulatory molecules (UCM) essential for the generation of robust T-cell responses. It is now evident that type I interferons (IFNs) play an important role in UCM and in the subsequent maturation of APCs. The recently identified adaptor molecules Trif and Tram, unlike their counterparts MyD88 and MAL/Tirap, induce type I IFN via the TLR4 signaling pathway, whereas Trif appears to be the sole adaptor molecule involved in TLR3 signaling, resulting in subsequent production of type I IFN. Here, we discuss how Trif and type I IFN are involved in the optimization of APC-T cell interaction in response not only to viral but also bacterial stimuli.

Adaptor Proteins, Vesicular Transport↗
PubMed2004

Velvet, a dominant Egfr mutation that causes wavy hair and defective eyelid development in mice.

In the course of a large-scale program of ENU mutagenesis, we isolated a dominant mutation, called Velvet. The mutation was found to be uniformly lethal to homozygotes, which do not survive E13.5. Mice heterozygous for the Velvet mutation are born with eyelids open and demonstrate a wavy coat and curly vibrissae. The mutation was mapped to the proximal end of chromosome 11 by genome-wide linkage analysis. On 249 meioses, the locus was confined to a 2.7-Mb region, which included the epidermal growth factor receptor gene (Egfr). An A --> G transition in the Egfr coding region of Velvet mice was identified, causing the amino acid substitution D833G. This substitution alters an essential triad of amino acids (DFG --> GFG) that is normally required for coordination of the ATP substrate. As such, kinase activity is at least mostly abolished, but quaternary structure of the receptor is presumably maintained, accounting for the dominant effect. Velvet is the first known dominant representative of the Egfr allelic series that is fully viable, a fact that makes it particularly useful for developmental studies.

Animals↗
PubMed2003

A common dominant TLR5 stop codon polymorphism abolishes flagellin signaling and is associated with susceptibility to legionnaires' disease.

Although Toll-like receptors (TLRs) are critical mediators of the immune response to pathogens, the influence of polymorphisms in this gene family on human susceptibility to infection is poorly understood. We demonstrated recently that TLR5 recognizes flagellin, a potent inflammatory stimulus present in the flagellar structure of many bacteria. Here, we show that a common stop codon polymorphism in the ligand-binding domain of TLR5 (TLR5392STOP) is unable to mediate flagellin signaling, acts in a dominant fashion, and is associated with susceptibility to pneumonia caused by Legionella pneumophila, a flagellated bacterium. We also show that flagellin is a principal stimulant of proinflammatory cytokine production in lung epithelial cells. Together, these observations suggest that TLR5392STOP increases human susceptibility to infection through an unusual dominant mechanism that compromises TLR5's essential role as a regulator of the lung epithelial innate immune response.

Codon, Terminator↗
PubMed2003

Upregulation of costimulatory molecules induced by lipopolysaccharide and double-stranded RNA occurs by Trif-dependent and Trif-independent pathways.

Both lipopolysaccharide (LPS) and double-stranded RNA (dsRNA) are adjuvants for the adaptive immune response, inducing upregulation of costimulatory molecules (UCM) on antigen-presenting cells. Trif, an adapter protein that transduces signals from Toll-like receptor 4 (TLR4) and TLR3, permits the induction of many cytokines, including interferon-beta, which signals through the type I interferon receptor. We show here that LPS-induced UCM was strictly dependent on the TLR4-->Trif axis, whereas dsRNA-induced UCM was only partly dependent on the TLR3-->Trif axis. But both LPS- and dsRNA-induced UCM were entirely dependent on type I interferon receptor signaling. These findings show that UCM involves an autocrine or paracrine loop, and indicate that an alternative TLR3-independent, Trif-independent pathway contributes to dsRNA-induced UCM.

Adaptor Proteins, Signal Transducing↗
PubMed2003

Use of transcriptome data to unravel the fine structure of genes involved in sepsis.

The sequence of the human genome is providing researchers with the scaffold upon which genes are built. The definition of the boundaries of the genes themselves and of their complex architecture requires a mapping of the transcriptome to the genome. A methodology was developed for generating a detailed transcriptome map and for reconstituting transcripts by using the genome as a template. As a demonstration of the potential of this method, the structure of the human Toll-like receptor (TLR) genes was reevaluated. For all TLR genes for which a genomic sequence was available (i.e., all except TLR10), novel features of the gene structure were discovered. These features include multiple alternative polyadenylation sites, additional exons or splice variants, and overlaps with other genes. These findings have implications for the analysis of TLR gene expression and for the diversity of the proteins encoded by these genes.

Gene Expression Profiling↗
PubMed2003

From phenomenon to phenotype and from phenotype to gene: forward genetics and the problem of sepsis.

Genetic tools (especially classical tools) have enlightened our understanding of biology as no other approach could. Mendel, Morgan, Bridges, and their heirs began with phenotypic traits and ended with genes. At first, the chemical identity of genes was not known, and even after years of methodologic refinement, more years of effort were needed to find the gene and the mutational difference that caused a particular phenotype. Chemistry has now outraced phenotypic analysis; all the genes are suddenly known, but most of their functions are not. The greatest challenge confronting all fields in biology is to establish correspondence between genes and discrete biologic functions. Sepsis is a devastating problem that has eluded a solution, despite the introduction of highly effective antimicrobial agents. Sepsis is an orchestrated process, understood in broad outline, but not in all details. Which genes are involved in the pathogenesis of sepsis? As in the golden age of genetics, the answer requires the solution of phenotypic puzzles, which, in turn, requires the creation of phenotypes.

Animals↗
PubMed2003

Assay of locus-specific genetic load implicates rare Toll-like receptor 4 mutations in meningococcal susceptibility.

As the central component of the human endotoxin sensor, Toll-like receptor 4 (TLR4) functions in the early detection and response to Gram-negative infection. We therefore examined a large collection of patients with meningococcal sepsis, comparing the frequency of rare TLR4 coding changes to those in an ethnically matched control population. TLR2 sequences were also acquired and compared. Total nucleotide variation at TLR4 and TLR2 loci was assayed by using a novel computational method. A total of 3.01 megabases of coding sequence was captured at these loci from white subjects with or without meningococcal disease. Authentic mutations were found and high-quality, bidirectional coverage was measured across the coding region by using mutationseeker, a program specifically designed to assay locus-specific genetic load. Using a method that obviates the confounding effect of linkage disequilibrium, we observed that rare heterozygous missense mutations of TLR4 contribute to the development of systemic meningococcal disease among white populations of the southern United Kingdom (P = 0.02; odds ratio 8.2). When results from all white populations were pooled, an overwhelmingly significant excess of such mutations was observed among individuals with disease (P = 2 x 10(-6); odds ratio 27.0). The common white TLR4 variant (TLR4B), synonymous TLR4 substitutions, and variant TLR2 alleles were not significantly over-represented among patients with systemic meningococcal infections. No single variant of TLR4 was significantly over-represented in the meningococcal population. Collectively, however, rare TLR4 coding variants were markedly over-represented. Sensing via TLR4 probably contributes to the early containment of meningococcal infection, and sensing defects create increased risk of disease.

Alleles↗