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Qureshi, Salman T.; Larivière, Line; Leveque, Gary; Clermont, Sophie; Moore, Karen J.; Gros, Philippe; Malo, Danielle
doi: 10.1084/jem.189.4.615pmid: 9989976
Bacterial lipopolysaccharide (LPS) provokes a vigorous, generalized proinflammatory state in the infected host. Genetic regulation of this response has been localized to the Lps locus on mouse chromosome 4, through study of the C3H/HeJ and C57BL/10ScCr inbred strains. Both C3H/HeJ and C57BL/10ScCr mice are homozygous for a mutant Lps allele ( Lps d/d ) that confers hyporesponsiveness to LPS challenge, and therefore exhibit natural tolerance to its lethal effects. Genetic and physical mapping of 1,345 backcross progeny segregating this mutant phenotype confined Lps to a 0.9-cM interval spanning 1.7 Mb. Three transcription units were identified within the candidate interval, including Toll-like receptor 4 ( Tlr4 ), part of a protein family with members that have been implicated in LPS-induced cell signaling. C3H/HeJ mice have a point mutation within the coding region of the Tlr4 gene, resulting in a nonconservative substitution of a highly conserved proline by histidine at codon 712, whereas C57BL/ 10ScCr mice exhibit a deletion of Tlr4 . Identification of distinct mutations involving the same gene at the Lps locus in two different hyporesponsive inbred mouse strains strongly supports the hypothesis that altered Tlr4 function is responsible for endotoxin tolerance. lipopolysaccharide inflammation positional cloning Salmonella mice/ inbred C3H Footnotes Abbreviations used in this paper: EST expressed sequence tag LRR leucine-rich repeat NF nuclear factor ORF open reading frame PAPPA pregnancy-associated plasma protein A PFGE pulsed field gel electrophoresis RACE rapid amplification of cDNA ends RT reverse transcription SSCP single-strand conformational polymorphism SSLP simple sequence length repeat STS sequence-tagged site TIR Toll IL-1 receptor TLR Toll-like receptor Tlr4 murine Toll-like receptor 4 UTR untranslated region Submitted: 25 November 1998 Revision received 7 December 1998
Robert, Caroline; Fuhlbrigge, Robert C.; Kieffer, J. David; Ayehunie, Seyoum; Hynes, Richard O.; Cheng, Guiying; Grabbe, Stephan; von Andrian, Ulrich H.; Kupper, Thomas S.
doi: 10.1084/jem.189.4.627pmid: 9989977
The goal of this study was to determine the mechanisms by which dendritic cells (DCs) in blood could interact with endothelium, a prerequisite to extravasation into tissues. Our results indicate that DCs express both HECA-452–reactive and nonreactive isoforms of P-selectin glycoprotein ligand 1 (PSGL-1) and can tether and roll efficiently on E- and P-selectin under flow conditions in vitro. Freshly isolated blood DCs were further observed to roll continuously along noninflamed murine dermal endothelium in vivo. This interaction is strictly dependent on endothelial selectins, as shown by experiments with blocking antibodies and with E- and P-selectin–deficient mice. We hypothesize that DCs in blood are constitutively poised at the interface of blood and skin, ready to extravasate upon induction of inflammation, and we showed that cutaneous inflammation results in a rapid recruitment of DCs from the blood to tissues. We propose that this is an important and previously unappreciated element of immunosurveillance. inflammation immunosurveillance selectins rolling extravasation Footnotes Abbreviations used in this paper: CLA cutaneous lymphocyte-associated antigen DC dendritic cell PSGL-1 P-selectin glycoprotein ligand 1 VCAM-1 vascular cell adhesion molecule 1 VLA-4 very late antigen 4 Submitted: 13 October 1998 Revision received 29 December 1998
Angela Montesano, M.; Colley, Daniel G.; Eloi-Santos, Silvana; Freeman, George L.; Secor, W. Evan
doi: 10.1084/jem.189.4.637pmid: 9989978
Exposure to maternal idiotypes (Ids) or antigens might predispose a child to develop an immunoregulated, asymptomatic clinical presentation of schistosomiasis. We have used an experimental murine system to address the role of Ids in this immunoregulation. Sera from mice with 8-wk Schistosoma mansoni infection, chronic (20-wk infection) moderate splenomegaly syndrome (MSS), or chronic hypersplenomegaly syndrome (HSS) were passed over an S . mansoni soluble egg antigen (SEA) immunoaffinity column to prepare Ids (8WkId, MSS Id, HSS Id). Newborn mice were injected with 8WkId, MSS Id, HSS Id, or normal mouse immunoglobulin (NoMoIgG) and infected with S . mansoni 8 wk later. Mice exposed to 8WkId or MSS Id as newborns had prolonged survival and decreased morbidity compared with mice that received HSS Id or NoMoIgG. When stimulated with SEA, 8WkId, or MSS Id, spleen cells from mice neonatally injected with 8WkId or MSS Id produced more interferon γ than spleen cells from mice neonatally injected with HSS Id or NoMoIgG. Furthermore, neonatal exposure to 8WkId or MSS Id, but not NoMoIgG or HSS Id, led to significantly smaller granuloma size and lower hepatic fibrosis levels in infected mice. Together, these results indicate that perinatal exposure to appropriate anti-SEA Ids induces long-term effects on survival, pathology, and immune response patterns in mice subsequently infected with S. mansoni . schistosomiasis idiotypes granuloma splenomegaly mice Footnotes Abbreviations used in this paper: CCA circulating cathodic antigen CRI cross-reactive Id HSS hypersplenomegaly syndrome Id idiotype MSS moderate splenomegaly syndrome NoHuIgG normal human Ig NoMoIgG normal mouse Ig SEA schistosome soluble egg antigen(s) SWAP schistosome adult worm antigenic preparation Submitted: 9 July 1998 Revision received 9 November 1998
Centurion-Lara, Arturo; Castro, Christa; Barrett, Lynn; Cameron, Caroline; Mostowfi, Maryam; Van Voorhis, Wesley C.; Lukehart, Sheila A.
doi: 10.1084/jem.189.4.647pmid: 9989979
We have identified a family of genes that code for targets for opsonic antibody and protective immunity in T . pallidum subspecies pallidum using two different approaches, subtraction hybridization and differential immunologic screening of a T . pallidum genomic library. Both approaches led to the identification of a polymorphic multicopy gene family with predicted amino acid homology to the major sheath protein of Treponema denticola . One of the members of this gene family, tpr K , codes for a protein that is predicted to have a cleavable signal peptide and be located in the outer membrane of the bacterium. Reverse transcription polymerase chain reaction analysis of T . pallidum reveals that Tpr K is preferentially transcribed in the Nichols strain of T . pallidum . Antibodies directed to purified recombinant variable domain of Tpr K can opsonize T . pallidum , Nichols strain, for phagocytosis, supporting the hypothesis that this portion of the protein is exposed at the surface of the treponeme. Immunization of rabbits with the purified recombinant variable domain of Tpr K provides significant protection against infection with the Nichols strain of T . pallidum . This gene family is hypothesized to be central to pathogenesis and immunity during syphilis infection. syphilis vaccine subpopulation surface antigens antigenic variation Footnotes Abbreviations used in this paper: msp major sheath protein NRS normal rabbit serum ORS opsonized rabbit serum RT reverse transcription tpr Treponema pallidum repeat Submitted: 6 July 1998 Revision received 17 November 1998
Gao, Ji-Liang; Lee, Eric J.; Murphy, Philip M.
doi: 10.1084/jem.189.4.657pmid: 9989980
N -formylpeptides derive from bacterial and mitochondrial proteins, and bind to specific receptors on mammalian phagocytes. Since binding induces chemotaxis and activation of phagocytes in vitro, it has been postulated that N -formylpeptide receptor signaling in vivo may be important in antimicrobial host defense, although direct proof has been lacking. Here we test this hypothesis in mice lacking the high affinity N -formylpeptide receptor (FPR), created by targeted gene disruption. FPR −/− mice developed normally, but had increased susceptibility to challenge with Listeria monocytogenes , as measured by increased mortality compared with wild-type littermates. FPR −/− mice also had increased bacterial load in spleen and liver 2 d after infection, which is before development of a specific cellular immune response, suggesting a defect in innate immunity. Consistent with this, neutrophil chemotaxis in vitro and neutrophil mobilization into peripheral blood in vivo in response to the prototype N -formylpeptide fMLF (formyl-methionyl-leucyl-phenylalanine) were both absent in FPR −/− mice. These results indicate that FPR functions in antibacterial host defense in vivo. chemotaxis Listeria inflammation chemoattractant neutrophil Footnotes Abbreviations used in this paper: fMLF formyl-methionyl-leucyl-phenylalanine FPR high affinity N -formylpeptide receptor FPRL1 low affinity N -formylpeptide receptor or lipoxin A4 receptor MIP macrophage inflammatory protein ORF open reading frame TP neutrophils thioglycollate-elicited peritoneal neutrophils Submitted: 31 August 1998 Revision received 25 November 1998
Leib, David A.; Harrison, Travis E.; Laslo, Kathleen M.; Machalek, Michael A.; Moorman, Nathaniel J.; Virgin, Herbert W.
doi: 10.1084/jem.189.4.663pmid: 9989981
Mechanisms responsible for neuroattenuation of herpes simplex virus (HSV) have been defined previously by studies of mutant viruses in cultured cells. The hypothesis that null mutations in host genes can override the attenuated phenotype of null mutations in certain viral genes was tested. Mutants such as those in infected cell protein (ICP) 0, thymidine kinase, ribonucleotide reductase, virion host shutoff, and ICP34.5 are reduced in their capacity to replicate in nondividing cells in culture and in vivo. The replication of these viruses was examined in eyes and trigeminal ganglia for 1–7 d after corneal inoculation in mice with null mutations (−/−) in interferon receptors (IFNR) for type I IFNs (IFN-α/βR), type II IFN (IFN-γR), and both type I and type II IFNs (IFN-α/β/γR). Viral titers in eyes and ganglia of IFN-γR −/− mice were not significantly different from congenic controls. However, in IFN-α/βR −/− or IFN-α/β/γR −/− mice, growth of all mutants, including those with significantly impaired growth in cell culture, was enhanced by up to 1,000-fold in eyes and trigeminal ganglia. Blepharitis and clinical signs of infection were evident in IFN-α/βR −/− and IFN-α/β/γR −/− but not control mice for all viruses. Also, IFNs were shown to significantly reduce productive infection of, and spread from intact, but not scarified, corneas. Particularly striking was restoration of near-normal trigeminal ganglion replication and neurovirulence of an ICP34.5 mutant in IFN-α/βR −/− mice. These data show that IFNs play a major role in limiting mutant and wild-type HSV replication in the cornea and in the nervous system. In addition, the in vivo target of ICP34.5 may be host IFN responses. These experiments demonstrate an unsuspected role for host factors in defining the phenotypes of some HSV mutants in vivo. The phenotypes of mutant viruses therefore cannot be interpreted based solely upon studies in cell culture but must be considered carefully in the context of host factors that may define the in vivo phenotype. herpes simplex virus mutants interferons mice pathogenesis Footnotes 1 Abbreviations used in this paper: ICP, infected cell protein; HSV, herpes simplex virus; PKR, double-stranded RNA-dependent protein kinase R; rr , ribonucleotide reductase; tk , thymidine kinase; vhs , virion host shutoff. Submitted: 25 September 1998 Revision received 15 December 1998
Banu, Yasmin; Watanabe, Takeshi
doi: 10.1084/jem.189.4.673pmid: 9989982
Histamine is considered one of the important mediators of immediate hypersensitivity and inflammation, and acts via G protein–coupled receptors. Here, we report that histamine may affect antigen receptor–mediated immune responses of T and B cells via a signal(s) from histamine H1 receptors (H1Rs). Histamine exhibited enhancing effects on the in vitro proliferative responses of anti-CD3ε– or anti-IgM–stimulated spleen T and B cells, respectively, at the culture condition that the fetal calf serum was dialyzed before culture and c-kit–positive cells were depleted from the spleen cells. In studies of histamine H1R knockout mice, H1R-deficient T cells had low proliferative responses to anti-CD3ε cross-linking or antigen stimulation in vitro. B cells from H1R-deficient mice were also affected, demonstrating low proliferative responses to B cell receptor cross-linking. Antibody production against trinitrophenyl-Ficoll was reduced in H1R-deficient mice. Other aspects of T and B cell function were normal in the H1R knockout mice. H1R-deficient T and B cells showed normal responses upon stimulation with interleukin (IL)-2, IL-4, CD40 ligand, CD40 ligand plus IL-4, and lipopolysaccharide. Collectively, these results imply that the signal generated by histamine through H1R augments antigen receptor–mediated immune responses, suggesting cross-talk between G protein–coupled receptors and antigen receptor–mediated signaling. G protein antigen receptor signaling histamine H1 receptor G protein– coupled receptor Footnotes We express our sincere thanks to Dr. Peter Burrows for reading the manuscript and for his helpful comments. We also thank Dr. M. Nakashima for his invaluable assistance with the experiments. 1 Abbreviations used in this paper: BCR, B cell receptor; Btk, Bruton's tyrosine kinase; GPCR, G protein–coupled receptor; G protein, guanine-nucleotide binding protein; HRP, horseradish peroxidase; MAPK, mitogen-activated protein kinase; PLC, phospholipase C; PTK, protein tyrosine kinases; TMB, tetramethylbenzidine. Submitted: 28 September 1998 Revision received 1 December 1998
Hermans, Mirjam H.A.; Antonissen, Claudia; Ward, Alister C.; Mayen, Angelique E.M.; Ploemacher, Rob E.; Touw, Ivo P.
doi: 10.1084/jem.189.4.683pmid: 9989983
In approximately 20% of cases of severe congenital neutropenia (SCN), mutations are found in the gene encoding the granulocyte colony-stimulating factor receptor (G-CSF–R). These mutations introduce premature stop codons, which result in truncation of 82–98 COOH-terminal amino acids of the receptor. SCN patients who develop secondary myelodysplastic syndrome and acute myeloid leukemia almost invariably acquired a GCSFR mutation, suggesting that this genetic alteration represents a key step in leukemogenesis. Here we show that an equivalent mutation targeted in mice ( gcsfr-Δ715 ) results in the selective expansion of the G-CSF– responsive progenitor (G-CFC) compartment in the bone marrow. In addition, in vivo treatment of gcsfr-Δ715 mice with G-CSF results in increased production of neutrophils leading to a sustained neutrophilia. This hyperproliferative response to G-CSF is accompanied by prolonged activation of signal transducer and activator of transcription (STAT) complexes and extended cell surface expression of mutant receptors due to defective internalization. In view of the continuous G-CSF treatment of SCN patients, these data provide insight into why progenitor cells expressing truncated receptors clonally expand in vivo, and why these cells may be targets for additional genetic events leading to leukemia. neutropenia severe congenital neutropenia granulocyte colony-stimulating factor receptor mutations acute myeloid leukemia Footnotes This work was financed by a grant from the Netherlands Organization for Scientific Research NWO (to M.H.A. Hermans, C. Antonissen, and I.P. Touw), a European Molecular Biology Organization Long-term Fellowship (to A.C. Ward), and grants from the Dutch Cancer Society (to I.P. Touw). Abbreviations used in this paper: AML acute myeloid leukemia BM bone marrow CAFC cobblestone area–forming cell CFC colony-forming cell EPO erythropoietin SCF stem cell factor SCN severe congenital neutropenia STAT signal transducer and activator of transcription Submitted: 14 October 1998 Revision received 21 December 1998
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