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Griselli, M.; Herbert, J.; Hutchinson, W.L.; Taylor, K.M.; Sohail, M.; Krausz, T.; Pepys, M.B.
doi: 10.1084/jem.190.12.1733pmid: 10601349
Myocardial infarction in humans provokes an acute phase response, and C-reactive protein (CRP), the classical acute phase plasma protein, is deposited together with complement within the infarct. The peak plasma CRP value is strongly associated with postinfarct morbidity and mortality. Human CRP binds to damaged cells and activates complement, but rat CRP does not activate complement. Here we show that injection of human CRP into rats after ligation of the coronary artery reproducibly enhanced infarct size by ∼40%. In vivo complement depletion, produced by cobra venom factor, completely abrogated this effect. Complement depletion also markedly reduced infarct size, even when initiated up to 2 h after coronary ligation. These observations demonstrate that human CRP and complement activation are major mediators of ischemic myocardial injury and identify them as therapeutic targets in coronary heart disease. heart ischemia necrosis inflammation acute phase response Footnotes Abbreviations used in this paper: CRP, C-reactive protein; NBT, nitroblue tetrazolium; SAP, serum amyloid P component. Submitted: 14 July 1999 Revision requested 4 October 1999 Accepted: 8 October 1999
Arai, Fumio; Miyamoto, Takeshi; Ohneda, Osamu; Inada, Tomohisa; Sudo, Tetsuo; Brasel, Kenneth; Miyata, Takashi; Anderson, Dirk M.; Suda, Toshio
doi: 10.1084/jem.190.12.1741pmid: 10601350
Osteoclasts are terminally differentiated cells derived from hematopoietic stem cells. However, how their precursor cells diverge from macrophagic lineages is not known. We have identified early and late stages of osteoclastogenesis, in which precursor cells sequentially express c-Fms followed by receptor activator of nuclear factor κB (RANK), and have demonstrated that RANK expression in early-stage of precursor cells (c-Fms + RANK − ) was stimulated by macrophage colony-stimulating factor (M-CSF). Although M-CSF and RANKL (ligand) induced commitment of late-stage precursor cells (c-Fms + RANK + ) into osteoclasts, even late-stage precursors have the potential to differentiate into macrophages without RANKL. Pretreatment of precursors with M-CSF and delayed addition of RANKL showed that timing of RANK expression and subsequent binding of RANKL are critical for osteoclastogenesis. Thus, the RANK–RANKL system determines the osteoclast differentiation of bipotential precursors in the default pathway of macrophagic differentiation. osteoclastogenesis commitment macrophage RANK ligand M-CSF Footnotes F. Arai and T. Miyamoto contributed equally to this work. Abbreviations used in this paper: BM, bone marrow; Dex, dexamethasone; Epo, erythropoietin; L, ligand; MNCs, multinucleated cells; NF, nuclear factor; OPG, osteoprotegerin; RANK, receptor activator of nuclear factor κB; RT, reverse transcriptase; s, soluble; SCF, stem cell factor; TRAFs, TNFR-associated factors; TRAP, tartrate-resistant acid phosphatase. Submitted: 29 June 1999 Revision requested 27 September 1999 Accepted: 7 October 1999
Charbonnier, Anne-Sophie; Kohrgruber, Norbert; Kriehuber, Ernst; Stingl, Georg; Rot, Antal; Maurer, Dieter
doi: 10.1084/jem.190.12.1755pmid: 10601351
Certain types of dendritic cells (DCs) appear in inflammatory lesions of various etiologies, whereas other DCs, e.g., Langerhans cells (LCs), populate peripheral organs constitutively. Until now, the molecular mechanism behind such differential behavior has not been elucidated. Here, we show that CD1a + LC precursors respond selectively and specifically to the CC chemokine macrophage inflammatory protein (MIP)-3α. In contrast, CD14 + precursors of DC and monocytes are not attracted by MIP-3α. LCs lose the migratory responsiveness to MIP-3α during their maturation, and non-LC DCs do not acquire MIP-3α sensitivity. The notion that MIP-3α may be responsible for selective LC recruitment into the epidermis is further supported by the following observations: (a) MIP-3α is expressed by keratinocytes and venular endothelial cells in clinically normal appearing human skin; (b) LCs express CC chemokine receptor (CCR)6, the sole MIP-3α receptor both in situ and in vitro; and (c) non-LC DCs that are not found in normal epidermis lack CCR6. The mature forms of LCs and non-LC DCs display comparable sensitivity for MIP-3β, a CCR7 ligand, suggesting that DC subtype–specific chemokine responses are restricted to the committed precursor stage. Although LC precursors express primarily CCR6, non-LC DC precursors display a broad chemokine receptor repertoire. These findings reflect a scenario where the differential expression of chemokine receptors by two different subpopulations of DCs determines their functional behavior. One type, the LC, responds to MIP-3α and enters skin to screen the epidermis constitutively, whereas the other type, the “inflammatory” DC, migrates in response to a wide array of different chemokines and is involved in the amplification and modulation of the inflammatory tissue response. Langerhans cell dendritic cell chemokine migration epidermis Footnotes Abbreviations used in this paper: CB, cord blood; CCR, CC chemokine receptor; CXCR, CXC chemokine receptor; DC, dendritic cell; DMEC, dermal microvascular EC; EC, endothelial cell; E-cad, E-cadherin; HPC, hematopoietic precursor cell; HUVEC, human umbilical vein EC; LC, Langerhans cell; MCP, monocyte chemotactic protein; mdDC, monocyte-derived DC; MIP, macrophage inflammatory protein; MNC, mononuclear cell; PB, peripheral blood; PerCP, peridinin chlorophyll protein; PFA, paraformaldehyde; RANTES, regulated upon activation, normal T cell expressed and secreted; RPE, R-phycoerythrin; RT, reverse transcription; SA-Cy5, Cy5 RPE–conjugated streptavidin; SDF, stromal cell–derived factor; SLC, secondary lymphoid tissue chemokine. Submitted: 23 July 1999 Revision requested 20 September 1999 Accepted: 28 September 1999
Yang, Jing; Hirata, Takako; Croce, Kevin; Merrill-Skoloff, Glenn; Tchernychev, Boris; Williams, Eric; Flaumenhaft, Robert; Furie, Barbara C.; Furie, Bruce
doi: 10.1084/jem.190.12.1769pmid: 10601352
P-selectin glycoprotein ligand 1 (PSGL-1) is a mucin-like selectin counterreceptor that binds to P-selectin, E-selectin, and L-selectin. To determine its physiological role in cell adhesion as a mediator of leukocyte rolling and migration during inflammation, we prepared mice genetically deficient in PSGL-1 by targeted disruption of the PSGL-1 gene. The homozygous PSGL-1–deficient mouse was viable and fertile. The blood neutrophil count was modestly elevated. There was no evidence of spontaneous development of skin ulcerations or infections. Leukocyte infiltration in the chemical peritonitis model was significantly delayed. Leukocyte rolling in vivo, studied by intravital microscopy in postcapillary venules of the cremaster muscle, was markedly decreased 30 min after trauma in the PSGL-1–deficient mouse. In contrast, leukocyte rolling 2 h after tumor necrosis factor α stimulation was only modestly reduced, but blocking antibodies to E-selectin infused into the PSGL-1–deficient mouse almost completely eliminated leukocyte rolling. These results indicate that PSGL-1 is required for the early inflammatory responses but not for E-selectin–mediated responses. These kinetics are consistent with a model in which PSGL-1 is the predominant neutrophil P-selectin ligand but is not a required counterreceptor for E-selectin under in vivo physiological conditions. selectin leukocyte rolling cell adhesion P-selectin E-selectin Footnotes J. Yang's present address is Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104. The online version of this article contains supplemental material. J. Yang, T. Hirata, and K. Croce contributed equally to this work. Abbreviations used in this paper: ES, embryonic stem; PSGL-1, P-selectin glycoprotein ligand 1. Submitted: 10 June 1999 Revision requested 24 August 1999 Accepted: 21 September 1999
Mordue, Dana G.; Desai, Naishadh; Dustin, Michael; Sibley, L. David
doi: 10.1084/jem.190.12.1783pmid: 10601353
The protozoan parasite Toxoplasma gondii actively penetrates its host cell by squeezing through a moving junction that forms between the host cell plasma membrane and the parasite. During invasion, this junction selectively controls internalization of host cell plasma membrane components into the parasite-containing vacuole. Membrane lipids flowed past the junction, as shown by the presence of the glycosphingolipid G M1 and the cationic lipid label 1.1′-dihexadecyl-3-3′-3-3′-tetramethylindocarbocyanine (DiIC 16 ). Glycosylphosphatidylinositol (GPI)-anchored surface proteins, such as Sca-1 and CD55, were also readily incorporated into the parasitophorous vacuole (PV). In contrast, host cell transmembrane proteins, including CD44, Na + /K + ATPase, and β1-integrin, were excluded from the vacuole. To eliminate potential differences in sorting due to the extracellular domains, parasite invasion was examined in host cells transfected with recombinant forms of intercellular adhesion molecule 1 (ICAM-1, CD54) that differed in their mechanism of membrane anchoring. Wild-type ICAM-1, which contains a transmembrane domain, was excluded from the PV, whereas both GPI-anchored ICAM-1 and a mutant of ICAM-1 missing the cytoplasmic tail (ICAM-1–Cyt − ) were readily incorporated into the PV membrane. Our results demonstrate that during host cell invasion, Toxoplasma selectively excludes host cell transmembrane proteins at the moving junction by a mechanism that depends on their anchoring in the membrane, thereby creating a nonfusigenic compartment. membrane sorting lipid domains phagocytosis moving junction invasion Footnotes Abbreviations used in this paper: BHK, baby hamster kidney; CM-DiI, chloromethyl-benzamido DiIC 16 ; CTB, cholera toxin B; DiIC 16 , 1.1′-dihexadecyl-3-3′-3-3′-tetramethylindocarbocyanine; EM, electron microscopy; GPI, glycosylphosphatidylinositol; HF, human fibroblast; ICAM-1, intercellular adhesion molecule 1; IF, immunofluorescence; immunoEM, immunoelectron microscopy; PV, parasitophorous vacuole. Submitted: 10 August 1999 Revision requested 4 October 1999 Accepted: 5 October 1999
Van den Eynde, Benoît J.; Gaugler, Béatrice; Probst-Kepper, Michael; Michaux, Lucienne; Devuyst, Olivier; Lorge, Francis; Weynants, Patrick; Boon, Thierry
doi: 10.1084/jem.190.12.1793pmid: 10601354
By stimulating blood lymphocytes from a renal cell carcinoma patient in vitro with the autologous tumor cells, we obtained cytolytic T lymphocyte (CTL) clones that killed several autologous and allogeneic histocompatibility leukocyte antigen (HLA)-B7 renal carcinoma cell lines. We identified the target antigen of these CTLs by screening COS cells transfected with the HLA-B7 cDNA and with a cDNA library prepared with RNA from the tumor cells. The antigenic peptide recognized by the CTLs has the sequence LPRWPPPQL and is encoded by a new gene, which we named RU2 . This gene is transcribed in both directions. The antigenic peptide is not encoded by the sense transcript, RU2S, which is expressed ubiquitously. It is encoded by an antisense transcript, RU2AS, which starts from a cryptic promoter located on the reverse strand of the first intron and ends up on the reverse strand of the RU2S promoter, which contains a polyadenylation signal. This mechanism of antigen expression is unprecedented and further illustrates the notion that many peptides recognized by T cells cannot be predicted from the primary structure of the major product of the encoding gene. Antisense transcript RU2AS is expressed in a high proportion of tumors of various histological types. It is absent in most normal tissues, but is expressed in testis and kidney, and, at lower levels, in urinary bladder and liver. Short-term cultures of normal epithelial cells from the renal proximal tubule expressed significant levels of RU2AS message and were recognized by the CTLs. Therefore, this antigen is not tumor specific, but corresponds to a self-antigen with restricted tissue distribution. renal cell carcinoma cytolytic T lymphocytes antisense peptides Footnotes B. Gaugler's present address is Laboratoire d'Immunologie des Tumeurs, Institut Paoli-Calmettes, 232 Bd. de Ste. Marguerite, F-13009 Marseille, France. Abbreviations used in this paper: RACE, rapid amplification of cDNA ends; RCC, renal cell carcinoma; RT, reverse transcription. Submitted: 21 September 1999 Accepted: 5 October 1999
Vance, Russell E.; Jamieson, Amanda M.; Raulet, David H.
doi: 10.1084/jem.190.12.1801pmid: 10601355
The heterodimeric CD94/NKG2A receptor, expressed by mouse natural killer (NK) cells, transduces inhibitory signals upon recognition of its ligand, Qa-1 b , a nonclassical major histocompatibility complex class Ib molecule. Here we clone and express two additional receptors, CD94/NKG2C and CD94/NKG2E, which we show also bind to Qa-1 b . Within their extracellular carbohydrate recognition domains, NKG2C and NKG2E share extensive homology with NKG2A (93–95% amino acid similarity); however, NKG2C/E receptors differ from NKG2A in their cytoplasmic domains (only 33% similarity) and contain features that suggest that CD94/NKG2C and CD94/NKG2E may be activating receptors. We employ a novel blocking anti-NKG2 monoclonal antibody to provide the first direct evidence that CD94/NKG2 molecules are the only Qa-1 b receptors on NK cells. Molecular analysis reveals that NKG2C and NKG2E messages are extensively alternatively spliced and ∼20-fold less abundant than NKG2A message in NK cells. The organization of the mouse Cd94/Nkg2 gene cluster, presented here, shows striking similarity with that of the human, arguing that the entire CD94/NKG2 receptor system is relatively primitive in origin. Analysis of synonymous substitution frequencies suggests that within a species, NKG2 genes may maintain similarities with each other by concerted evolution, possibly involving gene conversion–like events. These findings have implications for understanding NK cells and also raise new possibilities for the role of Qa-1 in immune responses. CD94 NKG2 Qa-1 natural killer cell MHC class I Footnotes Abbreviations used in this paper: BAC, bacterial artificial chromosome; CHO, Chinese hamster ovary; CRD, carbohydrate recognition domain; HA, hemagglutinin; KIRs, killer cell immunoglobulin-like receptors; ORFs, open reading frames; UTRs, untranslated regions. Submitted: 16 August 1999 Revision requested 7 October 1999 Accepted: 20 October 1999
Tesch, Gregory H.; Maifert, Stefanie; Schwarting, Andreas; Rollins, Barrett J.; Kelley, Vicki Rubin
doi: 10.1084/jem.190.12.1813pmid: 10601356
Infiltrating leukocytes may be responsible for autoimmune disease. We hypothesized that the chemokine monocyte chemoattractant protein (MCP)-1 recruits macrophages and T cells into tissues that, in turn, are required for autoimmune disease. Using the MRL- Fas lpr strain with spontaneous, fatal autoimmune disease, we constructed MCP-1–deficient MRL- Fas lpr mice. In MCP-1–intact MRL- Fas lpr mice, macrophages and T cells accumulate at sites (kidney tubules, glomeruli, pulmonary bronchioli, lymph nodes) in proportion to MCP-1 expression. Deleting MCP-1 dramatically reduces macrophage and T cell recruitment but not proliferation, protects from kidney, lung, skin, and lymph node pathology, reduces proteinuria, and prolongs survival. Notably, serum immunoglobulin (Ig) isotypes and kidney Ig/C3 deposits are not diminished in MCP-1–deficient MRL- Fas lpr mice, highlighting the requirement for MCP-1–dependent leukocyte recruitment to initiate autoimmune disease. However, MCP-1–deficient mice are not completely protected from leukocytic invasion. T cells surrounding vessels with meager MCP-1 expression remain. In addition, downstream effector cytokines/chemokines are decreased in MCP-1–deficient mice, perhaps reflecting a reduction of cytokine-expressing leukocytes. Thus, MCP-1 promotes MRL- Fas lpr autoimmune disease through macrophage and T cell recruitment, amplified by increasing local cytokines/chemokines. We suggest that MCP-1 is a principal therapeutic target with which to combat autoimmune diseases. mouse kidney lung chemokine gene disruption Footnotes Abbreviations used in this paper: gcs, glomerular cross sections; MCP, monocyte chemoattractant protein; NSN, nephrotoxic serum nephritis; PAS, periodic acid Schiffs; PCNA, proliferating cell nuclear antigen; TECs, tubular epithelial cells. Submitted: 20 April 1999 Revision requested 27 September 1999 Accepted: 5 October 1999
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