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R A Ezekowitz

Publications and source records attributed to R A Ezekowitz.

At least 37 records · Page 2Linked to original sources
PubMed1998

Spastic diplegia as a complication of interferon Alfa-2a treatment of hemangiomas of infancy.

We report the development of spastic diplegia in infants during the course of interferon Alfa-2a (IFN) therapy for potentially life-endangering hemangiomas. Five infants who displayed diplegia were selected from a group of 26 infants treated with IFN. Diplegia persisted in three infants, and in the remaining two significant recovery occurred after IFN was discontinued. Magnetic resonance imaging showed no significant brain or spinal abnormalities except minor to moderate delayed myelination in two patients. Myelination was normal on subsequent radiographic examination in all five patients. We conclude that IFN can adversely affect the immature central nervous system and produce spastic diplegia, which is potentially reversible. We recommend careful clinical assessment of neurodevelopmental status during IFN therapy.

Cerebral Palsy↗
PubMed1998

The mannose receptor is a pattern recognition receptor involved in host defense.

The mannose receptor recognizes the patterns of carbohydrates that decorate the surfaces and cell walls of infectious agents. This macrophage and dendritic cell pattern-recognition receptor mediates endocytosis and phagocytosis. The mannose receptor is the prototype of a new family of multilectin receptor proteins (membrane-spanning receptors containing eight-ten lectin-like domains, which appear to play a key role in host defense) and provides a link between innate and adaptive immunity. Recent advances include the identification of three new members of the mannose receptor family, additional work on defining the molecular requirements for sugar binding, a role for the mannose receptor in antigen presentation of lipoglycan antigens and evidence that the mannose receptor is associated with a signal transduction pathway leading to cytokine production.

Animals↗
PubMed1998

Human mannose-binding protein inhibits infection of HeLa cells by Chlamydia trachomatis.

The role that collectin (mannose-binding protein) may play in the host's defense against chlamydial infection was investigated. Recombinant human mannose-binding protein was used in the inhibition of cell culture infection by Chlamydia trachomatis (C/TW-3/OT, E/UW-5/Cx, and L2/434/Bu), Chlamydia pneumoniae (AR-39), and Chlamydia psittaci (6BC). Mannose-binding protein (MBP) inhibited infection of all chlamydial strains by at least 50% at 0.098 microg/ml for TW-3 and UW-5, and at 6.25 microg/ml for 434, AR-39, and 6BC. The ability of MBP to inhibit infection with strain L2 was not affected by supplementation with complement or addition of an L2-specific neutralizing monoclonal antibody. Enzyme-linked immunosorbent assay and dot blot analyses showed MBP bound to the surface of the organism to exert inhibition, which appeared to block the attachment of radiolabeled organisms to HeLa cells. Immunoblotting and affinity chromatography indicated that MBP binds to the 40-kDa glycoprotein (the major outer membrane protein) on the outer surface of the chlamydial elementary body. Hapten inhibition assays with monosaccharides and defined oligosaccharides showed that the inhibitory effects of MBP were abrogated by mannose or high-mannose type oligomannose-oligosaccharide. The latter carbohydrate is the ligand of the 40-kDa glycoprotein of C. trachomatis L2, which is known to mediate attachment, suggesting that the MBP binds to high mannose moieties on the surface of chlamydial organisms. These results suggest that MBP plays a role in first-line host defense against chlamydial infection in humans.

Bacterial Adhesion↗
PubMed1998

Cerebral vasculopathy and neurologic sequelae in infants with cervicofacial hemangioma: report of eight patients.

PURPOSE: To determine the association of cerebral arterial anomalies and progressive cerebral arterial occlusive disease in infants with facial hemangiomas. MATERIALS AND METHODS: The cases of eight infants (seven girls and one boy) with the diagnosis of cervicofacial hemangioma and intracranial arterial anomalies were reviewed retrospectively. Findings from clinical and imaging examinations--including cranial computed tomography, magnetic resonance imaging and angiography, and catheter angiography--were evaluated. Serial imaging findings were studied to document progressive intracranial vascular changes. RESULTS: Five patients had additional associated congenital anomalies. Seven were treated with corticosteroids, interferon alfa-2a, or both. Progressive cerebrovascular occlusive changes were documented in four of the seven patients with serial imaging findings. Four other patients (all treated pharmacologically) had MR imaging documentation of cerebral infarction, and all had consistent, acquired neurologic symptoms. CONCLUSION: Intracranial arterial anomalies can coexist with cervicofacial hemangioma. Aneurysmal and occlusive changes are potentially progressive and can result in cerebral infarction. A causative association between occlusive cerebrovascular disease and pharmacologic treatment has not been excluded.

Abnormalities, Multiple↗
PubMed1998

Th1 and Th2 cytokines cooperate to stimulate mannose-receptor-mediated phagocytosis.

The mannose receptor is a macrophage surface receptor that mediates both endocytosis and phagocytosis. Previous work has demonstrated that the prototypical Th2 cytokine, interleukin-4 (IL-4), increases both cell-surface receptor expression and mannose receptor-mediated endocytosis, whereas the prototypical Th1 cytokine, interferon-gamma (IFN-gamma), decreases both surface expression and endocytosis. In many aspects of the immune response, Th1 and Th2 cytokines oppose each others' actions. We demonstrate that IL-4 and IFN-gamma alone and together enhance mannose receptor-mediated phagocytosis, despite opposing effects on cell-surface mannose receptor expression and endocytosis. Thus these usually antagonistic cytokines cooperate in increasing mannose receptor phagocytic function. The cooperative effect of these cytokines is not observed for Fc receptor-mediated phagocytosis. The Th2 cytokine IL-13 exerts similar effects to IL-4. Our results suggest that Th1 and Th2 cytokines may act in concert at sites of inflammation to enhance mannose receptor-mediated phagocytosis of microorganisms.

Animals↗
PubMed1997

Murine macrophage mannose receptor promoter is regulated by the transcription factors PU.1 and SP1.

The mannose receptor (MR) is a transmembrane protein that functions primarily as a phagocytic receptor for a wide range of microorganisms. Its expression appears to be restricted to tissue macrophages and Langerhans cells. To gain an understanding of the regulation of the gene, we have isolated the 5' flanking sequence of the murine MR gene and have analyzed a 536-bp sequence upstream of the ATG start site for transcriptional activity. This sequence lacks a TATA box but contains an initiator (Inr) consensus element overlapping the single transcriptional start site. Transcription factor binding sites contained within this sequence include PU.1, Sp1, ETS, GATA, and MYB motifs. Serial 100-bp deletions of this promoter fragment fused to a luciferase reporter gene showed various patterns of activity when transfected into different cell types. In myeloid cells, sequence elements upstream of bp -300 appeared to have a silencing effect on promoter activity. Of the four potential PU.1 binding sites contained within the fragment, one site (at -164) bound the PU.1 factor most strongly, whereas the adjacent PU.1 site (at -177 bp) bound PU.1 to a lesser degree. Mutations of these sites decreased transcriptional activity but did not abolish it. However, promoter activity was abrogated when both the -164 bp PU.1 site and the adjacent -177 bp PU.1 site were mutated. In addition, mutation of the Sp1 site also significantly reduced promoter activity. Cotransfection studies in Drosophila Schneider cells indicated that PU.1 and Sp1 may function synergistically in transactivating the murine MR. This study indicates that MR gene expression is regulated in part by the interaction between the ubiquitously expressed factor Sp1 and the lymphoid/myeloid factor PU.1 and provides a basis for studying the regulation of this gene.

Animals↗
PubMed1997

Treatment of l(2)mbn Drosophila tumorous blood cells with the steroid hormone ecdysone amplifies the inducibility of antimicrobial peptide gene expression.

Insects rely on both humoral and cellular mechanisms to defend themselves against microbial infections. The humoral response involves synthesis of a battery of potent antimicrobial peptides by the fat body and, to a lesser extent, by blood cells. The cellular response on the other hand consists of phagocytosis of small microorganisms and melanization and encapsulation of larger parasites. The l(2)mbn cell line, established from tumorous larval hemocytes, represents a system of choice to dissect the molecular events controlling cellular immunity. We report here that l(2)mbn cells can be efficiently induced to differentiate in adherent, macrophage-like cells by treatment with 20-hydroxyecdysone. Ecdysone treatment increases both the phagocytic capacity of l(2)mbn cells and their competence to express antimicrobial genes in response to immune challenge. We also report that expression of several regulatory molecules thought to be involved in the immune response is up-regulated by ecdysone in l(2)mbn cells.

Animals↗
PubMed1997

Interaction of human mannose-binding protein with Mycobacterium avium.

The interaction between human mannose-binding protein (MBP) and Mycobacterium avium was explored. By ELISA, calcium-dependent and mannan-inhibitable binding of human recombinant MBP (rMBP) to live M. avium was observed. Preincubation of M. avium with rMBP resulted in a 2-fold increase in uptake by human neutrophils. Mycobacterial cell wall components were assessed by ELISA for their ability to bind the carbohydrate recognition domain of rMBP. The best ligand was mannosyl-lipoarabinomannan, followed by lipomannan, phosphatidylinositol mannoside, arabinosyl-lipoarabinomannan, and dimycolated trehalose (cord factor). rMBP did not bind to partially purified lipid fractions containing glycopeptidolipids. These results are consistent with the known structural basis for rMBP ligand recognition. They suggest that MBP may play a role in host defense against M. avium by opsonizing both whole organisms and free cell wall components for internalization.

Acute-Phase Proteins↗
PubMed1997

Role of gamma interferon in the host immune and inflammatory responses to Pneumocystis carinii infection.

The role of gamma interferon (IFN-gamma) in host defense to Pneumocystis carinii was investigated by use of three different murine models of infection. C57BL/6 scid/scid (severe combined immunodeficient [SCID]) mice were given intratracheal inoculations of P. carinii and reconstituted with splenocytes from either mice with disrupted IFN-gamma genes (IFN-gamma-/- mice) or homozygous wild-type (IFN-gamma+/+) mice. Unreconstituted SCID mice had log10 7.08 +/- 0.13 P. carinii nuclei in their lungs at day 22 postinfection, whereas SCID mice reconstituted with splenocytes from either wild-type or IFN-gamma-/- mice had cleared the infection. However, there was a prolonged and exacerbated inflammatory response in the lungs of SCID mice reconstituted with IFN-gamma-/- splenocytes which was characterized by interstitial pneumonia, eosinophilia, and multinucleated giant cell formation. Similar results were found in C.B17 SCID mice reconstituted with CD4+ cells from P. carinii-immunized donors treated with neutralizing anti-IFN-gamma monoclonal antibody (MAb). These mice resolved their P. carinii infections; however, they also exhibited exacerbated lung pathology compared with mice treated with a control MAb. Finally, IFN-gamma-/- mice challenged intratracheally with P. carinii resolved their infection within 56 days as did IFN-gamma+/- mice. Furthermore, depletion of T cells in vivo with a MAb resulted in IFN-gamma-/- mice becoming susceptible to P. carinii infection. Together, these data indicate that IFN-gamma is not required for resolution of P. carinii infection; however, in the absence of IFN-gamma, there is a prolonged and exacerbated P. carinii-driven interstitial pneumonia characterized by eosinophilia and formation of multinucleated giant cells.

Animals↗
PubMed1996

Hepatic vascular anomalies in infancy: a twenty-seven-year experience.

OBJECTIVE: Infantile hemangioma and arteriovenous malformation (AVM) of the liver have a similar presentation but a different natural history, and therefore require different treatment. This study was undertaken to clarify differential diagnosis and management of these two biologically distinct vascular disorders. STUDY DESIGN: We retrospectively analyzed the records of 43 children with hepatic vascular anomalies treated during the past 27 years. RESULTS: Ninety percent were hemangiomas (n = 39); 10% were AVM (n = 4). Infants with AVM or large solitary hemangioma had hepatomegaly, congestive heart failure, and anemia as presenting symptoms at birth. Multiple hepatic hemangiomas manifested at 1 to 16 weeks of age with the same clinical triad, plus multiple cutaneous lesions (19/23). The mortality rate after treatment of hepatic AVM was 50% (2/4). The mortality rates after treatment of liver hemangiomas were as follows: resection of solitary lesions, 20% (2/10); embolization, 43% (3/7); corticosteroids, 30% (3/10); and interferon alfa-2a, 15% (2/13). CONCLUSION: Solitary hepatic hemangioma cannot always be distinguished from hepatic AVM without radiologic studies. Multiple hepatic hemangiomas are differentiated from hepatic AVM by coexistence of multiple cutaneous hemangioma and by radiologic imaging. We recommend combined embolization and surgical resection for hepatic AVM and for solitary symptomatic hemangioma, if drug therapy fails. Pharmacologic treatment is used for symptomatic multiple liver hemangiomas. Embolization allows interim control of heart failure. A decreased mortality rate after interferon alfa-2a therapy is encouraging.

Arteriovenous Malformations↗
PubMed1996

The collectins in innate immunity.

The collectins are proteins with collagen tails and globular lectin domains that appear to play an important role in mammalian first line host defense. Recent insights have clarified the structural basis of ligand recognition, the interactions of collectins with complement cascades, and the association with disease susceptibility.

Animals↗
PubMed1996

Croquemort, a novel Drosophila hemocyte/macrophage receptor that recognizes apoptotic cells.

Programmed cell death is first observed at stage 11 of embryogenesis in Drosophila. The systematic removal of apoptotic cells is mediated by cells that are derived from the procephalic mesoderm and differentiate into macrophages. We describe a macrophage receptor for apoptotic cells. This receptor, croquemort (catcher of death), is a member of the CD36 superfamily. Croquemort-mediated phagocytosis represents the concept that phagocytosis evolved primarily as a cellular process for the removal of effete cells. Our findings support the idea that the primordial function of macrophages may have been in tissue modeling and that their adapted role is in host defense.

Amino Acid Sequence↗
PubMed1996

Interactions of human mannose-binding protein with lipoteichoic acids.

We explored the interaction of human recombinant mannose-binding protein and lipoteichoic acids (LTAs) by enzyme-linked immunosorbent assay. The best ligand was Micrococcus luteus lipomannan, followed by Enterococcus spp. LTA containing mono-, di-, and oligoglucosyl substituents. LTAs lacking terminal sugars (those of Streptococcus pyogenes and Staphylococcus aureus) or containing galactosyl substituents (those of Listeria spp. and Lactococcus spp.) were poor ligands. These results are consistent with known structural requirements for binding through the mannose-binding protein carbohydrate recognition domain.

Acute-Phase Proteins↗
PubMed1996

The major surface glycoprotein of Trypanosoma cruzi amastigotes are ligands of the human serum mannose-binding protein.

Trypanosoma cruzi, an obligate intracellular protozoan parasite, chronically infects mammals and causes Chagas' disease in humans. T. cruzi evasion of the mammalian immune response and establishment of chronic infection are poorly understood. During T. cruzi infection, amastigotes and trypomastigotes disseminate in the mammalian host and invade multiple cell types. Parasite surface carbohydrates and mammalian lectins have been implicated in the invasion of mammalian cells. A recent study has demonstrated that the human mannose-binding protein and the macrophage mannose receptor, two mammalian C-type lectins, bind to T. cruzi (S. J. Kahn, M. Wleklinski, A. Aruffo, A. Farr, D. Coder, and M. Kahn, J. Exp. Med. 182:1243-1258,1995). In this report we identify the major surface glycoproteins, including the SA85-1 glycoproteins, as T. cruzi ligands of the mannose-binding protein. Further characterization of the interaction between the mannose-binding protein and T. cruzi demonstrates that (i) the SA85-1 glycoproteins are expressed by amastigotes and trypomastigotes but only amastigotes express the mannose-binding protein ligand, (ii) treatment of amastigotes with alpha-mannosidase inhibits the binding of mannose-binding protein, and (iii) amastigote binding of mannose-binding protein is stable despite the spontaneous shedding of some glycoproteins from its surface. Together, the data indicate that developmentally regulated glycosylation of surface glycoproteins controls the expression of ligands that affect the interactions between T. cruzi and mannose-binding protein. It has been established that the binding of mannose-binding protein to microorganisms facilitates their uptake into phagocytic cells. Preferential opsonization of amastigotes with mannose-binding proteins may account for their clearance from the circulation and may contribute to the parasite's ability to invade different cell types.

Animals↗
PubMed1995

A serum mannose-binding lectin mediates complement-dependent lysis of influenza virus-infected cells.

The mechanism of lysis of influenza virus-infected BHK-21 cells by guinea pig serum (GPS) was investigated. Lysis was shown to involve activation of the classical complement pathway and was dependent on the presence of a mannose-binding lectin in GPS. FACS analysis demonstrated Ca(2+)-dependent binding of the lectin to influenza virus-infected, but not uninfected, cells. Cells infected with mutant strains of virus lacking a particular high-mannose oligosaccharide at the tip of the hemagglutinin molecule showed reduced binding of the lectin and were correspondingly less sensitive to lysis by GPS than cells infected with the parent viruses. The degree or pattern of glycosylation of influenza viruses thus influences susceptibility to this mechanism of viral clearance. By interfering with the infectious process, lectin-dependent complement-mediated lysis of infected cells may be an important component of innate immunity to influenza and other enveloped viruses.

Animals↗
PubMed1995

The Gly-54-->Asp allelic form of human mannose-binding protein (MBP) fails to bind MBP-associated serine protease.

The human mannose-binding protein (MBP) is a pattern recognition molecule that appears to play a role in initial host defence. MBP activates the complement cascade and it may act as an opsonin both in the absence and in the presence of complement. A number of distinct MBP allelic forms exist in different population groups. An allele that occurs in 5-7% of Caucasians was identified by an inability to activate the complement system. A homozygous mutation at base pair 230 of the MBP gene results in a Gly-to-Asp substitution at the fifth collagen repeat. It appears that the resultant protein, MBPD, is able to form high-order multimers that bind bacteria but do not support complement activation. Recently a novel serine protease, the MBP-associated serine protease (MASP), has been described. MBP-MASP complexes circulate in serum and result in the direct activation of a novel complement pathway (lectin pathway) in the absence of the first complement components. In this study we demonstrate that MASP and its proenzyme proMASP are unable to bind to recombinant (r)MBPD. This lack of a MASP-rMBPD association corresponds to a failure of the Gly-54-->Asp form of MBP to activate complement. Our results provide a biochemical basis for the functional deficit in the Gly-54-->Asp allelic form of MBP and suggest that the proMASP/MASP binding site maps to the fifth collagen repeat of MBP.

Alleles↗