Showing papers by "Jeffrey V. Ravetch published in 1994"
TL;DR: Loss of gamma chain does not appear to perturb T cell development, since both thymic and peripheral T cell populations appear normal, and these mice represent an important tool for evaluating the role of these receptors in humoral and cellular immune responses.
979 citations
TL;DR: It is shown that FcγRIIB modulates membrane immunoglobulin-induced Ca2+ mobilization by inhibiting Ca1+ influx, without changing the pattern of tyrosine phosphorylation.
Abstract: The Fc receptor on B lymphocytes, Fc gamma RIIB (beta 1 isoform), helps to modulate B-cell activation triggered by the surface immunoglobulin complex. Crosslinking of membrane immunoglobulin by antigen or anti-Ig F(ab')2 antibody induces a transient increase in cytosolic free Ca2+, a rise in inositol-3-phosphate, activation of protein kinase C, and enhanced protein tyrosine phosphorylation. Crosslinking Fc gamma RIIB with the surface immunoglobulin complex confers a dominant signal that prevents or aborts lymphocyte activation triggered through the ARH-1 motifs of the signal transduction subunits Ig-alpha and Ig-beta. Here we show that Fc gamma RIIB modulates membrane immunoglobulin-induced Ca2+ mobilization by inhibiting Ca2+ influx, without changing the pattern of tyrosine phosphorylation. A 13-amino-acid motif in the cytoplasmic domain of Fc gamma RIIB is both necessary and sufficient for this effect. Tyrosine at residue 309 in this motif is phosphorylated upon co-crosslinking with surface immunoglobulin; mutation of this residue aborts the inhibitory effect of Fc gamma RIIB. This inhibition is directly coupled to signalling mediated through Ig-alpha and Ig-beta as evidenced by chimaeric IgM/alpha and IgM/beta molecules. The 13-residue motif in Fc gamma RIIB controls lymphocyte activation by inhibiting a Ca2+ signalling pathway triggered through ARH-1 motifs as a result of recruitment of novel SH2-containing proteins that interact with this Fc gamma RIIB cytoplasmic motif.
578 citations
TL;DR: It is demonstrated that F&s have a central role in initiating immunocomplex-triggered inflammation and are likely to be major contributors to the process of lymphocyte regulation of antibody production.
372 citations
TL;DR: The results suggest that immune complex-triggered inflammation is initiated by cell bound Fc receptors and is then amplified by cellular mediators and activated complement, redefine the inflammatory cascade and may offer other approaches for the study and treatment of immunological injury.
Abstract: Antibody-antigen complexes initiate the inflammatory response and are central to the pathogenesis of tissue injury. The classical model for this immunopathological cascade, the Arthus reaction, was reinvestigated with a murine strain deficient in Fc receptor expression. Despite normal inflammatory responses to other stimuli, the inflammatory response to immune complexes was markedly attenuated. These results suggest that immune complex-triggered inflammation is initiated by cell bound Fc receptors and is then amplified by cellular mediators and activated complement. These results redefine the inflammatory cascade and may offer other approaches for the study and treatment of immunological injury.
350 citations
TL;DR: The ability of these mutants to attenuate mlg- induced B-cell activation was correlated with the presence of this region, suggesting its functional involvement in regulating the activation process.
Abstract: Nature 368, 70-73 (1994) IN this letter we neglected to mention in our citation of ref. 13 that Amigorena et al.1 had previously expressed in IIA1.6 cells deletion mutants of mFc/RII-Bl and B2 that did or did not include the 13-amino-acid cytoplasmic domain motif analysed in our report. The ability of these mutants to attenuate mlg- induced B-cell activation was correlated with the presence of this region, suggesting its functional involvement in regulating the activation process.
211 citations
TL;DR: The promoter structure, the proximal DNA sequences responsible for transcription of Fc gamma RIIIA in macrophages and the protein factors which interact with these sequences are reported and two cis‐acting elements have been identified and required for full promoter function.
Abstract: Expression of the low-affinity Fc receptor for IgG (murine Fc gamma RIIIA) is restricted to cells of myelomonocytic origin. We report here the promoter structure, the proximal DNA sequences responsible for transcription of Fc gamma RIIIA in macrophages and the protein factors which interact with these sequences. A 51 bp sequence, termed the myeloid restricted region (MRR), was both necessary and sufficient for conferring cell type-specific expression in macrophages. Reporter constructs containing mutations in this sequence result in the loss of MRR activity upon transfection into the macrophage cell line, RAW264.7. Two cis-acting elements have been identified and are required for full promoter function. These same elements analyzed by EMSA define two binding sites recognized by nuclear factors derived from macrophages. A 3' purine tract (-50 to -39) within the MRR binds the macrophage and B cell-specific factor, PU.1, and a second E box-like element, termed MyE, upstream of the PU.1 box (-88 to -78) binds the HLH factors TFE3 and USF. EMSA studies using RAW cell extracts suggest that both PU.1 and MyE factors may bind simultaneously to the MRR resulting in a ternary complex that is responsible, in part, for the myeloid-specific activity of the Fc gamma RIIIA promoter.
91 citations
TL;DR: It is suggested that these subtelomeric elements promote chromosome pairing in P. falciparum and facilitate meiotic recombination and gene conversion between telomere-proximal genes.
Abstract: The human malaria parasite Plasmodium falciparum exhibits a high degree of chromosomal polymorphism, which may contribute to its ability to evade host defenses The analysis of parasite chromosomes has revealed that these polymorphisms are confined to the subtelomeric regions, which are transcriptionally silent and contain repetitive sequence elements Several subtelomeric repetitive elements have been isolated and mapped by using P falciparum yeast artificial chromosome (YAC) clones Structural analysis of parasite telomeric and subtelomeric YAC clones demonstrated that these repetitive elements are conserved between P falciparum chromosome ends We suggest that these subtelomeric elements promote chromosome pairing in P falciparum and facilitate meiotic recombination and gene conversion between telomere-proximal genes
72 citations
Patent•
18 Aug 1994TL;DR: In this article, a non-naturally occurring non-human vertebrate animal incapable of expressing a functional Fc receptor which may optionally be expressing a protein which comprises a domain of a human Fc-RBP, as well as DNA encoding such Fc RBP-based proteins is described.
Abstract: Disclosed herein is a non-naturally occurring non-human vertebrate animal incapable of expressing a functional Fc receptor which may optionally be capable of expressing a protein which comprises a domain of a human Fc receptor, as well as DNA encoding such Fc receptor-based proteins. Also disclosed are in vivo methods for identifying proinflammatory agents that depend on a functional Fc receptor, in vivo methods for identifying proinflammatory agents that do not depend on a functional Fc receptor, and both in vivo and in vitro methods of identifying anti-inflammatory agents. Pharmaceutical compositions containing, and methods of treating inflammation with anti-inflammatory agents are also described.
43 citations
TL;DR: Data suggest that, in P. falciparum, the chromatin structure is involved in the molecular process of chromosome breakage, a mechanism that may be common in other eukaryotes.
Abstract: Spontaneous chromosome breakages are frequently observed in the human malaria parasite Plasmodium falciparum and are responsible for the generation of novel phenotypes, which may contribute to the pathogenicity and virulence of this protozoan parasite. The identification of a hot spot of chromosome breakage within the coding region of the KAHRP gene revealed that these events do not occur randomly but follow a regular pattern with a periodicity of 155 bp. This phasing corresponds to the average repeat unit of P. falciparum nucleosomes. Furthermore, breakage events preferentially occur within the linker regions of nucleosomes, as demonstrated by mapping endonuclease hypersensitive sites of chromatin. These data suggest that, in P. falciparum, the chromatin structure is involved in the molecular process of chromosome breakage, a mechanism that may be common in other eukaryotes.
42 citations
TL;DR: It is proposed that the chromosome ends play a functional role in generating genetic diversity by promoting meiotic and mitotic recombination and chromosomal rearrangement events.
28 citations
TL;DR: Analysis of the chromatin structure revealed that both the transcribed domain and the subtelomeric region are organized as nucleosomes with a periodicity of 155 +/- 5 bp.
Abstract: We have recently demonstrated that Plasmodium falciparum chromosomes are compartmentalized into different domains: conserved and polymorphic domains; transcriptionally active and silent domains. Here we have analyzed the transition between these domains at the structural and nucleosomal level. This study was conducted with the end of chromosome 2 that is associated with cytoadherence. At this end of the chromosome, the first set of erythrocytic genes has been mapped 85 kb from the telomere. These genes are monocistronically transcribed as revealed by nuclear run-on analysis. Two of these genes, PfEMP3 and KAHRP, are deleted in cytoadherent negative mutants, whereas the third gene, GLARP, is expressed in all the strains investigated. The data indicate that the polymorphic domain at this end of chromosome 2 extends into the transcribed region. Analysis of the chromatin structure revealed that both the transcribed domain and the subtelomeric region are organized as nucleosomes with a periodicity of 155 +/- 5 bp.
TL;DR: The genetic map of most FcγRs will soon be complete providing a valuable tool to evaluating involvement of these genes in karyotypic instability and landmarks in the search for linked human genes/conditions.
Abstract: Immune complex cross-linking of cell surface receptors for immunoglobulin (Ig) triggers pleiotropic cellular events that underpin a wide variety of immune responses. In this fashion receptors for immunoglobulin form a molecular bridge between the humoral and cellular immune responses. Elucidation of the primary structure of receptors for the Fc domain of Ig (FcγRs) has provided invaluable insight into their contribution to immune cell regulation. This revelation has been made possible as the result of cloning of both cDNAs and genes that encode this diverse family of molecules. Over the past decade a nearly complete “dissection” of the molecules that mediate this binding of immune complexes to cells has been accomplished. Current efforts focus on putting these pieces back into an organismic context and determining their roles in systemic processes such as inflammation, autoimmunity, allergy and development. The genetic map of most FcγRs will soon be complete providing a valuable tool to evaluating involvement of these genes in karyotypic instability and landmarks in the search for linked human genes/conditions.