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Yosuke Kameda, Motoki Hanayama, Atsushi Kishimoto, Masahiko Kume, Kazuo Yamamoto, Naoki Matsumoto
Dendritic cell inhibitory receptor 4 (DCIR4, Clec4a1) is a lectin receptor and a member of mouse dendritic cell immunoreceptor family. Due to the lack of antibodies against DCIR4, expression of DCIR4 protein remains unknown. In this study, we established a specific monoclonal antibody against DCIR4 and investigated the expression of DCIR4 among immune cells. We found that DCIR4 was expressed on non-granulocytic subsets of CD11b(+) cells in various immune organs including bone marrow, peripheral blood, spleen, skin-associated lymph nodes and mesenteric lymph nodes...
October 13, 2016: Biochemical and Biophysical Research Communications
Masanori Inui, Akiko Sugahara-Tobinai, Hiroshi Fujii, Ari Itoh-Nakadai, Hidehiro Fukuyama, Tomohiro Kurosaki, Tomonori Ishii, Hideo Harigae, Toshiyuki Takai
Plasmablasts and plasma cells (PBs/PCs) producing pathogenic autoantibodies in patients with systemic autoimmune diseases could be a better target for specific therapies for the disease than general immunosuppression or pan- or activated B-cell targeting. Our previous study indicated that Leukocyte Ig-like receptor (LILR)B4 (B4, also known as ILT3/LIR-5/CD85k), a tolerogenic receptor in antigen-presenting cells, is ectopically expressed on the PB/PC surface in healthy individuals. Here we show that the enlarged population size of PBs/PCs with augmented B4 expression is characteristic in non-treated systemic lupus erythematosus (SLE)...
October 14, 2016: International Immunology
Ya-Hui Chiu, Edward Schwarz, Dongge Li, Yuexin Xu, Tzong-Ren Sheu, Jinbo Li, Karen L de Mesy Bentley, Changyong Feng, Baoli Wang, Jhih-Cheng Wang, Liz Albertorio-Saez, Ronald Wood, Minsoo Kim, Wensheng Wang, Christopher T Ritchlin
DC-STAMP is a multi-pass transmembrane protein essential for cell-cell fusion of osteoclast precursors during osteoclast (OC) development. DC-STAMP-/- mice have mild osteopetrosis and form mononuclear cells with limited resorption capacity. The identification of an Immunoreceptor Tyrosine-based Inhibitory Motif (ITIM) on the cytoplasmic tail of DC-STAMP suggested a potential signaling function but the absence of known DC-STAMP ligand has hindered examination of downstream signaling pathways. To address this problem, we engineered a light-activatable DC-STAMP chimeric molecule in which light exposure mimics ligand engagement that can be traced by downstream Ca2+ signaling...
October 10, 2016: Journal of Cellular Physiology
Elisa Albini, Verdiana Rosini, Marco Gargaro, Giada Mondanelli, Maria L Belladonna, Maria Teresa Pallotta, Claudia Volpi, Francesca Fallarino, Antonio Macchiarulo, Cinzia Antognelli, Roberta Bianchi, Carmine Vacca, Paolo Puccetti, Ursula Grohmann, Ciriana Orabona
The enzyme indoleamine 2,3-dioxygenase 1 (IDO1) catalyses the initial, rate-limiting step in tryptophan (Trp) degradation, resulting in tryptophan starvation and the production of immunoregulatory kynurenines. IDO1's catalytic function has long been considered as the one mechanism responsible for IDO1-dependent immune suppression by dendritic cells (DCs), which are master regulators of the balance between immunity and tolerance. However, IDO1 also harbours immunoreceptor tyrosine-based inhibitory motifs, (ITIM1 and ITIM2), that, once phosphorylated, bind protein tyrosine phosphatases, (SHP-1 and SHP-2), and thus trigger an immunoregulatory signalling in DCs...
September 30, 2016: Journal of Cellular and Molecular Medicine
Uwe Rueckschloss, Stefanie Kuerten, Süleyman Ergün
Carcinoembryonic antigen (CEA)-related cell adhesion molecules belong to the immunoglobulin superfamily, are expressed in a broad spectrum of tissues and cell types and exert context-dependent activating as well as inhibitory effects. Among these molecules, the CEA-related cell adhesion molecule-1 (CEACAM1) is a transmembrane molecule with an extracellular, a transmembrane and a cytoplasmic domain. The latter contains immunoreceptor tyrosine-based inhibitory motifs and functions as a signaling molecule. CEACAM1 can form homo- and heterodimers which is relevant for its signaling activities...
September 30, 2016: Histochemistry and Cell Biology
Jatinder Singh, Ramanpreet Shah, Dhandeep Singh
The mast cells are integral part of immune system and they have pleiotropic physiological functions in our body. Any type of abnormal stimuli causes the mast cells receptors to spur the otherwise innocuous mast cells to degranulate and release inflammatory mediators like histamine, cytokines, chemokines and prostaglandins. These mediators are involved in various diseases like allergy, asthma, mastocytosis, cardiovascular disorders, etc. Herein, we describe the receptors involved in degranulation of mast cells and are broadly divided into four categories: G-protein coupled receptors, ligand gated ion channels, immunoreceptors and pattern recognition receptors...
September 29, 2016: International Immunopharmacology
Spandan Shah, Andrew W Gibson, Chuanyi Ji, Eric Darrington, James Mobley, Kyoko Kojima, Jeffrey C Edberg, Robert P Kimberly
The common FcRγ, an immunoreceptor tyrosine-based activation motif (ITAM)- containing adaptor protein, associates with multiple leukocyte receptor complexes and mediates signal transduction through the ITAM in the cytoplasmic domain. The presence of multiple serine and threonine residues within this motif suggests the potential for serine/threonine phosphorylation in modulating signaling events. Single-site mutational analysis of these residues in RBL-2H3 cells indicates that each may contribute to net FcRγ-mediated signaling, and mass spectrometry of WT human FcRγ from receptor-stimulated cells shows consistent preferential phosphorylation of the serine residue at position 51...
September 14, 2016: Journal of Leukocyte Biology
Zhen Bian, Lei Shi, Ya-Lan Guo, Zhiyuan Lv, Cong Tang, Shuo Niu, Alexandra Tremblay, Mahathi Venkataramani, Courtney Culpepper, Limin Li, Zhen Zhou, Ahmed Mansour, Yongliang Zhang, Andrew Gewirtz, Koby Kidder, Ke Zen, Yuan Liu
Rapid clearance of adoptively transferred Cd47-null (Cd47(-/-)) cells in congeneic WT mice suggests a critical self-recognition mechanism, in which CD47 is the ubiquitous marker of self, and its interaction with macrophage signal regulatory protein α (SIRPα) triggers inhibitory signaling through SIRPα cytoplasmic immunoreceptor tyrosine-based inhibition motifs and tyrosine phosphatase SHP-1/2. However, instead of displaying self-destruction phenotypes, Cd47(-/-) mice manifest no, or only mild, macrophage phagocytosis toward self-cells except under the nonobese diabetic background...
September 13, 2016: Proceedings of the National Academy of Sciences of the United States of America
Yangnan Gu, Sophia G Zebell, Zizhen Liang, Shui Wang, Byung-Ho Kang, Xinnian Dong
Nuclear transport of immune receptors, signal transducers, and transcription factors is an essential regulatory mechanism for immune activation. Whether and how this process is regulated at the level of the nuclear pore complex (NPC) remains unclear. Here, we report that CPR5, which plays a key inhibitory role in effector-triggered immunity (ETI) and programmed cell death (PCD) in plants, is a novel transmembrane nucleoporin. CPR5 associates with anchors of the NPC selective barrier to constrain nuclear access of signaling cargos and sequesters cyclin-dependent kinase inhibitors (CKIs) involved in ETI signal transduction...
September 8, 2016: Cell
Benoit Favier
Neutrophils are the most abundant subset of leukocytes and play a crucial role in the immune responses against the daily pathogen attacks faced by the host. Neutrophils exhibit several functions for fighting microbes, including the release of granules containing highly toxic molecules, the production of reactive oxygen species and inflammatory cytokines as well as NETosis. Therefore, immune responses mediated by neutrophils must be tightly regulated to protect the host from pathogen assaults without inducing detrimental inflammation and tissue damage...
September 2016: Immunological Reviews
Birgit Manno, Thomas Oellerich, Tim Schnyder, Jasmin Corso, Marion Lösing, Konstantin Neumann, Henning Urlaub, Facundo D Batista, Michael Engelke, Jürgen Wienands
The SH2 domain-containing inositol 5'-phosphatase (SHIP) plays a key role in preventing autoimmune phenomena by limiting antigen-mediated B cell activation. SHIP function is thought to require the dual engagement of the BCR and negative regulatory coreceptors as only the latter appear capable of recruiting SHIP from the cytosol to the plasma membrane by virtue of phosphorylated immunoreceptor tyrosine-based inhibitory motifs. Here we demonstrate a coreceptor-independent membrane recruitment and function of SHIP in B cells...
August 23, 2016: European Journal of Immunology
Samantha D Pauls, Arnab Ray, Sen Hou, Andrew T Vaughan, Mark S Cragg, Aaron J Marshall
SHIP is an important regulator of immune cell signaling that functions to dephosphorylate the phosphoinositide phosphatidylinositol 3,4,5-trisphosphate at the plasma membrane and mediate protein-protein interactions. One established paradigm for SHIP activation involves its recruitment to the phospho-ITIM motif of the inhibitory receptor FcγRIIB. Although SHIP is essential for the inhibitory function of FcγRIIB, it also has critical modulating functions in signaling initiated from activating immunoreceptors such as B cell Ag receptor...
September 1, 2016: Journal of Immunology: Official Journal of the American Association of Immunologists
A Marom, A F Barak, M P Kramer, H Lewinsky, I Binsky-Ehrenreich, S Cohen, A Tsitsou-Kampeli, V Kalchenko, Y Kuznetsov, V Mirkin, N Dezorella, M Shapiro, P L Schwartzberg, Y Cohen, L Shvidel, M Haran, S Becker-Herman, Y Herishanu, I Shachar
Chronic lymphocytic leukemia (CLL) is a malignant disease of small mature lymphocytes. Signals from the CLL microenvironment promote progression of the disease and induce drug resistance. This phenomenon is largely dependent on direct contact between the malignant B cells and stromal cells. CD84 belongs to the signaling lymphocyte activation molecule family of immunoreceptors, which self-associates, forming an orthogonal homophilic dimer. We therefore hypothesized that CD84 may bridge between CLL cells and their microenvironment, promoting cell survival...
July 25, 2016: Oncogene
Mollie Capone, John Matthew Bryant, Natalie Sutkowski, Azizul Haque
Members of the family of Fc receptor-like (FcRL) proteins, homologous to FcγRI, have been identified by multiple research groups. Consequently, they have been described using multiple nomenclatures including Fc receptor homologs (FcRH), immunoglobulin superfamily receptor translocation-associated genes (IRTA), immunoglobulin-Fc-gp42-related genes (IFGP), Src homology 2 domain-containing phosphatase anchor proteins (SPAP), and B cell cross-linked by anti-immunoglobulin M-activating sequences (BXMAS). They are now referred to under a unified nomenclature as FCRL...
June 2016: Journal of Clinical & Cellular Immunology
Karla K Frietze, Adlai L Pappy, Jack W Melson, Emily E O'Driscoll, Carolyn M Tyler, David H Perlman, Lisa M Boulanger
BACKGROUND: Major histocompatibility complex class I (MHCI) proteins present antigenic peptides for immune surveillance and play critical roles in nervous system development and plasticity. Most MHCI are transmembrane proteins. The extracellular domain of MHCI interacts with immunoreceptors, peptides, and co-receptors to mediate immune signaling. While the cytoplasmic domain also plays important roles in endocytic trafficking, cross-presentation of extracellularly derived antigens, and CTL priming, the molecular mediators of cytoplasmic signaling by MHCI remain largely unknown...
2016: BMC Immunology
Christoph T Ellebrecht, Vijay G Bhoj, Arben Nace, Eun Jung Choi, Xuming Mao, Michael Jeffrey Cho, Giovanni Di Zenzo, Antonio Lanzavecchia, John T Seykora, George Cotsarelis, Michael C Milone, Aimee S Payne
Ideally, therapy for autoimmune diseases should eliminate pathogenic autoimmune cells while sparing protective immunity, but feasible strategies for such an approach have been elusive. Here, we show that in the antibody-mediated autoimmune disease pemphigus vulgaris (PV), autoantigen-based chimeric immunoreceptors can direct T cells to kill autoreactive B lymphocytes through the specificity of the B cell receptor (BCR). We engineered human T cells to express a chimeric autoantibody receptor (CAAR), consisting of the PV autoantigen, desmoglein (Dsg) 3, fused to CD137-CD3ζ signaling domains...
July 8, 2016: Science
Andrew J Long, Erik Sampson, Richard W McCarthy, Christopher M Harris, Marc Barnard, Dan Shi, Donna Conlon, Robert Caldwell, David Honor, Neil Wishart, Michael Hoemann, Lori Duggan, Douglas Fritz, Christopher Stedman, Elizabeth O'Connor, Igor Mikaelian, Annette Schwartz
Spleen tyrosine kinase (Syk) is a nonreceptor tyrosine kinase that is an important signaling enzyme downstream of immunoreceptors containing an intracellular immunoreceptor tyrosine activating motif (ITAM). These receptors encompass a wide variety of biological functions involved in autoimmune disease pathogenesis. There has been considerable interest in the development of inhibitors of the Syk pathway for the treatment of rheumatoid arthritis and systemic lupus erythematosus. We report that Syk inhibition mechanistically caused peri-islet hemorrhages and fibrin deposition in the rat pancreas and that this finding is due to a homeostatic functional defect in platelets...
October 2016: Toxicologic Pathology
Yuka Miyoshi, Osamu Ogawa, Yu Oyama
Programmed cell death-1 (PD-1), an immunoreceptor, is located on T cells and pro-B cells and interacts with its ligands to inhibit T cell activation and proliferation, thereby promoting immunological self-tolerance. Nivolumab, an anti-PD1 antibody, blocks PD-1 and can restore anticancer immune responses by abrogating PD-1 pathway-mediated T-cell inhibition. Autoimmune adverse events are expected with PD-1 therapy. Fulminant type 1 diabetes is the subtype of type 1 diabetes. The clinical feature is the extremely rapid progression of hyperglycemia and ketoacidosis...
2016: Tohoku Journal of Experimental Medicine
Jie Chen, Hong Wang, Wei-Ping Xu, Si-Si Wei, Hui Joyce Li, Yun-Qing Mei, Yi-Gang Li, Yue-Peng Wang
CD22 is a surface immunoglobulin implicated in negative regulation of B cell receptor (BCR) signaling; particularly inhibiting intracellular Ca2+ (Ca2+i)signals. Its cytoplasmic tail contains six tyrosine residues (Y773/Y783/Y817/Y828/Y843/Y863, designated Y1~Y6 respectively), including three (Y2/5/6) lying within immunoreceptor tyrosine-based inhibitory motifs (ITIMs) that serve to recruit the protein tyrosine phosphatase SHP-1 after BCR activation-induced phosphorylation. The mechanism of inhibiting Ca2+i by CD22 has been poorly understood...
June 2, 2016: Oncotarget
Besma Aouar, Denisa Kovarova, Sebastien Letard, Albert Font-Haro, Jonathan Florentin, Jan Weber, David Durantel, Laurence Chaperot, Joel Plumas, Katerina Trejbalova, Jiri Hejnar, Jacques A Nunès, Daniel Olive, Patrice Dubreuil, Ivan Hirsch, Ruzena Stranska
Crosslinking of regulatory immunoreceptors (RR), such as BDCA-2 (CD303) or ILT7 (CD85g), of plasmacytoid dendritic cells (pDCs) efficiently suppresses production of type-I interferon (IFN)-α/β and other cytokines in response to Toll-like receptor (TLR) 7/9 ligands. This cytokine-inhibitory pathway is mediated by spleen tyrosine kinase (Syk) associated with the ITAM-containing adapter of RR. Here we demonstrate by pharmacological targeting of Syk that in addition to the negative regulation of TLR7/9 signaling via RR, Syk also positively regulates the TLR7/9 pathway in human pDCs...
2016: PloS One
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