DOCSLIB.ORG

FCGR2B) Is Associated with the Production of Anti-Cyclic Citrullinated Peptide Autoantibodies in Taiwanese RA

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
FCGR2B) Is Associated with the Production of Anti-Cyclic Citrullinated Peptide Autoantibodies in Taiwanese RA Genes and Immunity (2008) 9, 680–688 & 2008 Macmillan Publishers Limited All rights reserved 1466-4879/08 $32.00 www.nature.com/gene ORIGINAL ARTICLE A transmembrane polymorphism in FcgRIIb (FCGR2B) is associated with the production of anti-cyclic citrullinated peptide autoantibodies in Taiwanese RA J-Y Chen1, C-M Wang2, C-C Ma1, L-A Hsu3, H-H Ho1, Y-JJ Wu1, S-N Kuo1 and J Wu4 1Division of Allergy, Immunology and Rheumatology, Department of Medicine, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Tao-Yuan, Taiwan, Republic of China; 2Department of Rehabilitation, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Tao-Yuan, Taiwan, Republic of China; 3Department of Medicine, Division of First Cardiovascular, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Tao-Yuan, Taiwan, Republic of China and 4Division of Clinical Immunology and Rheumatology, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA The aim of the current study was to determine whether the FcgRIIb 187-Ile/Thr polymorphism is a predisposition factor for subtypes of RA defined by disease severity and production of autoantibodies against cyclic citrullinated peptides (anti-CCPs) in Taiwanese RA patients. Genotype distributions and allele frequencies of FcgRIIb 187-Ile/Thr were compared between 562 normal healthy controls and 640 RA patients as stratified by clinical parameters and autoantibodies. Significant enrichment of 187-Ile allele was observed in RA patients positive for anti-CCP antibodies as compared with the anti-CCP negative RA patients (P ¼ 0.001, OR 1.652 (95% CI 1.210–2.257)) or as compared with the normal controls (P ¼ 0.005, OR 1.348 (95% CI 1.092–1.664)). In addition, 187-Ile allele was found to be enriched in RA patients positive for rheumatoid factor (RF) compared to the RF negative RA patients (P ¼ 0.024, OR 1.562 (95% CI 1.059–2.303)). Furthermore, the homozygotes were enriched in destructive male RA patients (P ¼ 0.035; OR 2.038 (95% CI 1.046–3.973)) and the 187-Ile allele was associated with early- onset of RA in Taiwanese patients (P ¼ 0.045, OR 1.548 (95% CI 1.007–2.379)). Thus, FcgRIIb SNP 187-Ile/Thr may influence the RA phenotypes in Taiwanese RA. Genes and Immunity (2008) 9, 680–688; doi:10.1038/gene.2008.56; published online 17 July 2008 Keywords: rheumatoid arthritis; anti-CCP antibody; FcgR; polymorphism Introduction aid the treatment of those patients with early aggressive Disease Modifying Anti-Rheumatic Drugs that could Rheumatoid arthritis (RA) is a chronic inflammatory thwart the progression of the pathologic process. disease characterized by joint inflammation, infiltration of Immunoglobulin molecules mediate various immune- immune cells, proliferation of synovial cells, destruction of related functions including phagocytosis, degranulation, cartilage and bony erosion in multiple joints. The functional antibody-dependent cell-mediated cytotoxicity, cytokine disability caused by RA leads to severe work and daily release and antigen presentation through binding of their living disturbance. Although the precise etiology and Fc portions to specific cell surface receptors. In humans, pathogenesis remain incompletely understood, multiple eight genes (FcgRIA, FcgRIB, FcgRIC, FcgRIIA, FcgRIIB, factors including genetic composition, possible infection FcgRIIC, FcgRIIIA and FcgRIIIB) encoding the classical Fcg triggering and other immune dysfunction all are thought to receptors are clustered in the 1q21-23 region of chromo- contribute to RA pathogenesis.1 The important contribution some 1. Polymorphisms in human FcgR genes signifi- of genetic factors in RA development was demonstrated by cantly affect the receptor functions and play important twin and genome-scan studies.2–6 The identification of roles in modulating the immune response and in the genetic factors associated with destructive forms of RA will pathogenesis of autoimmune diseases.7,8 FcgRIIb (CD32B) is generally considered as an inhibi- tory Fcg receptor in both humans and mice.9–11 Cross- Correspondence: Dr J-Y Chen, Division of Allergy, Immunology and linking of FcgRIIb leads to the downregulation of B-cell Rheumatology, Department of Medicine, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, No. 5, activation and immunoglobulin production and there- Fu-Shin St Kuei-Shan, Tao-Yuan, Taiwan 333, Republic of China. fore, FcgRIIb is the major receptor that provides feedback E-mail: [email protected] or inhibitory signals for cell activation by immune com- Dr J Wu, Division of Clinical Immunology and Rheumatology, plexes.9,11,12 On the other hand, myeloid cells (monocytes Department of Medicine, University of Alabama at Birmingham, Shelby and neutrophils) and follicular dendritic cells also 202, 1825 University Boulevard, Birmingham, AL 35294-2182, USA. express FcgRIIb. FcgRIIb on follicular dendritic cells is E-mail: [email protected] 13–16 Received 28 April 2008; revised 16 June 2008; accepted 18 June 2008; critical to mediate B cell recall responses. Therefore, published online 17 July 2008 FcgRIIb has multiple functions in different cell systems. Association of FccRIIb polymorphism with anti-CCP antibody in RA J-Y Chen et al 681 FcgRIIb 187-Ile/Thr polymorphism (rs1050501) is trends toward the increased 187-Ile homozygosity and located in the transmembrane segment of the receptor the increased 187-Ile allele frequency in RA patients as and the amino acid change significantly affects receptor- compared with those in normal healthy controls, but mediated functions.17–19 We hypothesize that this func- these increases did not reach statistical significance tional polymorphism might play an important role in the (P ¼ 0.098 and P ¼ 0.138 respectively). pathogenesis of human rheumatoid arthritis. In the current study, we demonstrated that FcgRIIb 187-Ile The common 187-Ile allele is associated with anti-CCP þ RA allele (the allele mediating more potent inhibitory signal Anti-CCP antibodies are highly specific for RA and are and the allele being more effectively recruited to lipid predictive of the progression of undifferentiated arthritis rafts) is significantly associated with anti-CCP antibody toward RA.21,22 In addition, anti-CCP antibodies are production, RF production, destructive RA and early associated with erosive disease in RA patients.23 To onset of RA in Taiwanese patients. Our observations may determine whether FCGR2B SNP c775T4C is associated provide new insights into the role of FcgRIIb in the with production of anti-CCP antibodies; we stratified RA pathogenesis of human RA and other human autoim- patients based on presence and absence of anti-CCP mune diseases driven by autoantibody production and antibodies. Among 595 RA patients assayed for anti-CCP immune complex formation. antibodies, 464 patients (78.0%) were positive for anti- CCP þ (titers X40 IU mlÀ1). As shown in Table 2, we observed significant differences in the genotype distribu- tion between anti-CCP þ and anti-CCPÀ RA patients Results (3 Â 2 contingency table, w2 ¼ 9.819, P ¼ 0.007). The 187-Ile Demographic and clinical characteristics of rheumatoid homozygous donors were significantly increased in anti- arthritis in Taiwan CCP þ RA patients compared with anti-CCPÀ RA The present study cohort included 550 female and patients (P ¼ 0.003, odds ratio 1.819 (95% CI 1.229– 90 male Taiwanese RA patients with a mean age±s.d. 2.691)). Multiple variable logistic regression analysis at RA disease onset of 46.5±13.4 years (range, 10–80). adjusted for age, sex, anti-CCP antibody, RF and These RA patients had the mean disease duration of ANA revealed significant enrichment of the 187-Ile 13.4±8.0 years and had been followed up for at least 2 homozygotes in anti-CCP þ RA patients as compared years to assess the disease course. Five hundred and ten with anti-CCPÀ patients (P ¼ 0.007, odds ratio 1.876 (95% of the total 640 RA patients (79.7%) were positive for CI 1.187–2.965)) (Table 2). The 187-Ile allele frequency rheumatoid factor (RF). Among 574 RA patients assayed was also significantly increased in anti-CCP þ RA for antinuclear antibodies (ANA), 308 patients (53.7%) patients compared with anti-CCPÀ RA patients were positive for ANA (titers X1:80). Based on X-ray (P ¼ 0.001 odds ratio 1.652 (95% CI 1.210–2.257)). Ad- radiography data of hands and wrist joints, 513 patients ditionally, we observed a significant enrichment of 187- displayed bony erosion (X ray stage XII), 401 patients Ile allele in anti-CCP þ RA patients as compared with demonstrated destruction of joint subluxation and/or normal healthy controls (P ¼ 0.005; odds ratio 1.348 (95% ankylosis (X ray stage XIII) and 204 patients documen- CI 1.092–1.664)) and a significant enrichment of 187-Ile ted cervical spine involvement. homozygotes in anti-CCP þ RA patients as compared In the current study, 640 Taiwanese RA patients and with normal controls (w2 ¼ 7.920, P ¼ 0.005; odds ratio 562 healthy controls were genotyped using the MALDI- 1.438 (95% CI 1.116–1.852)). Our data suggest that 187-Ile TOF genotyping method for FCGR2B SNP c775T4C. The allele is an important genetic risk factor for anti-CCP reliability of the genotyping with MALDI-TOF was antibody production in Taiwanese RA patients. confirmed as described previously.20 We did not observe any significant deviations from Hardy–Weinberg equili- Association of 187-Ile allele with rheumatoid factor production brium in RA patients (w2 ¼ 0.580, P ¼ 0.748) and in the in RA patients normal controls (w2 ¼ 0.000, P ¼ 1.00) by 3 Â 2 contin- Human rheumatoid arthritis patients produce a range of gency table analyses. As shown in Table 1, there were autoantibodies including antibodies against Fc portion of Table 1 Distribution of genotypes and allele frequencies of FcgRIIb 187-Ile/Thr polymorphism in Taiwanese normal controls and RA patients Controls (N ¼ 562) RA patients (N ¼ 640) OR (95% CI) P-value Genotype frequency, no.
Load more

Recommended publications
  • The Ligands for Human Igg and Their Effector Functions
    antibodies Review The Ligands for Human IgG and Their Effector Functions Steven W. de Taeye 1,2,*, Theo Rispens 1 and Gestur Vidarsson 2 1 Sanquin Research, Dept Immunopathology and Landsteiner Laboratory, Amsterdam UMC, University of Amsterdam, 1066 CX Amsterdam, The Netherlands; [email protected] 2 Sanquin Research, Dept Experimental Immunohematology and Landsteiner Laboratory, Amsterdam UMC, University of Amsterdam, 1066 CX Amsterdam, The Netherlands; [email protected] * Correspondence: [email protected] Received: 26 March 2019; Accepted: 18 April 2019; Published: 25 April 2019 Abstract: Activation of the humoral immune system is initiated when antibodies recognize an antigen and trigger effector functions through the interaction with Fc engaging molecules. The most abundant immunoglobulin isotype in serum is Immunoglobulin G (IgG), which is involved in many humoral immune responses, strongly interacting with effector molecules. The IgG subclass, allotype, and glycosylation pattern, among other factors, determine the interaction strength of the IgG-Fc domain with these Fc engaging molecules, and thereby the potential strength of their effector potential. The molecules responsible for the effector phase include the classical IgG-Fc receptors (FcγR), the neonatal Fc-receptor (FcRn), the Tripartite motif-containing protein 21 (TRIM21), the first component of the classical complement cascade (C1), and possibly, the Fc-receptor-like receptors (FcRL4/5). Here we provide an overview of the interactions of IgG with effector molecules and discuss how natural variation on the antibody and effector molecule side shapes the biological activities of antibodies. The increasing knowledge on the Fc-mediated effector functions of antibodies drives the development of better therapeutic antibodies for cancer immunotherapy or treatment of autoimmune diseases.
    [Show full text]
  • Supplementary Table 1: Adhesion Genes Data Set
    Supplementary Table 1: Adhesion genes data set PROBE Entrez Gene ID Celera Gene ID Gene_Symbol Gene_Name 160832 1 hCG201364.3 A1BG alpha-1-B glycoprotein 223658 1 hCG201364.3 A1BG alpha-1-B glycoprotein 212988 102 hCG40040.3 ADAM10 ADAM metallopeptidase domain 10 133411 4185 hCG28232.2 ADAM11 ADAM metallopeptidase domain 11 110695 8038 hCG40937.4 ADAM12 ADAM metallopeptidase domain 12 (meltrin alpha) 195222 8038 hCG40937.4 ADAM12 ADAM metallopeptidase domain 12 (meltrin alpha) 165344 8751 hCG20021.3 ADAM15 ADAM metallopeptidase domain 15 (metargidin) 189065 6868 null ADAM17 ADAM metallopeptidase domain 17 (tumor necrosis factor, alpha, converting enzyme) 108119 8728 hCG15398.4 ADAM19 ADAM metallopeptidase domain 19 (meltrin beta) 117763 8748 hCG20675.3 ADAM20 ADAM metallopeptidase domain 20 126448 8747 hCG1785634.2 ADAM21 ADAM metallopeptidase domain 21 208981 8747 hCG1785634.2|hCG2042897 ADAM21 ADAM metallopeptidase domain 21 180903 53616 hCG17212.4 ADAM22 ADAM metallopeptidase domain 22 177272 8745 hCG1811623.1 ADAM23 ADAM metallopeptidase domain 23 102384 10863 hCG1818505.1 ADAM28 ADAM metallopeptidase domain 28 119968 11086 hCG1786734.2 ADAM29 ADAM metallopeptidase domain 29 205542 11085 hCG1997196.1 ADAM30 ADAM metallopeptidase domain 30 148417 80332 hCG39255.4 ADAM33 ADAM metallopeptidase domain 33 140492 8756 hCG1789002.2 ADAM7 ADAM metallopeptidase domain 7 122603 101 hCG1816947.1 ADAM8 ADAM metallopeptidase domain 8 183965 8754 hCG1996391 ADAM9 ADAM metallopeptidase domain 9 (meltrin gamma) 129974 27299 hCG15447.3 ADAMDEC1 ADAM-like,
    [Show full text]
  • GP130 Cytokines in Breast Cancer and Bone
    cancers Review GP130 Cytokines in Breast Cancer and Bone Tolu Omokehinde 1,2 and Rachelle W. Johnson 1,2,3,* 1 Program in Cancer Biology, Vanderbilt University, Nashville, TN 37232, USA; [email protected] 2 Vanderbilt Center for Bone Biology, Department of Medicine, Division of Clinical Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA 3 Department of Medicine, Division of Clinical Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA * Correspondence: [email protected]; Tel.: +1-615-875-8965 Received: 14 December 2019; Accepted: 29 January 2020; Published: 31 January 2020 Abstract: Breast cancer cells have a high predilection for skeletal homing, where they may either induce osteolytic bone destruction or enter a latency period in which they remain quiescent. Breast cancer cells produce and encounter autocrine and paracrine cytokine signals in the bone microenvironment, which can influence their behavior in multiple ways. For example, these signals can promote the survival and dormancy of bone-disseminated cancer cells or stimulate proliferation. The interleukin-6 (IL-6) cytokine family, defined by its use of the glycoprotein 130 (gp130) co-receptor, includes interleukin-11 (IL-11), leukemia inhibitory factor (LIF), oncostatin M (OSM), ciliary neurotrophic factor (CNTF), and cardiotrophin-1 (CT-1), among others. These cytokines are known to have overlapping pleiotropic functions in different cell types and are important for cross-talk between bone-resident cells. IL-6 cytokines have also been implicated in the progression and metastasis of breast, prostate, lung, and cervical cancer, highlighting the importance of these cytokines in the tumor–bone microenvironment. This review will describe the role of these cytokines in skeletal remodeling and cancer progression both within and outside of the bone microenvironment.
    [Show full text]
  • Mouse Model Recapitulating Human Fcγ Receptor Structural and Functional Diversity
    Mouse model recapitulating human Fcγ receptor structural and functional diversity Patrick Smith1, David J. DiLillo1, Stylianos Bournazos, Fubin Li, and Jeffrey V. Ravetch2 Laboratory of Molecular Genetics and Immunology, The Rockefeller University, New York, NY 10021 Contributed by Jeffrey V. Ravetch, March 7, 2012 (sent for review March 2, 2012) The in vivo biological activities of IgG antibodies result from their a particular species, such that the absolute affinities of IgG sub- bifunctional nature, in which antigen recognition by the Fab is classes for their cognate FcγRs cannot be extrapolated between coupled to the effector and immunomodulatory diversity found in species, even for recently diverged human and primate species (1, the Fc domain. This diversity, resulting from both amino acid and 12). This situation is further complicated by the existence of poly- γ γ glycan heterogeneity, is translated into cellular responses through morphisms in the human population for Fc RIIA and Fc RIIIA γ γ that result in different affinities for huIgGs (13–16), as well as Fc receptors (Fc Rs), a structurally and functionally diverse family γ of cell surface receptors found throughout the immune system. polymorphisms in Fc RIIB regulating its level of expression or Although many of the overall features of this system are main- signaling (17). Attempts to model huIgG interactions with human FcγR-expressing cells in vitro fail to mirror the diversity of cellular tained throughout mammalian evolution, species diversity has pre- populations that may be required for an in vivo response. There- cluded direct analysis of human antibodies in animal species, and, fore, new systems to study the in vivo function of the huFcγRsystem thus, detailed investigations into the unique features of the human γ and the biological effects of engaging the activating and inhibitory IgG antibodies and their Fc Rs have been limited.
    [Show full text]
  • Cx3cr1 Mediates the Development of Monocyte-Derived Dendritic Cells During Hepatic Inflammation
    CX3CR1 MEDIATES THE DEVELOPMENT OF MONOCYTE-DERIVED DENDRITIC CELLS DURING HEPATIC INFLAMMATION. Supplementary material Supplementary Figure 1: Liver CD45+ myeloid cells were pre-gated for Ly6G negative cells for excluding granulocytes and HDCs subsequently analyzed among the cells that were CD11c+ and had high expression of MHCII. Supplementary Table 1 low/- high + Changes in gene expression between CX3CR1 and CX3CR1 CD11b myeloid hepatic dendritic cells (HDCs) from CCl4-treated mice high Genes up-regulated in CX3CR1 HDCs Gene Fold changes P value Full name App 4,01702 5,89E-05 amyloid beta (A4) precursor protein C1qa 9,75881 1,69E-22 complement component 1, q subcomponent, alpha polypeptide C1qb 9,19882 3,62E-20 complement component 1, q subcomponent, beta polypeptide Ccl12 2,51899 0,011769 chemokine (C-C motif) ligand 12 Ccl2 6,53486 6,37E-11 chemokine (C-C motif) ligand 2 Ccl3 4,99649 5,84E-07 chemokine (C-C motif) ligand 3 Ccl4 4,42552 9,62E-06 chemokine (C-C motif) ligand 4 Ccl6 3,9311 8,46E-05 chemokine (C-C motif) ligand 6 Ccl7 2,60184 0,009272 chemokine (C-C motif) ligand 7 Ccl9 4,17294 3,01E-05 chemokine (C-C motif) ligand 9 Ccr2 3,35195 0,000802 chemokine (C-C motif) receptor 2 Ccr5 3,23358 0,001222 chemokine (C-C motif) receptor 5 Cd14 6,13325 8,61E-10 CD14 antigen Cd36 2,94367 0,003243 CD36 antigen Cd44 4,89958 9,60E-07 CD44 antigen Cd81 6,49623 8,24E-11 CD81 antigen Cd9 3,06253 0,002195 CD9 antigen Cdkn1a 4,65279 3,27E-06 cyclin-dependent kinase inhibitor 1A (P21) Cebpb 6,6083 3,89E-11 CCAAT/enhancer binding protein (C/EBP),
    [Show full text]
  • Immune Complexes Stimulate CCR7-Dependent Dendritic Cell Migration to Lymph Nodes
    LETTERS Immune complexes stimulate CCR7-dependent dendritic cell migration to lymph nodes Menna R Clatworthy1,2, Caren E Petrie Aronin2, Rebeccah J Mathews1, Nicole Y Morgan3, Kenneth G C Smith4 & Ronald N Germain2 Antibodies are critical for defense against a variety of microbes, or activating FcγR cross-linking9,10. FcγRIIB provides a basal level of but they may also be pathogenic in some autoimmune inhibition to DC maturation in the presence of ICs, thereby regulat- diseases. Many effector functions of antibodies are mediated ing immunogenic antigen presentation to T cells and providing an by Fcg receptors (FcgRs), which are found on most immune important tolerance checkpoint11–15. A number of stimuli preferen- cells, including dendritic cells (DCs)—important antigen- tially reduce FcγRIIB expression on monocytes, notably interferon-γ presenting cells that play a central role in inducing antigen- (IFN-γ)16, allowing these cells to be activated and matured by sub- specific tolerance or immunity1,2. Following antigen acquisition sequent encounters with ICs. Deficiency or dysfunction of FcγRIIB in peripheral tissues, DCs migrate to draining lymph nodes confers susceptibility to the IC-mediated autoimmune disease SLE in via the lymphatics to present antigen to T cells. Here we both mice and humans17–22. demonstrate that FcgR engagement by IgG immune complexes To permit interactions with T cells, tissue-resident DCs not only (ICs) stimulates DC migration from peripheral tissues to the need to be mature but also must relocate from peripheral tissues to paracortex of draining lymph nodes. In vitro, IC-stimulated lymph nodes23–26. Studies to date on the role of FcγRs in DCs have mouse and human DCs showed greater directional migration in focused on the effects of antibody and FcγR cross-linking on DC a chemokine (C-C) ligand 19 (CCL19) gradient and increased maturation, but none has addressed the question of how antibody chemokine (C-C) receptor 7 (CCR7) expression.
    [Show full text]
  • CD47 Blockade Augmentation of Trastuzumab Antitumor Efficacy Dependent on Antibody- Dependent Cellular Phagocytosis
    CD47 blockade augmentation of trastuzumab antitumor efficacy dependent on antibody- dependent cellular phagocytosis Li-Chung Tsao, … , Herbert Kim Lyerly, Zachary C. Hartman JCI Insight. 2019;4(24):e131882. https://doi.org/10.1172/jci.insight.131882. Research Article Immunology Oncology The HER2-specific monoclonal antibody (mAb), trastuzumab, has been the mainstay of therapy for HER2+ breast cancer (BC) for approximately 20 years. However, its therapeutic mechanism of action (MOA) remains unclear, with antitumor responses to trastuzumab remaining heterogeneous and metastatic HER2+ BC remaining incurable. Consequently, understanding its MOA could enable rational strategies to enhance its efficacy. Using both murine and human versions of trastuzumab, we found its antitumor activity dependent on Fcg receptor stimulation of tumor-associated macrophages (TAMs) and antibody-dependent cellular phagocytosis (ADCP), but not cellular cytotoxicity (ADCC). Trastuzumab also stimulated TAM activation and expansion, but did not require adaptive immunity, natural killer cells, and/or neutrophils. Moreover, inhibition of the innate immune ADCP checkpoint, CD47, significantly enhanced trastuzumab-mediated ADCP and TAM expansion and activation, resulting in the emergence of a unique hyperphagocytic macrophage population, improved antitumor responses, and prolonged survival. In addition, we found that tumor- associated CD47 expression was inversely associated with survival in HER2+ BC patients and that human HER2+ BC xenografts treated with trastuzumab plus CD47 inhibition underwent complete tumor regression. Collectively, our study identifies trastuzumab- mediated ADCP as an important antitumor MOA that may be clinically enabled by CD47 blockade to augment therapeutic efficacy. Find the latest version: https://jci.me/131882/pdf RESEARCH ARTICLE CD47 blockade augmentation of trastuzumab antitumor efficacy dependent on antibody-dependent cellular phagocytosis Li-Chung Tsao,1 Erika J.
    [Show full text]
  • Fcγ Receptors As Regulators of Immune Responses
    REVIEWS Fcγ receptors as regulators of immune responses Falk Nimmerjahn* and Jeffrey V. Ravetch‡ Abstract | In addition to their role in binding antigen, antibodies can regulate immune responses through interacting with Fc receptors (FcRs). In recent years, significant progress has been made in understanding the mechanisms that regulate the activity of IgG antibodies in vivo. In this Review, we discuss recent studies addressing the multifaceted roles of FcRs for IgG (FcγRs) in the immune system and how this knowledge could be translated into novel therapeutic strategies to treat human autoimmune, infectious or malignant diseases. Regulatory T cells A productive immune response results from the effec- of antigenic peptides that are presented on the surface A T cell subset that is capable tive integration of positive and negative signals that of DCs to cytotoxic T cells, T helper cells, and regulatory of suppressing the activity have an impact on both innate and adaptive immune T cells. Thus, FcγRs are involved in regulating a multitude of other antigen-specific T cells cells. When positive signals dominate, cell activation of innate and adaptive immune responses, which makes including autoreactive T cells. Depletion of regulatory and pro-inflammatory responses ensue, resulting in the them attractive targets for the development of novel T cells results in the loss of elimination of pathogenic microorganisms and viruses. immunotherapeutic approaches (FIG. 1). peripheral tolerance and the In the absence of such productive stimulation, cell activa- In this Review, we summarize our current under- development of autoimmune tion is blocked and active anti-inflammatory responses standing of the role of different members of the FcγR disease.
    [Show full text]
  • Human CD Marker Chart Reviewed by HLDA1 Bdbiosciences.Com/Cdmarkers
    BD Biosciences Human CD Marker Chart Reviewed by HLDA1 bdbiosciences.com/cdmarkers 23-12399-01 CD Alternative Name Ligands & Associated Molecules T Cell B Cell Dendritic Cell NK Cell Stem Cell/Precursor Macrophage/Monocyte Granulocyte Platelet Erythrocyte Endothelial Cell Epithelial Cell CD Alternative Name Ligands & Associated Molecules T Cell B Cell Dendritic Cell NK Cell Stem Cell/Precursor Macrophage/Monocyte Granulocyte Platelet Erythrocyte Endothelial Cell Epithelial Cell CD Alternative Name Ligands & Associated Molecules T Cell B Cell Dendritic Cell NK Cell Stem Cell/Precursor Macrophage/Monocyte Granulocyte Platelet Erythrocyte Endothelial Cell Epithelial Cell CD1a R4, T6, Leu6, HTA1 b-2-Microglobulin, CD74 + + + – + – – – CD93 C1QR1,C1qRP, MXRA4, C1qR(P), Dj737e23.1, GR11 – – – – – + + – – + – CD220 Insulin receptor (INSR), IR Insulin, IGF-2 + + + + + + + + + Insulin-like growth factor 1 receptor (IGF1R), IGF-1R, type I IGF receptor (IGF-IR), CD1b R1, T6m Leu6 b-2-Microglobulin + + + – + – – – CD94 KLRD1, Kp43 HLA class I, NKG2-A, p39 + – + – – – – – – CD221 Insulin-like growth factor 1 (IGF-I), IGF-II, Insulin JTK13 + + + + + + + + + CD1c M241, R7, T6, Leu6, BDCA1 b-2-Microglobulin + + + – + – – – CD178, FASLG, APO-1, FAS, TNFRSF6, CD95L, APT1LG1, APT1, FAS1, FASTM, CD95 CD178 (Fas ligand) + + + + + – – IGF-II, TGF-b latency-associated peptide (LAP), Proliferin, Prorenin, Plasminogen, ALPS1A, TNFSF6, FASL Cation-independent mannose-6-phosphate receptor (M6P-R, CIM6PR, CIMPR, CI- CD1d R3G1, R3 b-2-Microglobulin, MHC II CD222 Leukemia
    [Show full text]
  • CD47 on Lentiviral Vectors Decreases Macrophage-Mediated Clearance and Increases Delivery to SIRPA-Expressing Lung Carcinoma Tumors DOI: 10.1038/Mtm.2016.80
    The University of Manchester Research "Marker of Self" CD47 on lentiviral vectors decreases macrophage-mediated clearance and increases delivery to SIRPA-expressing lung carcinoma tumors DOI: 10.1038/mtm.2016.80 Document Version Final published version Link to publication record in Manchester Research Explorer Citation for published version (APA): Sosale, N. G., Ivanovska, I., Tsai, R. K., Swift, J., Hsu, J. W., Alvey, C. M., Zoltick, P. W., & Discher, D. E. (2016). "Marker of Self" CD47 on lentiviral vectors decreases macrophage-mediated clearance and increases delivery to SIRPA-expressing lung carcinoma tumors. Molecular Therapy - Methods & Clinical Development. https://doi.org/10.1038/mtm.2016.80 Published in: Molecular Therapy - Methods & Clinical Development Citing this paper Please note that where the full-text provided on Manchester Research Explorer is the Author Accepted Manuscript or Proof version this may differ from the final Published version. If citing, it is advised that you check and use the publisher's definitive version. General rights Copyright and moral rights for the publications made accessible in the Research Explorer are retained by the authors and/or other copyright owners and it is a condition of accessing publications that users recognise and abide by the legal requirements associated with these rights. Takedown policy If you believe that this document breaches copyright please refer to the University of Manchester’s Takedown Procedures [http://man.ac.uk/04Y6Bo] or contact [email protected] providing relevant details, so we can investigate your claim. Download date:24. Sep. 2021 Article Citation: Molecular Therapy — Methods & Clinical Development (2016) 3, 16080; doi:10.1038/mtm.2016.80 Official journal of the American Society of Gene & Cell Therapy www.nature.com/mtm hCD47-Lenti delays clearance NG Sosale et al.
    [Show full text]
  • IL-4 Controls Activated Neutrophil Fcγr2b Expression and Migration Into Inflamed Joints
    IL-4 controls activated neutrophil FcγR2b expression and migration into inflamed joints Sudeepta Kumar Pandaa,b, Gustaf Wigerblada,c, Long Jianga, Yanek Jiménez-Andradea,d, Vaishnavi Srinivasan Iyera,e, Yunbing Shena, Sanjaykumar V. Boddula, André Ortlieb Guerreiro-Cacaisf, Bruno Raposoa, Zsolt Kaszaa, and Fredrik Wermelinga,1 aCenter for Molecular Medicine, Division of Rheumatology, Department of Medicine, Solna, Karolinska University Hospital, Karolinska Institutet, 17176 Stockholm, Sweden; bStructural Genomics Consortium, Department of Medicine, Karolinska University Hospital, Karolinska Institutet, 17176 Stockholm, Sweden; cSystemic Autoimmunity Branch, Intramural Research Program, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD 20892; dCutaneous Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129; eSchool of Physical and Mathematical Sciences, Nanyang Technological University, Singapore 639798; and fCenter for Molecular Medicine, Department of Clinical Neuroscience, Karolinska Institutet, 17176 Stockholm, Sweden Edited by Tak W. Mak, University Health Network, Toronto, ON, Canada, and approved December 31, 2019 (received for review August 19, 2019) Neutrophils are the most abundant immune cells found in actively histones and vimentin (15, 16). In these patients, the release of inflamed joints of patients with rheumatoid arthritis (RA), and such modified proteins locally in the joints is thought to result most animal models for RA depend on neutrophils for the in the formation of antibody–antigen immune complexes (ICs), induction of joint inflammation. Exogenous IL-4 and IL-13 protect further propagating inflammation by interaction with activating mice from antibody-mediated joint inflammation, although the Fcγ receptors (FcγRs) and by activating the complement system mechanism is not understood.
    [Show full text]
  • CD40 Enhances Type I Interferon Responses Downstream of CD47 Blockade, Bridging Innate and Adaptive Immunity a C Suresh De Silva, George Fromm, Casey W
    Published OnlineFirst December 18, 2019; DOI: 10.1158/2326-6066.CIR-19-0493 CANCER IMMUNOLOGY RESEARCH | RESEARCH ARTICLE CD40 Enhances Type I Interferon Responses Downstream of CD47 Blockade, Bridging Innate and Adaptive Immunity A C Suresh de Silva, George Fromm, Casey W. Shuptrine, Kellsey Johannes, Arpita Patel, Kyung Jin Yoo, Kaiwen Huang, and Taylor H. Schreiber ABSTRACT ◥ Disrupting the binding of CD47 to SIRPa has emerged as a No evidence of hemolysis, hemagglutination, or thrombocytopenia promising immunotherapeutic strategy for advanced cancers by was observed in vitro or in cynomolgus macaques. Murine SIRPa- potentiating antibody-dependent cellular phagocytosis (ADCP) of Fc-CD40L outperformed CD47 blocking and CD40 agonist anti- targeted antibodies. Preclinically, CD47/SIRPa blockade induces bodies in murine CT26 tumor models and synergized with immune antitumor activity by increasing the phagocytosis of tumor cells by checkpoint blockade of PD-1 and CTLA4. SIRPa-Fc-CD40L acti- macrophages and enhancing the cross-presentation of tumor anti- vated a type I interferon response in macrophages and potentiated þ gens to CD8 T cells by dendritic cells; both of these processes are the activity of ADCP-competent targeted antibodies both in vitro and potentiated by CD40 signaling. Here we generated a novel, two-sided in vivo. These data illustrated that whereas CD47/SIRPa inhibition fusion protein incorporating the extracellular domains of SIRPa and could potentiate tumor cell phagocytosis, CD40-mediated activation CD40L, adjoined by a central Fc domain, termed SIRPa-Fc-CD40L. of a type I interferon response provided a bridge between macro- SIRPa-Fc-CD40L bound CD47 and CD40 with high affinity and phage- and T-cell–mediated immunity that significantly enhanced activated CD40 signaling in the absence of Fc receptor cross-linking.
    [Show full text]