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Immunoglobulins: Metabolism and biological properties
Published in Gabriel Virella, Medical Immunology, 2019
Virtually every type of cell involved in the immune response has been found to be able to bind one or more immunoglobulin isotypes through Fc receptors (Table 6.2). These receptors have been classified according to the isotype of immunoglobulin that they preferentially bind as FcγR (receptors for IgG), FcαR (receptors for IgA), FcεR (receptors for IgE), and FcμR (receptors for IgM). The Fcγ receptors are the most diverse, since they exist in three major types: FcγRI (CD64), a high-affinity receptor, able to bind monomeric IgG, expressed exclusively by monocytes and macrophages.FcγRII (CD32), a low-affinity receptor for IgG expressed by phagocytic cells, platelets, and B lymphocytes. Two functionally distinct forms of FcγRII have been identified: FcγRIIa and FcγRIIb.FcγRIII (CD16), a second low-affinity IgG receptor expressed by phagocytic and NK cells.
Flow Cytometry
Published in Wojciech Gorczyca, Atlas of Differential Diagnosis in Neoplastic Hematopathology, 2014
Hematopoietic progenitors are positive for CD34, CD133, CD184, and HLA-DR. Neutrophilic maturation from blasts through promyelocytes, myelocytes, metamyelocytes, bands, and neutrophils is characterized by loss of CD34 and HLA-DR expression at promyelocytic stage, loss of CD117 expression at myelocytic stage, and acquisition of CD11b and CD11c expression at myelocytic stage and CD10 expression by neutrophils [88]. CD64 is expressed by promyelocytes through metamyelocytes. CD13 and CD33 are expressed at all stages of maturation, with CD13 being brightly expressed by blasts and neutrophils and dimly by metamyelocytes, and CD33 showing a slight decrease in the intensity of CD33 expression as the cells become more mature. Granulocytic precursors display dim expression of CD45. The intensity of expression increases in the final stages of differentiation (based on the SSC and CD45, neutrophils can be often separated from promyelocytes, myelocytes, metamyelocytes, and bands by having the strongest expression of CD45; Figure 3.60).
Clinical Studies In Oncology
Published in Siegfried Matzku, Rolf A. Stahel, Antibodies in Diagnosis and Therapy, 2019
Jan Schmielau, Wolff Schmiegel
Several aspects have to be considered regarding antibody-dependent tumor suppression. Most notable, antibodies mediate cytotoxic effects which are linked to the Fc-region and are depending on the Ig-class and subclass. Effector cells for IgG are infiltrating as well as circulating macrophages/monocytes, neutrophils and NK-cells. Their variable milieu-dependent behavior partially results in a different expression pattern of characterized Fc-receptors (Fanger et al., 1989). The heterogenic IgG-receptors (FcγR) are subdivided in three groups, which are all members of the Ig supergene family (Lin et al., 1994). All human FcγR bind human IgGl and IgG3, which are most effective in mediating antibody-dependent cell-mediated cytotoxicity (ADCC), with comparable affinity (Shaw et al., 1988). The FcγRI (CD64) is predominantly found on monocytes and macrophages and binds monomeric human IgGl and IgG3 and murine IgG2a and IgG3 with high avidity. As a common receptor on hematopoietic cells, including monocytes, neutrophils, platelets and B cells, FcγRII (CD32) have a low affinity to monovalent human IgGl and IgG3 and murine IgG2b, including subgroups binding human IgG2 and murine IgGl with similar affinity. They seem to especially bind immune complexes and interact in multiple receptor-ligand formations. For FcγRI and FcγRII IFN-γ acts as a competent enhancer of cytotoxicity, while introducing FcγRII-mediated cytotoxicity to neutrophils. The FcγRIII (CD 16) appears as a transmembrane and as a phosphatidylinositol glycan (PIG) membrane anchored receptor which is released upon specific phospholipase C action. Its transmembrane form is present on NK-cells and tissue macrophages but not monocytes, neutrophils and eosinophils and express a low affinity to monomeric human IgGl and IgG3 and murine IgG3 more than to IgG2a. Neutrophils express the PIG-anchored FcγRIII which ensures tight contact of neutrophils to IgG-covered antigen and thereby supports effects mediated through the FcγRII. NK-cells seem to exclusively express transmembrane FcγRIII which links its function especially to ADCC that is otherwise also established by FcγRI and FcγRII. Subsequent signal pathways are related to receptor aggregation and receptor-associated proteins, which initiate phosphorylation of protein tyrosine kinases (Daeron, 1997). Concerning ADCC with murine mAb, human effector cells were generally less effective than mouse effector cells where only a few mAb of murine IgG2a, IgG3 and IgGl isotype generated ADCC (Herlyn et al., 1985a).
LncRNA MEG8 sponging miR-181a-5p contributes to M1 macrophage polarization by regulating SHP2 expression in Henoch-Schonlein purpura rats
Published in Annals of Medicine, 2021
Mingyu Jiang, Jicheng Dai, Mingying Yin, Chunming Jiang, Mingyong Ren, Lin Tian
Macrophages are common innate immune cells that have crucial roles in many physiological and pathological processes, including tissue development, inflammatory responses, tissue remodelling, host defense and homeostasis [4]. The activated macrophages can be polarized into the classically activated type 1 (M1) or the alternatively activated type 2 (M2) depending on their differentiation state. M1-like polarized macrophages are usually triggered by granulocyte-macrophage colony stimulating factor, and exhibit high levels of proinflammatory and phagocytic activities. CD64+ and CD80+ are the most suitable biomarkers to characterize these macrophages, due to their ability to regulate acute inflammation. These surface markers are known to secrete proinflammatory cytokines, including IFN-γ, TNF-α, IL-1, -6 and -12 [5]. On the other hand, M2-like polarized macrophages are thought to be involved in fungal, helminthic and parasitic infections, and can be activated by Th2 cells. IL-4, -10, -13, macrophage colony-stimulating factor (M-CSF) and a combination of these factors can enhance the polarization of macrophages towards M2 phenotype. CD206+ and CD209+ are the best surface markers for the characterization of M2-like macrophages [6].
Cyclophosphamide alters the tumor cell secretome to potentiate the anti-myeloma activity of daratumumab through augmentation of macrophage-mediated antibody dependent cellular phagocytosis
Published in OncoImmunology, 2021
Serika D Naicker, Claire L Feerick, Kevin Lynch, Dawn Swan, Cian McEllistrim, Robert Henderson, Niamh A Leonard, Oliver Treacy, Alessandro Natoni, Athina Rigalou, Joana Cabral, Christopher Chiu, Kate Sasser, Thomas Ritter, Michael O’Dwyer, Aideen E Ryan
To functionally assess the impact of FcγRI/CD64, we repeated the experiment in the presence of an anti-CD64 blocking antibody. As seen in our previous experiments, low dose CTX-TCS (20 µM) significantly increased daratumumab-specific killing of MM1.S cells. This enhanced clearance of MM cells was abrogated in the presence of the FcγRI/CD64 blocking antibody (Figure 5(d)). Although not reaching statistical significance, a similar trend was recorded in daratumumab-specific killing of RPMI-8226 cells in the presence of an FCγRI CD64 blocking agent (Supplementary Figure 5). Together, these data indicate FcγRI/CD64 as a key player in daratumumab-specific ADCP of MM cells by CTX-TCS conditioned macrophages. We next investigated the effect of cyclophosphamide on macrophages from patients with active MM. FcγRI/CD64 was increased following conditioning macrophages from MM patients with 5 µM CTX-TCS ex vivo (Figure 5(e)). Previous data from our lab indicates that patients treated with CyBorD-DARA induces expression of FCγRI/CD64 on patient derived blood and bone marrow monocyte/macrophage cells. In addition to this, CyBorD was found to increase CD163, a marker of phagocytic activity, expression on macrophages isolated from both the bone marrow (Figure 5(f)) and PBMCs (Figure 5(g)). Although only a small sample set, this data would suggest that tumor-associated macrophages from MM patients are responsive to cyclophosphamide, showing increased FCγRI/CD64 surface expression and enhanced phagocytic activity, thereby supporting a potential synergistic increase in daratumumab-specific phagocytosis.
Drug delivery targets and systems for targeted treatment of rheumatoid arthritis
Published in Journal of Drug Targeting, 2018
The auto antibodies (Abs) of the IgG isotype have been found to be involved in the iniation and progression of RA. They exerted their functions mainly by binding to the Fc gamma receptors (FcγRs) that are expressed on a variety of immune cells and act as a kind of link between humoral and cellular responses [68]. These receptors have their naturally occurring polymorphisms, and for human beings, there are three different classes of FcγR: FcγRI (CD64), FcγRII (CD32A, CD32B, CD32C) and FcγRIII (CD16A, CD16B). It has been accepted that the FcγRI and FcγRIII contribute to the severity of RA via triggering cell activation through a common γ chain, whereas FcγRII suppresses RA via down-regulating the antibody production and immune complex-triggered activation [69,70]. These receptors vary in their antibody affinities due to the different molecular structures and the CD64 is the only high affinity FcγR in humans, which might be a potent target for treatment of RA [71].