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The Human Immune System Seen from a Biomedical Engineering Viewpoint
Published in Robert B. Northrop, Endogenous and Exogenous Regulation and Control of Physiological Systems, 2020
Mast cells are stimulated to release their granules by the binding of their high-affinity Fc receptors (FcRs) to the Fc region of IgE antibodies that, in turn, have high Fab affinities to allergen molecules such as pollens or danders. There can be as many as 5 × 105 FcRs per mast cell.59 The actual trigger that initiates the release of mast cell products is the cross-linking of the bound IgE-Ag complexes attached to the mast cell’s Fc receptors. Such cross-linking can occur if there are high enough concentrations of antigen and free IgE Abs and the Ag has multiple binding sites on it for the Abs. That mast cells secrete IL4, IL5, IL6, and TNFa means that other immune system cells such as eosinophils and T-cells are recruited into the inflammatory scenario, which is biochemically complex.
Characterization of Biosimilar Biologics
Published in Laszlo Endrenyi, Paul Jules Declerck, Shein-Chung Chow, Biosimilar Drug Product Development, 2017
The impact of the expression/production platform on product characteristics has been emphasized in the foregoing; however, it should equally be emphasized that when reporting functional activities, the parameters of the assay system employed determine the results obtained. A clear example is the determination/reporting of complement mediated lysis and binding. Early studies employed hamster or rabbit serum as source, each being more stable than human complement. However, there are significant structural and functional nuances between these species’ proteins. Another parameter is the epitope density expressed by the target cell (Rojko et al., 2014; Voice and Lachmann, 1997; Zhang et al., 1995). An important parameter in contemporary effector function studies is the source and/or expression of Fcγ receptors. Binding studies conducted, in vitro, have employed the soluble external domain of FcγR (sFcγR) produced in a variety of cell types, mostly sourced from commercial companies. The external domain of sFcγRIIIa bears five N-linked glycosylation sites, all occupied, one of which makes direct contacts with the IgG-Fc and determines binding affinity; therefore, the glycoform of the receptor is of equal importance. The impact of glycoform on binding to the other sFγR has not been reported. Similarly, when conducting ADCC studies, the FcγR expression level on the effector cell and the epitope density on the target cell and the sensitivity of the readout impact the apparent outcome. In the context of this chapter, it is relevant to include the following section emphasizing FcγR heterogeneities.
Bioartificial organs
Published in Ronald L. Fournier, Basic Transport Phenomena in Biomedical Engineering, 2017
The Fc receptor on an IgG molecule bound by the Fab fragments to a cellular antigen also binds to specific receptors on so-called natural killer lymphocytes (NK cells). The NK cells will then be attracted to and destroy the invading cell by the release of toxic substances called perforins (Ojcius et al., 1998). Perforins form channels in the cell membrane of the target cell, making them leak and resulting in the death of the cell. This process is called antibody-dependent cell-mediated cytotoxicity, or ADCC.
Traffic-related particulate matter aggravates ocular allergic inflammation by mediating dendritic cell maturation
Published in Journal of Toxicology and Environmental Health, Part A, 2021
Moonwon Hwang, Sehyun Han, Jeong-Won Seo, Ki-Joon Jeon, Hyun Soo Lee
Single cells from draining LNs were prepared by tissue homogenization followed by filtration through a 70 μm cell strainer and trypan blue exclusion test was used to determine cell viability. Cells were incubated with Fc-receptor blocking antibody in 0.5% BSA at 4°C for 30 min prior to immunostaining with PE-Cy7-conjugated anti-CD11c and APC-Cy7-conjugated anti-I-Ad antibodies. The isotype control was stained with the properly matched antibodies (eBioscience). Stained cells were analyzed with a flow cytometer (BD LSRFortessa, BD Biosciences) and the FlowJo program (Tree Star, Ashland, OR).
Benzo[a]pyrene osteotoxicity and the regulatory roles of genetic and epigenetic factors: A review
Published in Critical Reviews in Environmental Science and Technology, 2022
Jiezhang Mo, Doris Wai-Ting Au, Jiahua Guo, Christoph Winkler, Richard Yuen-Chong Kong, Frauke Seemann
OCs, which are derived from hematopoietic stem cells (HSCs), are responsible for bone resorption. Stimulated by the macrophage colony-stimulating factor (M-CSF), HSCs first differentiate into mononuclear precursor cells (MPCs) (Boyle et al., 2003). Thereafter, M-CSF and RANKL induce MPCs to further differentiate into osteoclast progenitors (OCPs) which ultimately become functional multinuclear osteoclasts (MOCs) following fusion and polarization (Figure 6) (Crockett et al., 2011; Tang et al., 2014). OC differentiation initially depends on signaling via colony-stimulating factor 1 receptor (CSF1R) − the receptor for M-CSF − in MPCs to upregulate the expression of RANK. Its ligand, RANKL (RANK competes with a decoy receptor, OPG, for RANKL), is expressed in OBs and stromal cells in response to PTH and stimulation by the active dihydroxy form of vitamin D3 (1,25 Vit D3) (Crockett et al., 2011; Hrdlicka et al., 2019). Upon binding of RANK to RANKL, tumor necrosis factor receptor (TNFR)-associated factor 6 (TRAF6) forms a complex with transforming growth factor-β-activated kinase 1 (TAK1) and TGF-β activated kinase 1 binding protein 1 (TAB1). They subsequently recruit SMAD3 and facilitate the downstream ubiquitination and degradation of IκBα, the inhibitor of transcription factors nuclear factor κB (NF-κB). The free NF-κB then translocates from the cytosol to the nucleus and promotes the transcription of the nuclear factor of activated T-cells cytoplasmic 1 (NFATc1) (Hrdlicka et al., 2019; Lozano et al., 2019). Alternatively, together with the immunoreceptor tyrosine-based activation motif (ITAM)-containing adaptors, DNAX-activating protein of 12 kDa (DAP12) and Fc receptor γ chain (FcRγ), binding of RANKL to RANK activates NF-κB, activator protein 1 (AP-1, composed of C-FOS and C-JUN) and NFATc1 (Lozano et al., 2019). All of these transcription factors induce the expression of key OC genes, which include dendritic cell-specific transmembrane protein (DC-STAMP), tartrate-resistant acid phosphatase (TRAcP), cathepsin K (CTSK), matrix metalloproteinases (MMPs), and β3 integrin in MOCs (Crockett et al., 2011; Hrdlicka et al., 2019).
Challenges and advancements in the pharmacokinetic enhancement of therapeutic proteins
Published in Preparative Biochemistry & Biotechnology, 2021
Farnaz Khodabakhsh, Morteza Salimian, Mohammad Hossein Hedayati, Reza Ahangari Cohan, Dariush Norouzian
The main mechanisms involved in the rapid clearance of proteins include proteolysis by proteases, glomerular filtration from the kidney, and receptor-mediated clearance in the liver.[4] Proteases play a key role in many physiological and pathological conditions such as blood coagulation, food digestion, complement activation, and chronic inflammation in the body. These proteases are able to digest the administered therapeutic proteins, and therefore, influence theirs in vivo half-life. Detrimental effects of proteases are not limited to the circulation, but they could exert deleterious effects at the site of injection. This is because many therapeutic proteins are administrated via subcutaneous (s.c.) injections in addition to intravenous (i.v.) route. Other instabilities like the formation of aggregates at the site of injection reduce the bioavailability of the administrated protein. Many studies have been performed to decrease the deleterious effect of such proteases on the protein structure.[5] One approach is amino acid changes in the recognition site of proteases in the protein sequence such that these changes do not have any influence on the structure or function of the desired protein. However, this approach does not apply to all proteins because the introduction of mutations usually does not give predictable results.[6] However, when the protein reaches circulation, glomerular filtration and receptor-mediated hepatocyte uptake play significant roles in reducing the plasma level of administrated protein. It is known that the glomerulus pores are about 60 angstroms in diameter (∼70 kDa) and also have a negative charge due to the presence of anionic proteoglycans in the extracellular matrix of the base membrane. Since many therapeutic proteins, except monoclonal antibodies, have a small size, often less than 6 nanometers, they can easily pass from the glomerular capsule and subsequently released to the urine.[7] In contrast, larger proteins with a negative charge on the surface, like human serum albumin (HSA), are resistant to pass through kidney filtration. Besides the glomerular filtration, protein degradation also occurs in the liver. Hepatic clearance happens by the interaction between the sialoglycoprotein receptor existed on the hepatocyte cell membranes, which is followed by endocytosis and protein degradation.[8] In addition to the mentioned mechanisms, it has been demonstrated that an endosomal recycling process, called neonatal Fc receptor-mediated recycling, increases the plasma half-life of albumin and immunoglobulins in the circulation. In this mechanism, the protein strongly binds to neonatal Fc receptor (FcRn) at acidic conditions and is protected from the availability of lysosomes in the endosomal space. But when the pH increases to 7.4, the binding becomes weak and the bonded protein returns to the blood circulation.[9] In the next section, we will describe the strategies currently used for in vivo half-life extension of therapeutic proteins.