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Antibody-Based Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
The Complement-Dependent Cytotoxicity (CDC) pathway comprises of a number of proteins in the blood that can cause cell death after an antibody binds to the cell surface. Usually, this pathway is activated to destroy foreign cells such as bacteria but can also be activated by therapeutic antibodies binding to the surface of tumor cells. In this case the C1 complex binds to these antibodies and protein pores subsequently appear in the cell membrane, ultimately leading to cell death. This process can be triggered by chimeric, humanized, or human antibodies, and those containing an IgG1 Fc region. Once triggered, cell death occurs by several mechanisms, including activation of the membrane attack complex (i.e., Complement-Dependent Cytotoxicity), enhancement of ADCC, or CR3-dependent cellular cytotoxicity.
Urticaria and Angioedema
Published in Pudupakkam K Vedanthan, Harold S Nelson, Shripad N Agashe, PA Mahesh, Rohit Katial, Textbook of Allergy for the Clinician, 2021
Jenny M Stitt, Stephen C Dreskin
In HAE type I, C1 inhibitor level and function will be decreased while in HAE type II, the C1 inhibitor function will be low. In AAE, C1 inhibitor level will be decreased, as will C4. AAE is unique in demonstrating a decreased C1q level, a component of the complement factor C1 complex. C1 inhibitor autoantibody may also be present in AAE, although it is not needed to make the diagnosis. ACE-i associated angioedema should be considered in any patient who develops angioedema while taking an ACE-i, but the diagnosis is only made after the suspected agent is discontinued and lasting resolution of symptoms occurs. ACE-i angioedema typically resolves with discontinuation of the medication, although this may take several weeks, and in rare cases, several months. HAE with normal complements should be diagnosed only after all other possible etiologies have been ruled out and the patient has failed to improve with a trial of antihistamines.
Complement-Mediated Lipopolysaccharide Release
Published in Helmut Brade, Steven M. Opal, Stefanie N. Vogel, David C. Morrison, Endotoxin in Health and Disease, 2020
Several investigators noted that the human mannose-binding protein (MBP) and lung surfactant proteins are structurally similar to the C1q molecule (reviewed in Ref. 18). This led to the speculation that proteins other than C1q may participate in complement activation. Human MBP directly binds to the C1 complex serine proteases C1r and C1s and can mediate activation of the classical pathway of complement. However, when isolated from serum, MBP is usually associated with a 100 kDa serine protease. This dimeric complex was originally designated Ra-reactive factor because it was shown to specifically bind rough LPS of the Ra chemotype (19). The MBP-associated serine protease (MASP) (1) shares approximately 39% amino acid homology with human C1r and C1s, (2) contains a histidine loop structure, which is highly conserved among serine proteases, and (3) can cleave C4 and C2, or may directly bind to and hydrolyze C3, to produce functional classical and alternative pathway C3 convertases (18). Thus, the MBP-MASP complex may bind TV-acetylglucosamine-, 7V-acetylmannosamine-, and mannose-containing lipopolysaccharides synthesized by E. coliand Salmonella spp. and directly activate the classical and alternative pathways of complement in an antibody- and C1q-independent manner.
Differential expression and transcription factor binding associated with genotype at a pharmacogenetic variant in OPRD1
Published in The American Journal of Drug and Alcohol Abuse, 2021
Richard C. Crist, Gabriella Arauco-Shapiro, Alexander Zhang, Benjamin C. Reiner, Wade H. Berrettini, Glenn A. Doyle
The known transcriptional regulation by XRCC6 involves the XRCC6/XRCC5 heterodimer; however, we were not able to confirm the presence of XRCC5 in the C1 complex. While there is currently no evidence that XRCC6 regulates transcription as a monomer, the protein is known to have functions independent of XRCC5. Mice lacking Xrcc5 or Xrcc6 do not have identical phenotypic profiles: Xrcc5 knockout animals demonstrate accelerated aging, whereas Xrcc6 knockouts develop thymic lymphoma (28,29). XRCC6 is also known to have other binding partners, including Cyclin E and Bax (30,31). Binding of XRCC6 to the C allele of rs678849 may therefore require unidentified proteins besides XRCC5. Furthermore, although the XRCC6/XRCC5 antibody did not disrupt formation of C1 (Figure 3D), we cannot completely exclude the possibility that XRCC5 is contained in the complex. For example, additional proteins included in C1 may have blocked the epitope targeted by the antibody or the phosphatase treatment may have disrupted binding of this specific antibody. Additional proteomic analyses are still required to determine the remaining components of the C1 complex.
Sepsis target validation for repurposing and combining complement and immune checkpoint inhibition therapeutics
Published in Expert Opinion on Drug Discovery, 2021
Patrícia R.S. Rodrigues, Noemi Picco, B Paul Morgan, Peter Ghazal
C1q has a similar structure and function to collectins; it comprises a collagen-like stalk or six intertwining chains that end in six globular heads that are the antibody (and other ligand) recognition domains. There are numerous receptors for C1q on a variety of cell types, suggesting direct roles in opsonization and other processes, but for complement activation, C1q must bind its effector molecules C1r and C1s to form the C1 complex. The classical and lectin pathways respectively are activated when C1q and MBL/ficolins bind to an activating structure. C1q also has important roles in maintaining immune tolerance via labeling and facilitating clearance of apoptotic cells, in phagocytosis of bacteria, and in neutralization of viruses. Deficiency of C1q is associated with autoimmune disease and increased susceptibility to infections [21].
Revisiting the complement system in systemic lupus erythematosus
Published in Expert Review of Clinical Immunology, 2020
Madhubala Sharma, Pandiarajan Vignesh, Karalanglin Tiewsoh, Amit Rawat
Genes that code for C1 s and C1 r are present on the short-arm of chromosome-12 in the tail to tail orientation at 3ʹend. C1 s and C1 r are paralogous proteins comprising 38% identities and 55% similarities. Each contains two CUB domain and an EGF domain separating the two CUB domains, EGF domain has Ca2+ binding site tracked by two CCP1 (complement controlling protein1) and CCP2 (Figure 3B). This is followed by a linker section and a chymotrypsin-like serine protease area at C-terminal end. C1 s and C1 r in circulation are orderly arranged as tetramer, C1 s-C1 r-C1 r-C1 s [23]. A multi-molecular C1 complex is formed after C1q attaches to Fc region of IgG in presence of calcium. C1 s further triggers C4 and C2 to C4b2a called C3 convertase [24].