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Ganglioside GD2 Specific Antibodies in the Diagnosis and Therapy of Human Neuroblastoma
Published in John T. Kemshead, Pediatric Tumors: Immunological and Molecular Markers, 2020
Nai-Kong V. Cheung, Floro D. Miraldi
Both the IgM and the IgG3 MAb to GD2 activate human complement efficiently in tumor cytotoxicity.20,25 Using the Hoechst stain method20 to monitor the rare tumor cells, as many 10% tumor cells in the bone marrow can be eliminated without damaging normal marrow stem cells. Normal human cells are resistant to complement lysis because of the presence of decay-accelerating factor (DAF) on their cell surface.16 However, neuroblastomas and many melanomas have low to absent expression of this protein and, therefore, are very sensitive to human complement. This sensitivity of human neuroblastoma cells to complement has important therapeutic implications. With the activation of human complement, anaphylatoxic and chemotactic properties of activated complement fragments can play an important role in the formation of local inflammatory response as well as the influx of important effector cells to tumor sites. Complement receptors for C3b and C3bi are present on granulocytes and natural killer cells. Since C3b and C3bi are deposited on tumor cells after MAb activation of human complement, they may enhance such cell mediated tumor cytotoxicity.
Host Defense I: Non-specific Immunity
Published in Constantin A. Bona, Francisco A. Bonilla, Textbook of Immunology, 2019
Constantin A. Bona, Francisco A. Bonilla
Several membrane components act to protect cells from complement lysis. Decay accelerating factor (DAF) is anchored in the cell membranes of erythrocytes, leukocytes, platelets, and endothelial cells. This protein interacts with complement complexes deposited on the cell’s surface and, as its name suggests, hastens their dissociation. Membrane cofactor protein (MCP) is found on leukocytes and platelets. It binds to C3b and iC3b and appears to enhance the activity of factor I. Homologous restriction factor (HRF) has a distribution similar to that of DAF. This protein binds to C8 and C9 and inhibits formation of an effective lytic unit. CD59 (also known as membrane attack complex inhibition factor, or membrane inhibitor of reactive lysis) has activity similar to HRF.
The complement system in health and disease
Published in Gabriel Virella, Medical Immunology, 2019
Decay-accelerating factor (DAF, CD55) is a complement-inhibitory protein widely expressed on host cell membranes. The name of this factor derives from the fact that it can accelerate the dissociation of active C4b2a complexes, turning off their ability to continue activating C3. In addition, DAF attaches to membrane-bound C4b and C3b and prevents the subsequent interaction of C4b with C2 and of C3b with factor B, respectively. As a consequence, the two types of C3 convertases, C4b2a and C3bBb, will not be formed or will become dissociated, and the rate of additional C3 activation is significantly limited. Thus, the host cell will be spared from complement-mediated membrane damage.
The case for complement component 5 as a target in neurodegenerative disease
Published in Expert Opinion on Therapeutic Targets, 2023
Amelia Stennett, Kallie Friston, Claire L. Harris, Adam J. M. Wollman, Agnieszka K. Bronowska, Katrina S. Madden
As the convertase enzymes are proinflammatory and easily amplified, it is essential that the components are tightly controlled and inactivated when they deposit on self surfaces. When this happens there is the potential for ‘bystander lysis’ of normal self-cells, hence these express an array of complement regulatory proteins including CD35 (complement receptor 1, CR1), CD46 (MCP, membrane cofactor protein), CD55 (DAF, decay accelerating factor) and CD59 that prevent complement activation (CD35, CD46), amplification (CD35, CD55) and MAC formation (CD59). There are also proteins in the fluid phase that recognize structures on self-cells and bind to deposited C3b (factor H, FH) or C4b (C4b binding protein, C4BP), causing rapid inactivation by acting as cofactors for factor I (FI), a proteolytic enzyme that cleaves and inactivates C3b (by forming iC3b) and C4b (forming C4c and C4d). Many of these protective proteins also possess an activity termed decay accelerating activity (FH, CD55, CD35, C4BP), whereby binding to a multimolecular convertases causes rapid dissociation of the enzymatic subunit, C2a or Bb. The lack of these protective proteins on pathogen surfaces facilitates amplification of complement and opsonization or lysis of foreign cells.
The role of the alternative pathway in paroxysmal nocturnal hemoglobinuria and emerging treatments
Published in Expert Review of Clinical Pharmacology, 2022
Jong Wook Lee, Robert A. Brodsky, Jun-Ichi Nishimura, Austin G. Kulasekararaj
Under normal physiologic conditions, complement activity is tightly controlled by complement regulators that protect the host against complement-mediated injury [3,21,22]. Membrane-bound complement regulators include, among others, CD55 (decay accelerating factor) and CD59 (membrane inhibitor of reactive lysis). CD55 inhibits the formation and stability of C3 and C5 convertases and thus limits the ability of C3 convertases to promote further complement activation, whereas CD59 prevents assembly of the MAC (C5b-9). The Inab phenotype, which indicates a genetic defect in CD55 on the erythrocyte membrane, shows no hemolytic findings [26]. On the other hand, the genetic deficiency of CD59 has the same hemolytic findings and symptoms as PNH [27]. These results suggest that the deficiency of CD59 is particularly important for the hemolytic mechanism of PNH. PNH cells can be further subdivided into type 2 (mutation causing a partial GPI defect) and type 3 (mutation causing a complete GPI defect) GPI-deficient clones [28]. Type 3 cells have been associated with higher LDH levels and greater hemolytic activity [28].
The Complement System in Retinal Detachment with Choroidal Detachment
Published in Current Eye Research, 2022
Shasha Luo, Yanghao Chen, Lufei Yang, Xuechun Gong, Zhifeng Wu
Complement regulatory protein DAF is a glycosylated membrane protein.15 To the best of our knowledge, this may be the first quantitative measurement of sDAF in the vitreous fluid of eyes with either RRDCD or RRD. An elegant study has shown that sDAF in urine has C4bp (or factor H) activity, indicating that it can inhibit the liquid phase activation of the complement cascade, which is equivalent to the role of serum C4–binding protein.16 Complement factor I (C3bINH) is an esterase that is a C3b inhibitory factor that can cleave and inactivate C3b to become the ineffective iC3B. It can also cleave C4b into C4d and C4c, thereby inhibiting the activation of the complement system.17 In the RRDCD group, the levels of sDAF and CFI in the vitreous humor were significantly increased, further indicating that eyes with RRDCD may still have normal complement regulation mechanisms, but that some persistent inflammatory mechanisms cause the continuous activation of the complement pathway and the level of complement inhibitory factors increase accordingly. Interestingly, the CFD and C2 were higher in the RRD group than in the control group, and the downstream components were not activated. This phenomenon may occur due to the increased levels of CFI.