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Specific Host Restance: The Effector Mechanisms
Published in Julius P. Kreier, Infection, Resistance, and Immunity, 2022
Other regulatory mechanisms include serum or cell-surface proteins of the host. The enzymatic step mediated by C1 is inhibited by a normal serum protein, C1-inhibitor, that binds and causes it to dissociate from , thereby limiting the activation of C2 and C4 and the formation of C3 covertase. C3 convertase can also be inactivated by a serum protein called C4 binding protein or a cell-surface protein called decay-accelerating factor (DAF). The key step in both the classical and alternative pathways is the deposition of on cells. Factor 1 in normal serum is a -inactivator that degrades and unless they are bound to a cell surface. Another normal serum protein, Factor H, enhances the inhibitory action of Factor 1. Protectin is a protein on host cell surfaces that prevents the formation of membrane attack complexes.
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 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.
Safety of current treatments for paroxysmal nocturnal hemoglobinuria
Published in Expert Opinion on Drug Safety, 2021
Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, progressive, and life-threatening hematopoietic stem cell disorder whose clinical manifestations include intravascular hemolysis, thrombosis, and bone marrow failure [1]. The disease arises as a consequence of a somatic mutation in the phosphatidylinositol glycan class A (PIG-A) gene that prevents synthesis of N-acetyl-D-glucosamine phosphatidylinositol, an essential component of glycosylphosphatidylinositol anchor protein (GPI-AP) [2]. Deficiency of GPI-anchored complement-inhibitor proteins, especially CD55 (decay-accelerating factor) and CD59 (membrane inhibitor of reactive lysis), causes chronic intravascular hemolysis, a hallmark clinical manifestation of PNH that is mediated by the alternative pathway of complement (APC). The APC cascade can be divided into amplification of the C3 and C5 convertases and the cytolytic membrane attack complex (MAC). CD55 regulates the formation and stability of the C3 and C5 convertases, and CD59 blocks the formation of the MAC [3]. Chronic hemolysis leads to release of free hemoglobin, which causes nitric oxide depletion, reactive oxygen species increases, endothelial dysfunction, and platelet and monocyte activation [4,5]. Consequently, PNH is typically characterized by thrombosis and organ damage, as well as severe hemolytic anemia, and symptoms include hemoglobinuria, severe fatigue, abdominal pain, dysphagia, erectile dysfunction, renal dysfunction, and pulmonary hypertension [6,7]. Despite best supportive care, PNH is associated with high morbidity and mortality [6,8–10].
Advances in the creation of animal models of paroxysmal nocturnal hemoglobinuria
Published in Hematology, 2021
The evaluation parameters for PNH mouse models include blood routine examination, flow cytometry, erythrocyte life span, and hemolytic tests. The results of blood routine examination of PNH mice reported in the literature show no anemia or elevated reticulocyte levels [15,16,19]. Jasinski suggested that this was due to the late timing of lox-PigA gene recombination, which made red blood cells in PNH mouse models more similar to type II PNH cells, where hemolysis and anemia may only be mild, if not absent [20]. Kawagoe speculated that GPI-AP might have a different role in regulating hematopoiesis in humans compared to mice [14]. Murakami et al. suggested that this might be due to lower complement activity in mice, especially in C57BL/6 mice, and the red blood cells of mice have transmembrane complement regulatory molecules, such as complement receptor 1-related gene/protein y (Crry) [29] and transmembrane accelerated aging factor (DAF) [30]. PNH red blood cells in people with complete DAF/ CD59 deficiency are 10–15 times more sensitive to complement than normal red blood cells [31]. However, the sensitivity of mouse GPI-AP-deficient red blood cells to complement action was only 3 times that of the normal red blood cells, and the presence of transmembrane complement regulating molecules on mouse red blood cells was the main reason for this difference [16].