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Specific Host Restance: The Effector Mechanisms
Published in Julius P. Kreier, Infection, Resistance, and Immunity, 2022
Activation of complement by the alternative pathway begins in the plasma. A small amount of C3 hydrolyzes spontaneously (“tickover”) to form and . The binds to the surfaces of cells, including those of the host. The lipopolysac-charide of Gram-negative bacteria and the carbohydrates of yeast cell walls, however, provide particularly hospitable sites for the stable deposition of . Bound associates with Factor B, an inactive protease in the plasma, to form a complex, . After deposition on the microbe, the Factor B in the complex is cleaved by the action of Factor D. The products of this reaction are Ba, which diffuses away, and . is a C3 convertase. When it is stabilized by the binding of properdin (P) molecules, it cleaves many C3 molecules, amplifying the deposition of on the cell surface. The stabilized large complex of eventually undergoes a conformational change to expose another enzymatic site on Bb which is a C5 convertase. When C5 is cleaved and is deposited on the cell surface, the assembly of the membrane attack complex follows.
The Chemistry and Biology of Lipooligosaccharides: The Endotoxins of Bacteria of the Respiratory and Genital Mucosae
Published in Helmut Brade, Steven M. Opal, Stefanie N. Vogel, David C. Morrison, Endotoxin in Health and Disease, 2020
J. McLeod Griffiss, Herman Schneider
Properdin (P), a regulatory protein of the alternative complement pathway (ACP) that stabilizes the ACP C3 convertase and thereby augments the density of C3b deposited following CP activation, binds to a gonococcal outer membrane protein that is variously surface exposed (31). Strains of N. gonorrhoeae bind various amounts of P, depending on their expression of the P-binding protein, and therefore variously support ACP augmentation of the C3b that is deposited following binding of gangliosyl IgM (31). Sers strains that bind equivalent amounts of gangliosyl IgM are therefore lysed at different titers (31).
Radiation Immunology
Published in Kedar N. Prasad, Handbook of RADIOBIOLOGY, 2020
In some animals, the production of properdin, a serum protein, takes place without any antigenic stimulation.1 This serum protein participates in the destruction of bacteria and in the neutralization of viruses. The properdin level, in dogs lethally irradiated with high doses, decreases during the postirradiation period. However, the properdin level increases in survivors. Zymosan, which alters the properdin level in vivo, provokes a double increase in the leukocytes of irradiated dogs at the time of maximum leukopenia.1 It has been reported that properdin partially protects the rats irradiated with the 30D90 dose.
Acute post-streptococcal glomerulonephritis: analysis of the pathogenesis
Published in International Reviews of Immunology, 2021
Jesús Mosquera, Adriana Pedreañez
Alternative pathway is activated by IgA immune complexes, bacterial endotoxins, polysaccharides, and cell walls, including products from streptococci [25]. Properdin and factor H (two key regulatory proteins with opposite functions) can be involved in the alternative pathway activation during APSGN. Properdin up-regulates and factor H down-regulates the alternative pathway by stabilizing the C3bBb complex and by promoting proteolytic degradation of C3b, respectively [26]. Decreased circulating levels of properdin and increased levels in glomeruli have been reported in APSGN [27] suggesting a role of properdin on local renal C3 activation. On the other hand, impairment of factor H activity has been related to prolonged course of group A streptococcus-associated nephritis [28]. In this regard, S. pyogenes has been shown to recruit factor H, decreasing its down regulator action [29]. The presence of positive risk alleles in the factor H gene is associated to altered complement regulation suggesting that streptococcal infection may trigger renal dense deposit disease in individuals genetically predisposed [30]. In addition of the capacity of factor H to downregulate the alternative pathway, it has been shown that this factor can directly compete with C1q in binding to anionic phospholipids from several bacteria [31] acting as a direct down regulator of the classical pathway. Streptococcal antigens associated to APSGN such as NAPlr and ETB activate the alternative complement pathway, resulting in low serum complement levels [5, 32].
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
Fluid-phase complement regulators target both host and non-host surfaces and act at multiple levels of the complement cascade [56]. For instance, C1 inhibitor (C1INH) inhibits the CP and LP of the complement system by neutralization of C1r and C1s or MASP activities and is the main inhibitor of the contact phase system by inhibition of factor FXIIa, kallikrein, and FXIa [57].Due to the anti-inflammatory properties of C1INH, it has been considered as a potential therapy to treat inflammatory diseases such as sepsis [58]. Properdin is the only known positive regulator of complement activation. A serum protein, it increases the production of complement activation products in the alternative pathway by binding and stabilizing the convertase complex, C3bBb [59]. In sepsis patients, properdin concentrations at ICU admission were decreased in non-survivors of sepsis, suggesting that Properdin may be used as a predictive marker of outcome in the initial stage of sepsis. Factor H is a fluid phase negative regulator of amplification through the alternative pathway [56].
Complement profile in microscopic polyangiitis and granulomatosis with polyangiitis: analysis using sera from a nationwide prospective cohort study
Published in Scandinavian Journal of Rheumatology, 2020
S Fukui, K Ichinose, K-E Sada, J Miyamoto, M Harigai, K Amano, T Atsumi, Y Takasaki, H Dobashi, Y Arimura, H Hasegawa, Y Yuzawa, K Yamagata, N Tsuboi, S Maruyama, S Matsuo, H Makino, T Maeda, A Kawakami
The lower serum levels of properdin in MPA and GPA patients compared with the HDs suggest the importance of the alternative pathway in MPA and GPA. Properdin stabilizes the C3 convertase of the alternative complement pathway and is released mainly by neutrophils from intracellular stores (22). It was reported that in ANCA-associated glomerulonephritis, properdin staining was associated with cellular crescents (14). Because Falk et al reported that ANCA induced neutrophils to degranulate (23), the lower serum levels of properdin in MPA and GPA may be the result of an excess consumption and deposition of properdin in the tissues, or the result of a negative feedback mechanism. This may be why properdin had the sole significant negative correlation with the BVAS. Moreover, our finding that the levels of properdin were not changed at 6 months suggests that properdin would not be affected by conventional treatments for MPA and GPA.