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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.
RAT α 2 -Macroglobulin and Related α-Macroglobulins in the Acute Phase Response
Published in Andrzej Mackiewicz, Irving Kushner, Heinz Baumann, Acute Phase Proteins, 2020
Rat α2-M has been shown to inhibit complement activity in a complement-induced immune hemolysis test by Bellot et al.65 The complement-inhibiting activity was not affected by the reaction of α2-M with trypsin or methylamine to convert it to the fast form. The authors suggest that this activity may be due to inhibition of the regulatory activity of the complement component, factor H.
Hereditary Leiomyomatosis and Renal Cell Cancer
Published in Dongyou Liu, Handbook of Tumor Syndromes, 2020
It is of interest to note that heterogeneous germline mutations observed in HLRCC chiefly occur in the 5′ end of the FH gene, in comparison with homozygous or compound heterozygous germline mutations implicated in autosomal recessive hereditary FH-deficiency causing rapidly progressive neurological impairment (e.g., hypotonia, seizures, and cerebral atrophy) and early mortality, which involve the 3′ end of the FH gene [11].
New findings in preventing recurrence and improving renal function in AHUS patients after renal transplantation treated with eculizumab: a systemic review and meta-analyses
Published in Renal Failure, 2023
Zhen Chun Tang, Huang Hui, Chunru Shi, Xiangmei Chen
Atypical hemolytic uremic syndrome (AHUS) is a rare, chronic multisystem disease that is life-threatening. The latest (2020) systematic review is the first to report the epidemiology of AHUS. The incidence of AHUS in the 20-year age group ranges from 0.26 to 0.75 per million population per year and 0.23 to 1.9 per million population for all age groups [1]. In the past, the prognosis of patients with AHUS was poor. Prior to the introduction of eculizumab, a majority of patients (over 50%) with this condition developed end-stage renal disease or succumbed to the illness within a year of initial diagnosis [2]. Inadequate complement regulation is thought to be a secondary cause of AHUS, and plasma therapy was once considered a potential contributing factor [3–7]. Although plasma infusion (PI) and plasma exchange (PEX) are sometimes used to treat AHUS, their efficacy is limited, and they may not prevent progression to end-stage renal disease [8]. Kidney transplantation therapy for AHUS patients is also not successful due to the high recurrence rate, especially for patients with complement Factor H (CFH) mutations. Bresin et al. reported a poor relapse rate of 85.7% after 1 year of organ transplantation [9], and the British and Italian registries reported almost equally poor results [10,11].
Avacopan for the treatment of ANCA-associated vasculitis: an update
Published in Expert Review of Clinical Immunology, 2023
Mohammed Osman, Jan Willem Cohen Tervaert, Christian Pagnoux
The complement protein network includes three different pathways: the classical, lectin, and alternative pathways (Figure 1) [20–22]. The previous version of this article, published in 2021, detailed more extensively all these three pathways [23]. Evidence for a role of alternative complement pathway in AAV is the strongest. This pathway is activated following C3 cleavage, promoted by properdin binding to myeloperoxidase (MPO) [24], and/or after C3 binds to bacterial surfaces [20,25,26]. C3 can also be cleaved spontaneously and then stabilized through its association with Factor B (and its co-activator, Factor D) to a C3 convertase ternary complex (C3bBb) [27]. Factor H competes with Factor B for binding to Bb, thereby reducing its activation and that of the alternative complement pathway [27]. Factor H provides other immunoregulatory roles, particularly in AAV as it can directly inhibit ANCA-mediated neutrophil activation [28]. It can also reduce T cell activation by dendritic cells [29] and promote regulatory T cell expansion. Polymorphisms in Factor H are more common in patients with AAV, particularly those with crescentic glomerulonephritis [14].
Copy number variation analysis using next-generation sequencing identifies the CFHR3/CFHR1 deletion in atypical hemolytic uremic syndrome: a case report
Published in Hematology, 2022
Joonhong Park, Ho-Young Yhim, Kyung Pyo Kang, Tae Won Bae, Yong Gon Cho
CFHR–Factor H gene cluster variations are associated with several kidney disorders, including aHUS, IgA nephropathy, and C3 glomerulopathy. These associations show the critical roles of the FHR proteins in maintaining glomerular integrity. FHR proteins are complement modulators and complement activators, and FHR1 regulates inflammasome activity [17]. Our patient experienced an acute episode of aHUS caused by heterozygous CFHR3/CFHR1 deletion, without underlying medical conditions that triggered complement activation. Hetero- and homozygous deletions of CFHR3 and CFHR1 through non-allelic homologous recombination events downstream of CFH is related to early-onset aHUS (under 21 years) [13]. The absence of both CFHR3 and CFHR1 proteins has been reported in approximately 10% of aHUS [14]. CFHR3/CFHR1 plasma deficiency is related to issues for most affected patients due to the formation of anti-CFH autoantibodies. These antibodies bind to both CFHR1 and to the CFH C-terminal, reduce CFH binding to C3b, and enhance alternative pathway-dependent lysis of sheep erythrocytes without influencing fluid-phase cofactor activity [14]. However, the causal link between CFHR3/CFHR1 deletion and CFH autoantibodies is not well known.