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Systemic Lupus Erythematosus
Published in Jason Liebowitz, Philip Seo, David Hellmann, Michael Zeide, Clinical Innovation in Rheumatology, 2023
Vaneet K. Sandhu, Neha V. Chiruvolu, Daniel J. Wallace
The complement system plays a key role in lupus pathophysiology, demonstrating consumption by way of reduced complement levels during disease flares. Either a genetic complement deficiency or a functional defect (i.e., antibodies targeting) in C1q, the initiator of the classical pathway and an opsonin, can lead to SLE. C1q not only is an opsonin but is also involved in removal of apoptotic cells without assembly of an inflammasome. Hence, any defect in C1q leading to decreased clearance of apoptotic cells can result in immune dysregulation. Other complements of the classical pathway including C1r, C1s, C4, and C2 have also been implicated, but to a lesser extent than C1q. Mutations in complement inhibitors such as FH and CD46 have been linked to lupus nephritis. Similarly, by amplifying the effect of C1q-driven immune complexes in kidneys, antibodies to C1q have become a predictive marker for lupus nephritis.39
Specific Host Restance: The Effector Mechanisms
Published in Julius P. Kreier, Infection, Resistance, and Immunity, 2022
C1 consists of three parts: C1q, C1r, and C1s. There is only one C1q in each C1 molecule, but there are two each of C1r and C1s. The C1q part is composed of six subunits with the extended ends tied together in a “stalk” and six globular “heads.” the Fc receptors that bind to constant regions of the antibody molecules (Figure 9.3B). The binding of C1q to the antibody molecules triggers an internal rearrangement in one of the C1r molecules to expose its active site. The activated C1r then cleaves the C1s molecule, exposing its active site. Active C1s is a serine protease.
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.
Emerging drugs for antibody-mediated rejection after kidney transplantation: a focus on phase II & III trials
Published in Expert Opinion on Emerging Drugs, 2022
Katharina A. Mayer, Klemens Budde, Bernd Jilma, Konstantin Doberer, Georg A. Böhmig
ABMR is a challenging post-transplant complication. Today, acute ABMR treatment relies on SOC treatment consisting of plasmapheresis and IVIG [11]. The evidence behind the use of such treatment is limited and mainly based on observational studies with or without historical control groups [22]. For immunoadsorption, a single trial has suggested efficacy. However, due to premature termination this trial only included 10 subjects [29]. Available evidence for adding rituximab to SOC is weak [81,84,86]. Similarly, the role of complement inhibitors is a matter of controversial discussion [49]. The results of an ongoing trial evaluating an anti-C1s monoclonal antibody are awaited [52]. Late (chronic) ABMR may be particularly challenging. In this indication, TRITON and BORTEJECT have failed to demonstrate efficacy of IVIG/rituximab or bortezomib, respectively [84,114]. Plasmapheresis and IVIG is not recommended and, currently, optimizing baseline immunosuppression and medical therapy is the only option outside investigational studies [11]. But even for this recommendation evidence is lacking. For ABMR treatment, there are promising concepts in the pipeline and systematic trials are currently underway. These include, among others, monoclonal antibodies against IL-6/IL-6 R [36,104], imlifidase for IgG cleavage [46] or the CD38 antibody felzartamab [127]. These studies will hopefully help to develop an optimal treatment schedule for ABMR.
Multi-functional antibody profiling for malaria vaccine development and evaluation
Published in Expert Review of Vaccines, 2021
D. Herbert Opi, Liriye Kurtovic, Jo-Anne Chan, Jessica L. Horton, Gaoqian Feng, James G. Beeson
Complement is an essential arm of the immune system comprising of more than 30 serum proteins, which act in a sequential cascade to mediate various immunological responses [118]. Complement can be activated by antibodies through interactions with complement protein C1q, which initiates the classical complement pathway. C1q-fixation (together with components C1r and C1s) leads to the deposition of complement protein C3 on target cells. Deposited C3 acts as an opsonin that interacts with complement receptors including CR1, CR2, C3, CR4, and CRIg that are expressed on immune cells including macrophages and neutrophils, to facilitate pathogen uptake and degradation via complement-mediated phagocytosis [118]. The terminal step in complement activation is the formation of the membrane attack complex (MAC) that inserts into the target cell membrane and causes cell lysis.
Is there a link between genetic defects in the complement cascade and Porphyromonas gingivalis in Alzheimer’s disease?
Published in Journal of Oral Microbiology, 2020
C1s complexes with two molecules, C1r and C1q, and form C1 as the first component of the classical complement activation. C1 is a serine esterase that activates C4 and C2 thereby driving the classical pathway of complement activation [38]. C1 is not stable as it dissociates rapidly by the activity of the fluid phase regulator C1 inhibitor [39]. Interestingly, the virulence associated gene 8 (Vag8) in Bordetella pertussis is a complement evasion molecule that mediates its effects by binding to the complement regulator C1 inhibitor (C1-INH), which is a fluid phase serine protease [40]. The absence of functional C1s (defected gene) suggests that C1 cannot be activated in the context of its ability to initiate the classical complement cascade [41]. In this scenario, the resident microglial cells that express the phagocytic C1qR receptor [42] would fail in their function. However, if the C1s subcomponent is seen as an inactive protein, this could represent a pool of ‘inactivated’ C1. ‘Inactivated’ C1 can complex with C1r and C1q and activate the classical complement pathway [41]. Literature supports incomplete complement activation in AD brains [11–15]. This suggests that ‘inactivated’ C1 eventually binds to other ‘activators’ (Aβ, NFTs, microbial pathogens, physical injury) which propagate the incomplete complement pathway activity by cleaving the next component in the cascade in demented brains.