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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.
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.
Proteomic signatures of neuroinflammation in Alzheimer’s disease, multiple sclerosis and ischemic stroke
Published in Expert Review of Proteomics, 2019
Camilla Thygesen, Martin Rössel Larsen, Bente Finsen
Inflammatory molecules found increased in MS CSF included ANG, B2M, CHI3L1, C1Q and C1R. The B2M protein is a component of the class I major histocompatibility complex (MHC) and is thereby involved in the presentation of peptide antigens to the immune system. It is primarily expressed on lymphocytes and macrophages and used as a marker of an activation of the cellular immune system [68]. Interestingly, also the C1Q and the C1R proteins, the first step of classical complement system activation, were consistently increased in CSF reflecting the involvement of the complement system in MS pathology. The complement system is known to be involved in MS as visualized by deposition of complement proteins in white and grey matter lesions [69,70], where it is considered to contribute to the damage of oligodendrocytes and myelin [71].
Emerging targets for the treatment of lupus erythematosus: There is no royal road to treating lupus
Published in Modern Rheumatology, 2019
Complement activation is an essential pathophysiologic feature of SLE. Deficiency of complement family members, including C1q, C1r, C1s, C4, and C2, also causes SLE-like disease [55]. However, most patients with SLE are not genetically deficient for complement. Therefore, treatment should be targeted against overactivation of the complement system. Eculizumab is a humanized mAb that inhibits C5 activation and is effective for atypical hemolytic uremic syndrome and paroxysmal nocturnal hemoglobinuria. Although the effectiveness of eculizumab was reported mainly in patients with thrombotic microangiopathy accompanied by SLE, whether this strategy is still effective for nonthrombotic SLE remains undetermined [56]. CCX168 (avacopan) is a C5a receptor antagonist currently under investigation a phase-III trial for antineutrophil cytoplasmic antibody-associated vasculitis. Because the results of a phase-II study demonstrated that avacopan could replace high-dose glucocorticoids [57], a clinical trial using this small molecule for SLE would be awaited.