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The complement system in health and disease
Published in Gabriel Virella, Medical Immunology, 2019
The lectin pathway is initiated by target recognition through the binding of circulating lectins, such as plasma mannan-binding lectin (MBL) and Ficolins 1–3. These protein components belong to the collectin family, structurally resemble C1q, and are involved with the recognition of foreign organisms such as bacteria and virus. Mannan, a constituent of the polysaccharide capsules of many pathogenic fungi and yeasts (e.g., Cryptococcus neoformans and Candida albicans), is one of several polysaccharide substances to which MBL binds via Ca2+-dependent interactions, while bacterial lipoteichoic acid and peptidoglycan associate with serum Ficolins. In addition to carbohydrate motifs of microorganisms, MBL can bind to glycoproteins on the envelope of several types of viruses. The activation of the lectin pathway does not involve antigen-antibody interactions. Like the alternative complement pathway, the lectin pathway is an innate system designed to activate the complement system independently of specific antibodies, and as such requires no adaptive immune system help. Both mannan-binding lectin and ficolins are acute-phase reactants, meaning that their concentration increases during infection and inflammation. Both types of lectins stay associated with serum serine proteases, and upon binding initiation proceeds through the activations of processes mediated by MBL-associated serine proteases (MASPs) such as MASP-1, MASP-2, and MASP-3. These proteases form a tetrameric complex similar to the one formed by C1r and C1s of the classical pathway, and MASP-2 subsequently cleaves C4 and C2, and then subsequently C3 in the same manner as that of the classical pathway (Figure 9.3).
Activation of Complement System in Henoch-Schönlein Purpura Nephritis
Published in Fetal and Pediatric Pathology, 2022
Hea Min Jang, Heesun Baek, Man Hoon Han, Yong Jin Kim, Chan-Duck Kim, Yong-Lim Kim, Sun-Hee Park, Min Hyun Cho
Many reports have suggested that the pathophysiology of IgAN is associated with complement activation [8,9,17]. Complement activation is initiated by mesangial IgA-immune complex (IgA-IC) deposition. In early studies, IgAN was associated with alternative pathways, but recently Roos et al. suggested that the lectin pathway plays an important role. The lectin pathway of complement is activated by the interaction of the plasma lectins, mannose-binding lectin (MBL), L-ficolin, or H-ficolin, with their carbohydrate ligands. It induces the activation of MBL-associated serine proteases (MASPs), and activated MASP-2 produces C4b2a and induces C3 cleavage [9]. Investigators found that, among 60 IgAN patients, 25% of renal biopsy had positive glomerular staining for MBL, and L-ficolin was positive for all MBL-positive patients [9]. With or without MBL staining, C3 deposition was positive in most biopsies, but C1q was negative. This suggests that the alternative pathway was activated in 75% of patients with IgAN, and the glomerular lectin pathway was involved in 25% of IgAN in that study.
Acute post-streptococcal glomerulonephritis: analysis of the pathogenesis
Published in International Reviews of Immunology, 2021
Jesús Mosquera, Adriana Pedreañez
Both classical and alternative pathways of complement activation can occur during the course of APSGN [18]. In this regard, the classical complement pathway is frequently activated in patients with early APSGN [19], suggesting the interaction of streptococcal antigens with their antibodies. In addition, streptococcal protein H attached to Fc region of IgG may activate the classic pathway [20]. A role of streptococcal protein H in the pathogenesis of APSGN has been reported [21]. A third complement activation pathway, termed the “lectin pathway” (LP) had been described [22]. LP is identical to the classical pathway except for the initiation of the complement cascade. Instead of a C1q/C1 complex the LP initiation is done by an opsonin named mannose-binding lectin (MBL). This lectin binds to mannose residues on the pathogen surface which in turn activates the associated serine proteases MASP1 and MASP2 [23]. The LP activation in APSGN is controversial, it has been reported LP activation in this disease [24], but others reports failed to find evidence of this activation [21].
Complement activation and coagulopathy - an ominous duo in COVID19
Published in Expert Review of Hematology, 2021
Sojit Tomo, Kiran Pvsn Kumar, Dipayan Roy, Shrimanjunath Sankanagoudar, Purvi Purohit, Dharamveer Yadav, Mithu Banerjee, Praveen Sharma, Sanjeev Misra
Existing evidence supports a procoagulant effect of the complement system in COVID-19. It can be mediated directly by mannose-associated serine protease-2 (MASP-2), a critical component of the lectin pathway, which activates thrombin and subsequent fibrin mesh formation. Indirectly, complement effectors can bring about changes in the endothelium which modulates the clotting cascade. Again, in addition to modulating the cascade proteins, complements are also actively involved in aggregation of platelets, a coagulation-initiating effect. On the other hand, the complement system can be activated by the coagulation pathway by activation of Factor XIIa which can activate complement complex C1 in the classical pathway [20]. Thus, there is a clear cross-talk of the two pathways and there may be a synergistic activation of these two pathways in the COVID-19 patients, which amounts to an enhanced rate of coagulopathy.