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Complement As a Therapeutic Target in Systemic Autoimmune Diseases

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Complement As a Therapeutic Target in Systemic Autoimmune Diseases cells Review Complement as a Therapeutic Target in Systemic Autoimmune Diseases María Galindo-Izquierdo * and José Luis Pablos Alvarez Servicio de Reumatología, Instituto de Investigación 12 de Octubre, Universidad Complutense de Madrid, 28040 Madrid, Spain; [email protected] * Correspondence: [email protected] Abstract: The complement system (CS) includes more than 50 proteins and its main function is to recognize and protect against foreign or damaged molecular components. Other homeostatic functions of CS are the elimination of apoptotic debris, neurological development, and the control of adaptive immune responses. Pathological activation plays prominent roles in the pathogenesis of most autoimmune diseases such as systemic lupus erythematosus, antiphospholipid syndrome, rheumatoid arthritis, dermatomyositis, and ANCA-associated vasculitis. In this review, we will review the main rheumatologic autoimmune processes in which complement plays a pathogenic role and its potential relevance as a therapeutic target. Keywords: complement system; pathogenesis; therapeutic blockade; rheumatic autoimmune diseases 1. Introduction The complement system (CS) includes more than 50 proteins that can be found as soluble forms, anchored to the cell membranes, or intracellularly [1]. Most of the com- plement proteins are synthesized in the liver, although other cell types, especially mono- cytes/macrophages, can produce them. Tissue distribution is variable and a higher con- Citation: Galindo-Izquierdo, M.; centration of these proteins is found in certain locations such as the kidney or brain. The Pablos Alvarez, J.L. Complement as a main function of the CS is to recognize and protect against foreign or damaged molecular Therapeutic Target in Systemic components, directly as microorganisms, and indirectly as immune complexes (IC). This is Autoimmune Diseases. Cells 2021, 10, 148. https://doi.org/10.3390/cells achieved through different mechanisms such as opsonization and phagocytosis, direct cell 10010148 lysis, and triggering of pro-inflammatory responses by anaphylotoxins. Other homeostatic functions of CS are the elimination of apoptotic debris, neurological development, and the Received: 11 December 2020 control of adaptive immune responses [2]. Accepted: 8 January 2021 The activation of CS occurs through three main pathways—classical, lectin, and Published: 13 January 2021 alternative—that converge in C3 activation (Figure1). Each pathway is activated by different conditions, but all three pathways result in the creation of a pro-inflammatory Publisher’s Note: MDPI stays neu- environment, the deposition of large amounts of C3 in target cells (opsonization), and tral with regard to jurisdictional clai- membrane disturbance, including lysis by the membrane attack complex (MAC). The ms in published maps and institutio- classical pathway is activated by the binding of C1q to the Fc portion of immunoglobulin nal affiliations. G or M in the IC [3]. Upon binding the target surface, C1q undergoes a structural change with activation of C1r, which subsequently divides and activates the two C1s molecules with serine protease activity [4,5]. Active C1s are divided into C4 and C2 to generate the C3 convertase, C4b2a. Once C3 is activated, the larger fragment C3b can covalently bind to the Copyright: © 2021 by the authors. Li- censee MDPI, Basel, Switzerland. target surface or to C4b in the C4b2a complex. This last reaction generates the C5 convertase This article is an open access article C4b3b2a, and the terminal pathway. Once C3b is deposited on a surface, the alternative distributed under the terms and con- pathway can be activated forming the C3b-FactorB complex, which is also activated, giving ditions of the Creative Commons At- rise to C3bBb convertase by the action of Factor D. The lectin complement pathway has an tribution (CC BY) license (https:// activation scheme comparable to that of the classical pathway, but lectins (carbohydrate- creativecommons.org/licenses/by/ linked proteins) replace antibodies and lectin-associated proteases replace C1r and C1s [6,7]. 4.0/). The lectin-associated serine proteases (mannan-associated lectin-binding serine proteases, Cells 2021, 10, 148. https://doi.org/10.3390/cells10010148 https://www.mdpi.com/journal/cells Cells 2021, 10, x FOR PEER REVIEW 2 of 19 Cells 2021, 10, 148 2 of 18 (carbohydrate-linked proteins) replace antibodies and lectin-associated proteases replace C1r and C1s [6,7]. The lectin-associated serine proteases (mannan-associated lectin-bind- MASPs)ing serine bind proteases, to mannose MASPs) and cleavebind to C4 mannose and C2 factorsand cleave [8]. TheC4 and alternative C2 factors pathway [8]. The does al- notternative require pathway antibodies does or not contact require with antibodies a microbe or contact to be activated with a microbe [9,10]. to Instead, be activated C3 is constantly[9,10]. Instead, self-activated C3 is constantly (C3 tick-over) self-activated at a low (C3 level, tick a- processover) at that a low is rapidlylevel, a amplifiedprocess that in theis rapidly presence amplified of a microbe, in the a presence damaged of host a microbe, cell, or importantly, a damaged by host deficiency cell, or importantly, of complement by regulatory proteins. The deposition of C3b on a target can be efficiently amplified by the deficiency of complement regulatory proteins. The deposition of C3b on a target can be feedback loop of the alternative pathway. efficiently amplified by the feedback loop of the alternative pathway. FigureFigure 1.1. Complement system. system. There There are are three three activation activation pathways pathways in the in thecomplement complement system: system: classical, classical, lectin lectin,, and alter- and native. All three pathways lead to the formation of C3 and C5 convertases, which rapidly amplify the complement re- alternative. All three pathways lead to the formation of C3 and C5 convertases, which rapidly amplify the complement sponse. In addition to the processes described above, several complement regulatory proteins are able to inhibit comple- response. In addition to the processes described above, several complement regulatory proteins are able to inhibit ment by inactivation of C3 and C5, and C3 and C5 convertases, or by preventing successful formation of the membrane complementattack complex. by inactivationDAF: decay- ofaccelerating C3 and C5, factor and or C3 CD55; and C5 FB: convertases, factor B; FD: or factor by preventing D; FH: factor successful H; FI: formationfactor I; MASPs: of the membraneMASP: MBL attack-associated complex. serine DAF: protea decay-acceleratingses; MCP: membrane factor cofactor or CD55; protein FB: factor or CD46; B; FD: MIRL: factor membrane D; FH: factor inhibitor H; FI: of factorreactive I; MASPs:lysis or CD59; MASP: P: MBL-associated properdin. serine proteases; MCP: membrane cofactor protein or CD46; MIRL: membrane inhibitor of reactive lysis or CD59; P: properdin. All these pathways result is the activation of inflammatory responses by releasing pro-inflammatoryAll these pathways peptides result known is the as activationanaphylatoxins of inflammatory (C3a, C4a, C responses5a), due to by their releasing ability pro-inflammatoryto induce mast cell peptides and basophil known degranulation as anaphylatoxins and hence (C3a, C4a,the release C5a), due of vasoactive to their ability and tochemoattractant induce mast cell mediators and basophil [11]. Cytokine degranulation signaling and contributes hence the releaseto an up of-regulation vasoactive of and an- chemoattractantaphylatoxin receptors mediators (C3aR, [11 C5aR)]. Cytokine by endothelial signaling cells contributes in small tovessels an up-regulation and circulating of anaphylatoxinleukocytes. Binding receptors of C3a (C3aR, and C5aR)C5a to bythe endothelial reciprocal receptors cells in small on these vessels cells and enha circulatingnces the leukocytes.release of cytokines Binding ofand C3a eicosanoids and C5a to that the contribute reciprocal to receptors an increase on these in vascular cells enhances permeabil- the release of cytokines and eicosanoids that contribute to an increase in vascular permeability, ity, vasodilation, and leukocyte extravasation. Anaphylatoxins up-regulate adhesion mol- vasodilation, and leukocyte extravasation. Anaphylatoxins up-regulate adhesion molecules ecules on endothelial cells and leukocytes, facilitating the adhesion of leukocytes to the on endothelial cells and leukocytes, facilitating the adhesion of leukocytes to the vascular vascular wall and their subsequent transmigration into the interstitial tissue at sites of wall and their subsequent transmigration into the interstitial tissue at sites of inflammation. inflammation. C3a and C5a stimulate mast cells to release histamine and proteases that C3a and C5a stimulate mast cells to release histamine and proteases that also contribute to vascular alterations. Monocyte-derived macrophages are among the first cells encountering Cells 2021, 10, 148 3 of 18 non-self-antigens, and through the pattern recognition system they initiate an innate immunity response [12]. While C3a and C5a are well recognized anaphylatoxins with specific receptors, C4a has also been found to be a ligand for protease-activated receptors 1 and 4 (PAR1 and PAR4), also with effects on endothelial permeability and inflammatory cell recruitment. There is a complex system of control of CS activation (Figure1). The regulatory proteins inhibit the CS by destabilizing the activation complexes or by mediating
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