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The Case for Lupus Nephritis Journal of Clinical Medicine Review Expanding the Role of Complement Therapies: The Case for Lupus Nephritis Nicholas L. Li * , Daniel J. Birmingham and Brad H. Rovin Department of Internal Medicine, Division of Nephrology, The Ohio State University, Columbus, OH 43210, USA; [email protected] (D.J.B.); [email protected] (B.H.R.) * Correspondence: [email protected]; Tel.: +1-614-293-4997; Fax: +1-614-293-3073 Abstract: The complement system is an innate immune surveillance network that provides defense against microorganisms and clearance of immune complexes and cellular debris and bridges innate and adaptive immunity. In the context of autoimmune disease, activation and dysregulation of complement can lead to uncontrolled inflammation and organ damage, especially to the kidney. Systemic lupus erythematosus (SLE) is characterized by loss of tolerance, autoantibody production, and immune complex deposition in tissues including the kidney, with inflammatory consequences. Effective clearance of immune complexes and cellular waste by early complement components protects against the development of lupus nephritis, while uncontrolled activation of complement, especially the alternative pathway, promotes kidney damage in SLE. Therefore, complement plays a dual role in the pathogenesis of lupus nephritis. Improved understanding of the contribution of the various complement pathways to the development of kidney disease in SLE has created an opportunity to target the complement system with novel therapies to improve outcomes in lupus nephritis. In this review, we explore the interactions between complement and the kidney in SLE and their implications for the treatment of lupus nephritis. Keywords: lupus nephritis; complement; systemic lupus erythematosus; glomerulonephritis Citation: Li, N.L.; Birmingham, D.J.; Rovin, B.H. Expanding the Role of Complement Therapies: The Case for Lupus Nephritis. J. Clin. Med. 2021, 1. Introduction: The Yin and Yang of Complement Protection Versus Injury 10, 626. https://doi.org/10.3390/ jcm10040626 Complement is a rapid and effective innate immune surveillance system that acts as a defense against bacterial pathogens, eliminates apoptotic cells and cellular debris, Academic Editor: Oliver Gross and bridges the innate and adaptive immune systems. Deficiencies in complement proteins Received: 31 December 2020 predispose to certain infections, for example with encapsulated organisms. Deficiencies in Accepted: 3 February 2021 complement components, especially those that result in accumulation of cellular debris, Published: 7 February 2021 also predispose to autoimmune diseases. Furthermore, to accomplish many of its protec- tive actions, the complement system leverages other components of the immune system Publisher’s Note: MDPI stays neutral and initiates inflammatory responses. To keep inflammation controlled and beneficial, with regard to jurisdictional claims in the complement cascade is tightly regulated. Triggers that upset the balance between published maps and institutional affil- activation and regulation and/or deficiencies in regulatory mechanisms can lead to un- iations. controlled inflammation and organ injury. The kidney often bears the consequences of uncontrolled complement activation, especially in the setting of autoimmune diseases. In this review, we will explore the relationship of complement to kidney injury in systemic lupus erythematosus (SLE) and the implications of this relationship for the treatment of Copyright: © 2021 by the authors. lupus nephritis (LN). Licensee MDPI, Basel, Switzerland. This article is an open access article 2. Complement Activation in Three Easy Steps distributed under the terms and Complement activation occurs via three distinct pathways that eventually merge into a conditions of the Creative Commons final common pathway leading to assembly of the membrane attack complex (MAC). These Attribution (CC BY) license (https:// activation pathways, termed the classical, lectin, and alternative pathways, are altogether creativecommons.org/licenses/by/ composed of greater than 30 soluble and membrane bound proteins (Figure1). Some 4.0/). J. Clin. Med. 2021, 10, 626. https://doi.org/10.3390/jcm10040626 https://www.mdpi.com/journal/jcm J. Clin. Med. 2021, 10, x FOR PEER REVIEW 2 of 13 J. Clin. Med. 2021, 10, 626 2 of 13 These activation pathways, termed the classical, lectin, and alternative pathways, are al- together composed of greater than 30 soluble and membrane bound proteins (Figure 1). Someof these of these proteins proteins are zymogens, are zymogens, which which require require cleavage cleavage for activation for activation of their of their enzymatic enzy- maticactivity activity that in that turn in drives turn drives further furthe signalingr signaling down down the complement the complement cascade. cascade. Figure 1. 1. OverviewOverview of ofthe the complement complement activation activation pathways. pathways. MBL, MBL, mannose-binding mannose-binding lectin, lectin, MASP, MASP, MBL-associated MBL-associated serine protease. serine protease. 2.1. The Classical Pathway 2.1. The Classical Pathway The classical complement pathway is activated through the binding of C1q to recog- The classical complement pathway is activated through the binding of C1q to recog- nition surfaces, such as immune complexes or apoptotic debris. This binding induces a nition surfaces, such as immune complexes or apoptotic debris. This binding induces a conformational change and the sequential activation of the associated proteases C1r and conformational change and the sequential activation of the associated proteases C1r and C1s. Once activated, C1s cleaves C4 into C4a and C4b, creating a binding site on C4b for C1s. Once activated, C1s cleaves C4 into C4a and C4b, creating a binding site on C4b for C2. C2 is then cleaved by C1s, releasing C2b and activating a serine protease site on C2a. C2. C2 is then cleaved by C1s, releasing C2b and activating a serine protease site on C2a. This results in a complex, C4b2a, known as the classical C3 convertase, which cleaves C3 intointo C3a C3a and and C3b. C3b. 2.2.2.2. The The Lectin Lectin Pathway Pathway TheThe lectin lectin pathway pathway is is initiated initiated by by a member of the collectin family. These molecules areare similar similar to to C1q C1q but but with with C-terminal C-terminal carb carbohydrateohydrate recognition recognition domains domains (CRDs) (CRDs) and and in- cludeinclude mannose-binding mannose-binding lectin lectin (MBL), (MBL), ficolins, ficolins, and and collectins. collectins. Collectins Collectins bind bind mainly mainly to carbohydratesto carbohydrates found found on onpathogens, pathogens, such such as as D-mannose D-mannose and and N-acetyl N-acetyl glucosamine, throughthrough their their CRDs. CRDs. Once Once bound, bound, collectins collectins un undergodergo conformational conformational changes changes that that activate acti- MBL-associatedvate MBL-associated serine serine proteases proteases (MASPs) (MASPs) in a manner in a manner analogous analogous to C1r and to C1r C1s and activa- C1s tion.activation. Activated Activated MASPs MASPs can cleave can cleave C4 and C4 C2, and fo C2,rming forming the same the sameC3 convertase C3 convertase as the as clas- the sicalclassical pathway. pathway. J. Clin. Med. 2021, 10, 626 3 of 13 2.3. The Alternative Pathway In contrast to the classical and lectin pathways, the alternative pathway is activated via a unique mechanism of spontaneous and continuous hydrolysis of C3, a process known as tickover. Hydrolyzed C3, termed C3H20, is able to bind complement factor B (fB), which then is cleaved by the serine protease complement factor D (fD), exposing an active serine protease site on Bb. The resulting complex, C3H20Bb, which is stabilized by the complement protein properdin, is the initial alternative pathway C3 convertase, capable of cleaving C3 into C3a and C3b. The formed C3b can bind additional fB, which again can be cleaved by fD, forming the major alternative pathway C3 convertase C3bBb. This feedback activity results in an amplification loop, accelerating C3 activation. 2.4. The Final Common Pathway Regardless of the pathway of initiation, the resulting C3 convertases provide binding sites for additional C3b, forming the complexes C4b2a3b (from the classical or lectin path- ways) or C3bBb3b (from the alternative pathway) with specificity for cleavage of C5 into C5a and C5b. When the classical/lectin and alternative pathways are both engaged there is likely more C3bBb3b than C4b2a3b because of the alternative pathway’s amplification loop. C5 cleavage initiates the terminal pathway, where C5b associates with C6 and C7 to form a complex that is capable of inserting into cell membranes via an exposed hydrophobic region on C7. To this membrane bound complex, the addition of C8 and multimers of C9 lead to the formation of the C5b-9 that comprises MAC, which creates pores in the cell membrane causing target cell lysis. 3. Complement and LN 3.1. Complement Protects against Autoimmunity The safe clearance of immune complexes (IC), apoptotic cells, and cellular debris is an important protective function of complement [1]. Cellular debris exposes the host to self-antigens and conceivably may foster autoantibody induction. C1q is a potent opsonin for apoptotic cells and its binding to cellular blebs can activate the classical complement pathway resulting in C3 cleavage. Subsequent recognition of C1q bound to cellular debris by its receptor expressed on phagocytes
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