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Complement Recognition Pathways in Renal Transplantation

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Complement Recognition Pathways in Renal Transplantation BRIEF REVIEW www.jasn.org Complement Recognition Pathways in Renal Transplantation Christopher L. Nauser, Conrad A. Farrar, and Steven H. Sacks Medical Research Council Centre for Transplantation, Division of Transplantation Immunology and Mucosal Biology, King’s College London, National Health Service Guy’s and St. Thomas’ Trust, London, United Kingdom ABSTRACT The complement system, consisting of soluble and cell membrane–bound compo- weigh its effect on organ injury and nents of the innate immune system, has defined roles in the pathophysiology of renal rejection with dampening the antimi- allograft rejection. Notably, the unavoidable ischemia-reperfusion injury inherent to crobial functions of the complement sys- transplantation is mediated through the terminal complement activation products tem, such as opsonisation, cell lysis, and C5a and C5b-9. Furthermore, biologically active fragments C3a and C5a, produced recruitment of neutrophils and other in- during complement activation, can modulate both antigen presentation and T cell flammatory cells.7 It is our belief that priming, ultimately leading to allograft rejection. Earlier work identified renal tubule therapeutic strategies can be designed cell synthesis of C3, rather than hepatic synthesis of C3, as the primary source of C3 to specificallytargetthekeyinitiators driving these effects. Recent efforts have focused on identifying the local triggers of of complement activation at the relevant complement activation. Collectin-11, a soluble C-type lectin expressed in renal tis- location, such as complement-binding sue, has been implicated as an important trigger of complement activation in renal anti-HLA antibodies in the vascular tissue. In particular, collectin-11 has been shown to engage L-fucose at sites of compartment or the initiator(s) of local ischemic stress, activating the lectin complement pathway and directing the innate complement activation in the extravas- immune response to the distressed renal tubule. The interface between collectin-11 cular compartment of the allograft itself. and L-fucose, in both the recipient and the allograft, is an attractive target for ther- In this article, we will discuss the roles of apies intended to curtail renal inflammation in the acute phase. various complement recognition path- ways in ischemia-reperfusion injury J Am Soc Nephrol 28: 2571–2578, 2017. doi: https://doi.org/10.1681/ASN.2017010079 and allograft rejection with particular focus on the role of carbohydrate both as a danger signal and a potential target The innate immune system, composed of complement helps direct the alloim- underpinning complement activation humoral, cellular, and physical barrier mune response to solid organ trans- after ischemic insult and likely down- defenses, plays an essential role in the plants not only through contributing stream adaptive immune recognition. 1 immediate and nonspecific response to to damage associated with ischemia- Our review will cover ( )TheCom- 2 invading pathogens. A vital subset of reperfusion injury but also through a plement System, ( )Complementinthe 3 innate immunity is the complement sys- significant role in the augmentation of Development of Adaptive Immunity, ( ) 4 tem. Complement defends against Tcell– and B cell–mediated immu- Role of Complement in ABMR, ( )The invading organisms, clears immune nity.2,3 Indeed, not only has the role of Lectin Pathway (LP) as a Mediator of 5 complexes and cell debris, and provides complement as an effector of Antibody- Organ Injury, ( ) Role of mannan-binding 6 an interface between innate and adaptive Mediated Rejection (ABMR) been upda- lectin (MBL) in Tissue Injury, ( ) Role of immunity.1 Specifically, complement ted,4 butitisalsorequiredtoprime consists of interactive soluble proteins, effective antibody production against 5 membrane-bound receptors, and regu- donor tissue. In addition, recent evi- Published online ahead of print. Publication date latory proteins. For many years, the fo- dence points to complement activation available at www.jasn.org. fi cus of immune modulation in organ as a signi cant factor in the progression Correspondence: Dr. Christopher L. Nauser, MRC transplantation has been on the adaptive of chronic native kidney disease, which is Centre for Transplantation, Division of Trans- immune system. However, it has been likely to have generic application rele- plantation Immunology and Mucosal Biology, King’sCollegeLondon,Guy’s Hospital, 5th Floor 6 within the last 15 years that several new vant to the transplanted organ. How TowerWing,GreatMazePond,LondonSE19RT, aspects of complement biology with these observations will be translated to UK. Email: [email protected] respect to solid organ transplantation the clinical realm remains to be identi- Copyright © 2017 by the American Society of have emerged. We now know that fied, as any intervention will need to Nephrology J Am Soc Nephrol 28: 2571–2578, 2017 ISSN : 1046-6673/2809-2571 2571 BRIEF REVIEW www.jasn.org Ficolins in Tissue Injury, and (7) Collec- and tissues from damage related to com- could indirectly play a role in antibody tin-11 as a Mediator of Renal Epithelial plement activation.13 During inflamma- production through regulation of T Inflammation, followed by our conclud- tion and cell stress this equilibrium shifts cell immunity,18 as well as direct stimu- ing remarks. away from regulation and can lead to un- lation of B cell priming by opsonized controlled complement-mediated in- antigen.25,26 jury and rejection.14 Indeed, after renal THE COMPLEMENT SYSTEM ischemia-reperfusion injury, which is an unavoidable consequence of transplan- ROLE OF COMPLEMENT IN ABMR Complement is activated on the surface tation, postischemic renal dysfunction is of pathogens as well as damaged or in- dependent on the local conversion ABMR is defined as the development of a fected cells via one of three main path- of tubule-derived C3 to its activated donor-specific antibody in conjunction ways: the classical, alternative, or lectin form,15 which growing evidence sug- with histologic changes on graft biopsy pathway.8 These distinct pathways con- gests is mediated through triggering and deterioration of graft function.27 As verge at the formation of C3, which is of the LP,16,17 discussed in more detail an effector of acute ABMR, the role of then cleaved to form C5 convertase, below. complement is well established, al- with the subsequent production of the though this function has recently been terminal pathway complement compo- extended in the context of chronic rejec- nents, comprising C5a and the mem- COMPLEMENT IN THE tion. In 1969, Terasaki showed that brane attack complex (C5b-9) (Figure DEVELOPMENT OF ADAPTIVE patients with alloantibody capable of in- 1). Classical pathway activation typically IMMUNITY ducing complement-dependent cell lysis occurs through antibody-antigen com- were more likely to suffer from hyper- plex binding of C1q to the Fc portion The role of complement in regulating T acute rejection.28 Donor-reactive anti- of IgM or IgG,1,9,10 which forms part of cell alloimmunity was discovered when it HLA antibodies have been described as the C1 complex with classical pathway– was observed that wild-type mice do not mediators of acute and chronic trans- specific serine proteases C1r and C1s. acutely reject renal allografts from C3- plant injury29 and it has been documen- The alternative pathway, activated by hy- deficient donors.18 Further support, ted that complement depletion impairs drolysis of plasma C3 and enhanced in implicating a role in regulating B cell al- antibody production.30 some circumstances by an absence of loimmunity, came from a study of ABMR occurs via the classical com- complement inhibitors on cell mem- C3-deficient mice that were unable to plement pathway when complement branes, also functions as an amplifica- produce high-affinity IgG responses component C1q binds to donor-specific tion pathway after the generation of against MHC in skin grafts.5 During in- anti-HLA antibody (DSA) at the site of C3b by the classical or lectin path- teractions between antigen presenting antibody attachment to the endothelium ways.11,12 In contrast, LP initiation takes cells and T cells, the alternative pathway (Figure 2). Loupy et al. have generated place through pattern-recognition mol- complement components C3, factor B, evidence that the capacity of serum DSA ecules such as MBL, ficolins, surfactant and factor D are released along with to interact with C1q could determine the proteins, and the recently identified the terminal pathway complement com- cytotoxic potential of these antibodies C-type lectin, Collectin-11 (CL-11; ponent C5.19–21 Additionally, comple- and therefore be used to risk stratify CL-K1), all of which bind to carbohy- ment receptors C3aR and C5aR are and diagnose ABMR.4 They reported drate motifs. upregulated on T cells in response to that the development of a C1q-binding Under normal physiologic condi- the expression of these complement DSA in the first year post-transplantation tions, complement activation is con- components.22,23 Increased production was an independent risk factor for allo- trolled by surface-bound and soluble of complement effector products and graftlossandwasassociatedwitha proteins that mediate the degradation corresponding receptor expression, in higher risk of ABMR. Furthermore, their of complement convertases, ultimately parallel with reduced cell surface DAF, results showed that patients who devel- preventing the formation of complement favors complement
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