Dixon BP

Dragon-Durey M-A

Frazer-Abel A

Marchbank KJ

Newcastle University E-Prints

EDITORIALpublished: 16 September 2020doi: 10.3389/fimmu.2020.591338Frontiers in Immunology | www.frontiersin.org 1 September 2020 | Volume 11 | Article 591338Edited and reviewed by:Betty Diamond,Feinstein Institute for MedicalResearch, United States*Correspondence:Kevin J. Marchbankkevin.marchbank@newcastle.ac.ukSpecialty section:This article was submitted toAutoimmune and AutoinflammatoryDisorders,a section of the journalFrontiers in ImmunologyReceived: 04 August 2020Accepted: 14 August 2020Published: 16 September 2020Citation:Marchbank KJ, Frazer-Abel A,Dragon-Durey M-A and Dixon BP(2020) Editorial: Autoantibodies inKidney Diseases.Front. Immunol. 11:591338.doi: 10.3389/fimmu.2020.591338Editorial: Autoantibodies in KidneyDiseasesKevin J. Marchbank 1,2*, Ashley Frazer-Abel 3, Marie-Agnes Dragon-Durey 4 andBradley P. Dixon 5,61 Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, United Kingdom, 2National RenalComplement Therapeutics Centre, Newcastle upon Tyne, United Kingdom, 3Medicine-Rheumatology, University of ColoradoDenver, Denver, CO, United States, 4 Laboratory of Immunology, Georges Pompidou European Hospital, APHP, INSERMUMRS1138, Cordeliers Research Center, Université de Paris, Paris, France, 5Department of Pediatric Nephrology, Universityof Colorado Denver, Denver, CO, United States, 6Department of Pediatric Nephrology, Children’s Hospital Colorado, Aurora,CO, United StatesKeywords: autoantibody (aAb), complement, aHUS, C3G, lupus, immune complex, IgAN pathogenesis, nephrologyEditorial on the Research TopicAutoantibodies in Kidney DiseasesThe purpose of this Frontier in Immunology Research Topic. Autoantibodies (aAb) in KidneyDiseases was to bring diverse knowledge, experience and view-points together into one collectionhighlighting the role of aAb to complement proteins in the genesis and severity of kidney disease,and providing evidence for common pathways that lead to autoantibody-induced pathology andthe emergence of the aAb themselves. It was postulated that deepened insight of the crosstalkbetween complement and autoantibody-based pathologies would provide unique opportunities tounderstand and treat these diseases. Reading this collection as a body of work should stimulatevivid conversations between you and your colleagues around new avenues of investigation.At time of writing, greater than 30 thousand views of the articles in the collection has occurred,suggesting that one key aim has already been met; the dissemination of collated thoughts and keyoriginal research on this topic. The association of anti-Complement aAb with disease has beenlong appreciated, yet our understanding of their roles in development of disease still remainsopen to interpretation. Herein, and since the days they were called immunoconglutinins (seeVasilev et al.), understanding the linkage between nephritic factors (antibodies that bind the C3/C5convertases) or the individual components of these complexes and their modification of diseaseprocesses is as important now (see the review by Hauer et al. and Corvillo et al.) as it ever was.Our collection provides considered perspective on the mechanisms of action of nephritic factorsat various stages of the complement pathway (see Hauer et al. Corvillo et al. and Zhao et al.), withdifferent consequences/outcomes depending on titer, subclass of Ig and context. Importantly, theprecision of current testing to characterize nephritic factors is also key from a clinical perspective,beautifully appraised by Corvillo et al.. Zhao et al. also reminds us that theCFHR gene deletions thatpredominately associate with anti-FH formation in aHUS do not co-associate with C3 nephriticfactors in C3G and speaks to multiple routes to the generation of aAb in kidney diseases. Thus, thearticles herein also provide insight into the evolution of anti-complement protein/convertase aAbby explaining the potential roles of the cryptic epitope, altered self and immune “danger signal” thatundoubtedly interact with patient genetic factors to deliver the perfect storm of events that generateaAb; to generate the immune complexes (IC) or non-lethal membrane attack complex (MAC) thatwreak havoc in the kidney.Collectively, we have learned that much still remains to be discovered from anti-FH aAbassociated with aHUS. Puraswani et al. noted in their large longitudinal cohort study that highanti-FH titers predict relapse, but do not correlate well with disease activity. The establishmentMarchbank et al. Editorial: Autoantibodies in Kidney Diseasesof an international reference titer has allowed a degree ofcorrelation between high titers (over 1,000 AU/RU) and lowlevels of C3, confirming activation of the alternative pathway.However, correlation between low free-FH levels, predictingearly relapses in patients, with high anti-FH titers as describedby Puraswani et al. is less common in other studies. Itlikely underlines that immune complexed FH is not well-tolerated, similar to anti-dsDNA (Wang and Xia). “Stable”autoantibody titer over time appears both historically andcontemporaneously a common feature of anti-complementprotein aAb in many patients across the reviews and primaryresearch in this collection.Another major commonality is the importance of promptdetection of aAb followed by rapid delivery of clinicalintervention to achieve optimal outcomes, eculizumab beingparticularly effective in many studies despite not altering aAbtiter. Interestingly, Zhao et al. also outlined the potential foreculizumab to halt complement dysregulation at the level ofC5 in the presence of C5 nephritic factors, again suggestingrationale for its use where high tire anti-complement aAbare identified early in the disease course. Through the use ofhighly defined control populations, Valoti et al. re-affirmed thegenetic and environmental aspects of the development of anti-FH aAb clarifying the complexity of both the genesis and patho-mechanistic outcomes associated with anti-FH aAb. Wang andXia provide a stellar review of anti-dsDNA aAbs allowing aside by side comparison of the commonality and key differencesnoted to anti-complement aAbs. For instance, we are remindedthat antigen presentation pathways and loss of tolerance areunderappreciated in the genesis of anti-complement protein aAb,and that similar mechanisms must lie behind breaks in toleranceacross these diseases.AAb targeting to cell surfaces in the kidney generatesmultifaceted immune activation through direct stimulation ofcells as is highlighted in the review of autoimmune membranousnephritis by Liu et al. Activation of cells through IC deposition,both directly and indirectly via multiple signaling pathways,exemplifies the challenges that are faced in deciphering themechanisms that drive kidney disease. Non-lethal effects ofcomplement activation are a significant factor in endothelial,epithelial, podocyte, and tubulointerstitial injury in the kidney.This is further confirmed through the study by Goutaudier et al.focused on C5b-9 as a biomarker of poor prognosis in thecontext of antibody mediated rejection, suggesting that assemblyofMACon renal tissues, understandably, is amarker for themoresevere cases of Ab mediated rejection, ineffective complementregulation and potentially a driver of GBM structural changes.Rizk et al. present a clear and compelling case for controlof complement hyperactivity in IgA Nephropathy (IgAN).Historically it is well-appreciated that C3 deposition is extremelycommon in the glomeruli of patients with IgAN and ourknowledge of the autoimmune process in IgAN is arguably themost developed. Altered self, driving auto-immunity–epitopedrift, failure to correctly solubilize or clear the resultant ICsystemically, and a failure to clear deposited IC in the kidneydue to continued load drives AP activation and C3 deposition inthe glomerular mesangium in a vicious cycle similar to other IC-driven disease discussed here. All in all, compelling evidence isgiven that restoration of the finely balanced control of the AP andLP in IgANmay have benefit formany patients, and together withmost diseases discussed herein, with the number of complement-directed drugs coming to the clinic, targeted options for thetreatment of these diseases may soon be at hand.AUTHOR CONTRIBUTIONSKM wrote the initial draft of the editorial, this was reviewedprincipally by BD with comments from AF-A and M-AD-D.All authors contributed to the article and approved thesubmitted version.FUNDINGKM thanks UKRI, Kidney Research UK and the NorthernCounties Kidney Research Fund for supporting his research inthis area.ACKNOWLEDGMENTSWe thank Dr. Isabel Y. Pappworth for proof readingthis Editorial.Conflict of Interest: The authors declare that the research was conducted in theabsence of any commercial or financial relationships that could be construed as apotential conflict of interest.Copyright © 2020 Marchbank, Frazer-Abel, Dragon-Durey and Dixon. This is anopen-access article distributed under the terms of the Creative Commons AttributionLicense (CC BY). The use, distribution or reproduction in other forums is permitted,provided the original author(s) and the copyright owner(s) are credited and that theoriginal publication in this journal is cited, in accordance with accepted academicpractice. No use, distribution or reproduction is permitted which does not complywith these terms.Frontiers in Immunology | www.frontiersin.org 2 September 2020 | Volume 11 | Article 591338

Editorial: Autoantibodies in Kidney Diseases

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