Kooten, C. van

Mok, C.C.

Pusey, C.D.

Teng, Y.K.O.

Vaglio, A.

Leiden University Scholary Publications

Editorial: immune monitoring responses in renal autoimmunediseasesTeng, Y.K.O.; Pusey, C.D.; Vaglio, A.; Mok, C.C.; Kooten, C. vanCitationTeng, Y. K. O., Pusey, C. D., Vaglio, A., Mok, C. C., & Kooten, C. van. (2021). Editorial:immune monitoring responses in renal autoimmune diseases. Frontiers In Immunology, 12.doi:10.3389/fimmu.2021.722791 Version: Publisher's VersionLicense: Creative Commons CC BY 4.0 licenseDownloaded from: https://hdl.handle.net/1887/3279556 Note: To cite this publication please use the final published version (if applicable).Frontiers in Immunology | www.frontiersin.Edited and reviewed by:Betty Diamond,Feinstein Institute for MedicalResearch, United States*Correspondence:Y. K. Onno Tengy.k.o.teng@lumc.nlSpecialty section:This article was submitted toAutoimmune andAutoinflammatory Disorders,a section of the journalFrontiers in ImmunologyReceived: 09 June 2021Accepted: 14 June 2021Published: 29 June 2021Citation:Teng YKO, Pusey CD,Vaglio A, Mok CC andvan Kooten C (2021) Editorial:Monitoring Immune Responses inRenal Autoimmune Disease.Front. Immunol. 12:722791.doi: 10.3389/fimmu.2021.722791EDITORIALpublished: 29 June 2021doi: 10.3389/fimmu.2021.722791Editorial: Immune MonitoringResponses in RenalAutoimmune DiseasesY. K. Onno Teng1*, Charles Dickson Pusey2, Augusto Vaglio3, Chi Chui Mok4and Cees van Kooten11 Center of Expertise for Lupus-, Vasculitis- and Complement-Mediated Systemic Autoimmune Diseases, Department ofInternal Medicine—Nephrology Section, Leiden University Medical Center, Leiden, Netherlands, 2 Centre for InflammatoryDisease, Department of Immunology and Inflammation, Imperial College London, Hammersmith Hospital, London,United Kingdom, 3 Department of Biomedical, Experimental and Clinical Sciences “Mario Serio”, University of Firenze, andNephrology and Dialysis Unit, Meyer Children’s Hospital, Firenze, Italy, 4 Division of Rheumatology, Department of Medicine,Tuen Mun Hospital, Hong Kong, Hong KongKeywords: Glomerulonefritis, renal autoimmune diseases, Lupus Nephritis, ANCA - associated vasculitis,membranoproliferative glomerulonephritis (MPGN)Editorial on the Research TopicMonitoring Immune Responses in Renal Autoimmune DiseaseExciting times for the field of renal autoimmune diseases have begun. In 2021, for the first time, twonew drugs belimumab (1) and voclosporin (2) are approved for the treatment of lupus nephritis (LN)(1, 2). Other novel targeted therapies demonstrate clinical efficacy in large, randomized trials, such asavacopan for ANCA-associated vasculitis (AAV) (3), imlifidase for Goodpasture’s disease and iptacopanfor IgA nephropathy (IgAN). Pathogenic molecules are specifically targeted by new drugs that help touncover novel aspects of disease mechanisms leading to glomerulonephritis. Simultaneously, the field isboosted by novel big data technologies on the single cell levels such as high-sensitive multi-color flowcytometry, single-cell genomics (single-cell RNA sequencing - scRNAseq), single cell metabolomics andproteomics. The novel treatment options in renal autoimmune diseases almost simultaneously requirenew immunomonitoring tools. ‘Immunomonitoring’ includes the wide range of approaches tomonitoring immune responses by the cellular immune system (e.g. T-cells, B-cells, plasma cells,dendritic cells, neutrophils etc.), or by the humoral immune system (e.g. cytokines, (auto-)antibodies,urinary markers, etc.). Monitoring relevant immune responses in patients with renal autoimmunediseases helps us to better understand a) the underpinning immunological pathophysiology of thesediseases; b) the beneficial effects of novel treatments on autoimmunity; and c) can potentially helpdoctors and patients guide a personalized treatment strategy, adding information on immunological(non-)response to a clinical (non-) response treatment and on disease prognosis. In the present ResearchTopic, we have been able to collect for you a vast amount of research addressing novel ways and the roleof immunomonitoring in the broad range of renal autoimmune disease including LN, AAV, IgAN,idiopathic membranous nephropathy (iMN) and complement-mediated disease (CMD).IMMUNOMONITORING IN LUPUS NEPHRITISA review by professor Rekvig sets the stage for this Research Topic by eluding to the fundaments ofimmunomonitoring in SLE/LN. It addresses the issue whether, from a principal point of view,org June 2021 | Volume 12 | Article 7227911Teng et al. Editorial: Immune Monitoring in Renal Autoimmune Diseasesanti-dsDNA antibodies can be accepted as a clinical biomarkerfor SLE, without clarifying what we define as an anti-dsDNAantibody, and in which biologic contexts these antibodies appear.The group of Wu et al. addressed the epitope spreading of anti-C1q autoantibodies in LN with regard to the “anti-C1q A08antibodies”. These are part of the anti-C1q antibody family, whichrecognize nearly complete cryptic epitope in ELISA. Of note, theseanti-C1q antibodies recognize the exposed epitope of C1q coated onan ELISA plate. C1q A08 was demonstrated to be important foractivation of classical complement pathway and is an importantcontributor to pathologically relevant anti-C1q antibodies in LN.The group of Hong et al. provided an overview of the recentadvances in our understanding of renal tubular epithelial cells inLN, and the potential role of tubular epithelial cells as biomarkersin the diagnosis, prognosis, and treatment of LN, as well as thefuture therapeutic potential of targeting the tubulointerstitiumfor the treatment of patients with LN. In line with this review,several newly identified urine biomarkers, including monocytechemoattractant protein-1 (MCP-1), neutrophil gelatinaseassociated lipocalin (NGAL), TNF-like WEAK inducer of apoptosis(TWEAK), and vascular cell adhesion molecule-1 (VCAM), areproteins that may arise directly from inflamed kidneys and havebeen promising in monitoring LN disease status. In this ResearchTopic, the group of Zhang et al. demonstrated that the urinarybiomarker sCD163 outperformed C3, C4, urinary protein-to-creatinine ratio, or anti-dsDNA antibody in discriminating non-proliferative LN class II or V from proliferative LN class III or IV. Apromising finding that can help identifying active LN patients inwhom a renal biopsy could be avoided.Lastly, two studies in this Research Topic address cell-directedimmunomonitoring in LN. With respect to T-cells, the group ofYe et al. demonstrated significant differences in TCR diversity andusage of TRBV/TRBJ genes between SLE patients and healthycontrols, identifying a set of signature V–J combinationscharacteristic for their SLE cohort. Further research in this fieldmay facilitate the development of novel immune biomarkers.Withrespect to B-cells, the group of Yap et al. explored B-cell subsetsdemonstrating an exhaustion of the naïve B-cell subset in the mostactive and relapsing LN patients. This observation relates to thephenomenon of ‘B-cell hyperactivation’ in LN and the groupdemonstrated that microRNA-148a is an important mediator andmight be a potential therapeutic target in LN.IMMUNOMONITORING IN IMNThe group of Liu et al. reviews the striking low quantity ofinflammatory cells in the kidney of iMN patients, related to theimmune responses leading to anti-podocyte IgG4 autoantibodiesin iMN. The expanding spectrum of anti-podocyte antibodiesidentified in iMN patients is reviewed by the group of Tesarand Hruskova.Both reviews set the stage for the findings by the group ofCremoni et al. who demonstrated a dysregulated cytokinebalance skewed towards Th17 immune responses in iMN, withworse prognosis with more relapses and thromboembolic events.Frontiers in Immunology | www.frontiersin.org 2Lastly, the group of Huang et al. demonstrated anti-PLA2Rautoantibodies in patients with autoimmune thyroid disease,notably Hashimoto hypothyroiditis, which is associated withproteinuric AutoImmune Thyroid Disease (AITD) associatednephropathy in 10% of the cases. Given the commonality of anti-PLA2R autoantibodies in these overlapping disease, thiscommon pathologic substrate may help identifying thosepatients that could profit from immunosuppressive or B-celltargeted therapies.IMMUNOMONITORING INANCA-ASSOCIATED VASCULITISMonitoring the immune responses in AAV patients is very muchdirected at dissecting the underpinning mechanisms of anti-neutrophil cytoplasmic autoantibodies (ANCAs). The group ofGranel et al. reflects on the Kurlander effect of PR3-ANCAautoantibodies and the arguments supporting the existence ofpathogenic as well as non-pathogenic PR3-ANCAs, which is arelevant concept when employing immunomonitoring in AAV.Subsequently, the group of Thompson et al. investigated serialmeasurements of PR3-ANCA in AAV patients and their relationto non-response to induction treatment (or vice versa, achievingremission to treatment) and prediction of future relapses Inconjunction, the group of van Dam et al. demonstrated a strongreduction in circulating B-cells after treatment of AAV patients withthe B-cell depleting agent rituximab (RTX). However, whenemploying high-sensitivity flow cytometry as an immunomonitoringtool, RTX treatment never resulted in complete B-cell depletionand residual ANCA-specific memory B-cells remained detectablewhich opens a whole, new field of immunomonitoring in AAVpatients undoubtedly warranting further research.IMMUNOMONITORING IN COMPLEMENT-MEDIATED DISEASES, IGANEPHROPATHY AND OTHER RENALAUTOIMMUNE DISEASESWith respect to IgAN, the group of Selvaskandan et al. provides atruly complete overview of the immense progress made inidentifying and validating new biomarkers to facilitatepersonalization of prognostication and treatment of IgAN.With respect to CMDs, the group of Gao et al. reviewed thedual roles of the C3a/C3aR interactions, that can exert anti-inflammatory or pro-inflammatory effects depending on the typeof kidney disease, with the aim of understanding in-depth itscontroversial roles and its potential therapeutic value.Lastly, the group of Ramponi et al. reviewed the current literatureto provide guidance on serum biomarkers that could support furthertesting for kidney involvement in primary Sjögren syndrome (pSS).Patients with pSS typically present with proximal renal tubularacidosis, distal renal tubular acidosis and/or acute (on chronic)kidney impairment for which the most classical kidney lesions areJune 2021 | Volume 12 | Article 722791Teng et al. Editorial: Immune Monitoring in Renal Autoimmune Diseasestubulointerstitial nephritis (TIN) and membranoproliferativeglomerulonephritis (MPGN).CONCLUSIONThe present Research Topic aims to foster knowledge anddiscussion on investigating and understanding relevantpathological mechanisms underpinning renal autoimmunediseases. As such, these collective research efforts strengthen ourImmuno-nephrology community’s capabilities to translating thewealth of data, mostly derived from recent technological advances,into useful discoveries for clinical applicability. Ultimately, themonitoring of the relevant immune phenomena in patients withFrontiers in Immunology | www.frontiersin.org 3renal autoimmune diseases will lead to useful intervention toinfluence disease progression with effective targeted drugs.AUTHOR CONTRIBUTIONSYT and CK prepared the manuscript. All authors contributed tothe article and approved the submitted version.FUNDINGThe work of YT is supported by the Dutch Kidney Foundation(17OKG04) and the Netherlands Scientific Organisation.REFERENCES1. FurieR,RovinBH,HoussiauF,MalvarA,TengYKO,ContrerasG, et al. Treatmentof Lupus Nephritis With Belimumab: A 2-Year Randomized Controlled Trial.N Engl J Med (2020) 282(12):1117–28. doi: 10.1056/NEJMoa20011802. Rovin BH, Teng YKO, Ginzler EM, Arriens C, Caster DJ, Romero-Diaz J, et al.Voclosporin Efficacy and Safety in Lupus Nephritis (AURORA 1): A Phase 3Double-Blind, Randomised, Multi-Centre, Placebo-Controlled Trial. Lancet(2021) 397(10289):2070–80. doi: 10.1016/S0140-6736(21)00578-X3. Jayne DRW, Merkel PA, Schall TJ, Bekker Pfor the ADVOCATE Study Group.Avacopan for the Treatment of ANCA-Associated Vasculitis. N Engl J Med(2021) 384:599–609. doi: 10.1056/NEJMoa2023386Conflict 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 © 2021 Teng, Pusey, Vaglio, Mok and van Kooten. This is an open-accessarticle distributed under the terms of the Creative Commons Attribution License(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 thatthe original publication in this journal is cited, in accordance with acceptedacademic practice. No use, distribution or reproduction is permitted which doesnot comply with these terms.June 2021 | Volume 12 | Article 722791

Editorial: immune monitoring responses in renal autoimmune diseases

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