BRIEF REVIEW www.jasn.org

Targeting B Cells and Plasma Cells in Glomerular Diseases: Translational Perspectives

Eva Schrezenmeier,1 David Jayne,2 and Thomas Dörner3

1Divisions of Nephrology and Intensive Care, and 3Rheumatology and Clinical Immunology, Department of Medicine, Charité Universitätsmedizin Berlin, Campus Mitte, Berlin, Germany; and 2Department of Medicine, University of Cambridge, Cambridge, United Kingdom

ABSTRACT The unique contributions of memory B cells and plasma cells in kidney diseases idiopathic membranous nephropathy remain unclear. In this review, we evaluate the clinical experience with treatments (IMN). In contrast, SLE did not show directed at B cells, such as rituximab, and at plasma cells, such as proteasome in- similarly convincing responses to CD20 hibition, to shed light on the role of these two B lineage compartments in glomerular targeting. In chronic antibody-mediated diseases. Specifically, analysis of these targeted interventions in diseases such as rejection (ABMR), the addition of PC ANCA-associated vasculitis, SLE, and antibody-mediated transplant rejection per- targeting agents (e.g., the proteasome in- mits insight into the pathogenetic effect of these cells. Notwithstanding the limita- hibitor bortezomib) appears to be bene- tions of preclinical models and clinical studies (heterogeneous populations, among ficial, with less evidence for rituximab.4 others), the data suggest that memory B and plasma cells represent two engines of Currently available data from more se- autoimmunity, with variable involvement in these diseases. Whereas memory B cells lective immune targeting suggests that and plasma cells appear to be key in ANCA-associated vasculitis and antibody- the pathogenic relevance of memory B mediated transplant rejection, respectively, SLE seems likely to be driven by both cells and PCs may vary between autoim- autoimmune compartments. These conclusions have implications for the future de- mune diseases (reviewed recently5), im- velopment of targeted therapeutics in immune-mediated renal disease. proving our understanding of individual diseases. J Am Soc Nephrol 29: 741–758, 2018. doi: https://doi.org/10.1681/ASN.2017040367 Here we will take a reverse translational perspective to learn from the clinical use of Bcell–directed therapies such as anti- CD20 or therapies that target the PC com- In health, memory B cells and plasma recirculate upon antigen re-exposure. partment in renal autoimmunity. cells (PCs) comprise important but Overall, memory B cells and PCs form independently regulated compartments two immune defense lines that allow pres- 1 of our immunologic memory (Figure 1). ervation of previous immune encounters INDUCTION OF MEMORY B CELLS Humoral immunity is key to the patho- by antibodies produced by long-lived PCs AND PCS genesis of many autoimmune renal dis- and a dynamic component to adapt hu- eases. Here B cells, when recognizing moral immunity by memory B cells. The Distinct PC subsets can be induced via (auto)antigens and receiving appropriate two cellular subsets ensure stability and different pathways (Figure 1). First, B fl fi T cell help, can differentiate into short- exibility to maintain a suf cient B cell cells from the B1 cell lineage, which lived PCs, memory B or long-lived PCs lineage defense. The extent to which these have been mainly studied in mice and also termed memory PCs2. However, their “two engines” of B cell lineage memory detailed contributions to different kidney contribute to different renal autoimmune diseases are not known. diseases is not fully understood, but is Published online ahead of print. Publication date Long-lived PCs are considered ulti- likely to differ between disorders. available at www.jasn.org. mately differentiated, bone marrow In this context, clinical experiences Correspondence: Dr. Thomas Dörner, Department (BM) resident cells secreting high-affinity with therapeutics selectively targeting of Medicine/Rheumatology and Clinical Immunol- + 2 ogy, Charité Universitätsmedizin Berlin, Campus antibodies that disseminate through the CD20 memory B cells but not CD20 Mitte, Berlin, Germany. Email: thomas.doerner@ body, whereas memory B cells3 can rap- PCs provided interesting lessons (Figure charite.de idly proliferate in a clonally and antigen 2A), e.g., the response to rituximab in Copyright © 2018 by the American Society of specific manner, and differentiate and ANCA-associated vasculitis (AAV) and Nephrology

J Am Soc Nephrol 29: 741–758, 2018 ISSN : 1046-6673/2903-741 741 BRIEF REVIEW www.jasn.org

Figure 1. Distinct developmental and differentiation pathways of normal B cells. B1 and B2 B cell lineages appear to be independently regulated and undergo tightly controlled differentiation into certain memory B and PC subsets (Adapted from Dörner T et al.187

lack a defined phenotype in humans, switch, first producing memory B cells Most but not all memory B cells have can form short-lived PCs, which pro- and subsequently long-lived PCs13 with undergone class-switch recombination, duce polyreactive IgM for immediate increasing affinity. It has long been sug- typically from IgM to IgG, and carry so- defense. Second, B cells from the B2 gested, but now experimentally proven, matically hypermutated IgV gene re- cell lineage can form short-lived PCs in that memory B cells can also develop in a arrangements16,17 as one signature of aTcell–independent manner (so-called T cell–dependent, but germinal center– previous T cell encounters. Loss of IgD 2 marginal zone B2 cells), for example by independent pathway.14 Bcelllineage expression (IgD )identifies B cells that stimulation with T cell-independent an- differentiation paths are summarized in have undergone class-switch recombi- tigens such as pneumococcal capsular Figure 1. The bulk of the data reported nation. Switched memory B cells de- polysaccharides, and predominantly se- above has been obtained from preclinical velop during T cell–dependent germinal crete low-affinity IgM antibodies.6,7 models, although it remains to be delin- center responses.13 In addition to Ig sub- Moreover, B2 lineage cells are the main eated which differentiation pathway(s) class B cell receptor (BCR) expression, source of long-lived PCs and memory B and B cell lineages are involved in certain other phenotypic B memory markers cells upon activation by cognate T cells autoimmune conditions. have been identified. Here, expression in germinal centers.8 The generation of of CD27 serves as a universal marker long-lived PCs is the result of a two-step for memory B cells in healthy donors. process. First, an extrafollicular response MEMORY B CELLS The BCR of memory B cells shows a leads to the generation of short-lived ac- high affinity to the immunizing antigen tivated B cells, of which some re-enter the The definition of a memory B cell com- compared with naïve B cells caused by B cell follicle and become plasmablasts prises an antigen-experienced, nonpro- using affinity-matured and somatically in a T cell–dependent pathway. Subse- liferating and, in the absence of antigen, hypermutated BCR genes.18 Memory B quently, plasmablasts migrate through persisting cell15 that responds more rap- cells that emerge from the T cell–dependent the blood stream and reside as long-lived idly and efficiently when re-exposed to but germinal center–independent PCs primarily in BM niches, possibly also antigen. In contrast to sessile PCs, mem- pathway do not show somatic hypermu- in inflamed tissues.9,10 It is currently de- ory B cells recirculate and scan the body tations, and thus are not affinity ma- bated whether a small number of BM continuously. Their phenotype does not tured.19 After a given immune response, memory PCs can be induced indepen- differ between certain lymphoid organs, memory B cells must repress their acti- dently of T cells.11,12 The germinal center and they do not depend on the presence vation program and rest in a quiescent response is a time-regulated developmental of the spleen or tonsil.3 state for a long period to maintain their

742 Journal of the American Society of Nephrology J Am Soc Nephrol 29: 741–758, 2018 www.jasn.org BRIEF REVIEW

Figure 2. Interventions and their potential to target distinctly B lineage subsets and plasma cells. (A) Principles of direct (anti-CD20, anti- CD22) and indirect targeting of B cells and PCs (anti-BAFF or anti-APRIL strategies) have preferential effects on naïve versus memory B cells and PCs. (B) Principle of unspecific B cell and PC targeting, i.e., by proteasome inhibition or autologous stem cell transplantation (ASCT) with or without antithymocyte globulin (ATG) as well as mycophenolate mofetil (MMF) or cyclophosphamide. There appears to be a distinct susceptibility of memory B cell and PC dependent on the pharmacologic mechanisms. memory capacity.20 Upon antigen reacti- is not clear if they result from incomplete high-affinity antibodies and reside preferen- vation, memory B cells become activated germinal center responses, increased extra- tially inthe BM. Onlyafew plasmablasts that and can differentiate either into PCs or follicular activity and/or enhanced T cell– arise from the germinal center response mi- further mature by re-entering the germi- independent B cell activation. Usually, these grate through the blood stream to become nal center for additional affinity matura- cells carry characteristics of B cell memory memory PCs.9 Crucialforthesurvivalof tion.21 The involvement of memory B (e.g., mutated IgV genes), expressed costi- a plasmablast to become an ultimately dif- cells during resolution of an immune re- mulatory molecules, or lacked an active ferentiated, long-lived PC is that they find sponse and the mechanisms by which res- ABCB1 transporter as functional character- appropriate soluble and insoluble (niche) ident memory B cells are prevented from istic of memory B cells. It is currently not survival conditions, whereas no postgerminal uncontrolled activation remain unclear clear if these abnormalities of B cell memory center selection processes of PCs are known. for immunity as well as autoimmunity. are a source of autoimmunity or result of Long-lived PCs, also called memory PCs, Notably, disturbances of circulating overly active immune activation. find optimal survival conditions in the memory B cells in patients with chronic The role of T cell–dependent memory BM in healthy individuals at the end of a immune activation have been reported in B cell induction in SLE, AAV, and ABMR competitive journey starting as an early B chronic autoimmune conditions,22,23 has been concluded from molecular data lineage cell. such as SLE,22,24 rheumatoid arthritis of Ig switched, hypermutated autoanti- As direct PC precursors, plasmablasts (RA)25 or in HIV infection26 compared bodies characteristic of these diseases,30–32 express the C-X-C chemokine receptor with healthy controls. In this context, and histologic data of germinal center-like type 4 (CXCR4)35 and downregulate 2 2 enhanced CD27 IgD B cells as well as structures in affected tissues.33,34 CXCR5 and CXCR7 when they start to 2 2 CD27 IgD coexpressing CD95+,27 migrate toward the BM. The BM survival CD21low28 or intracellular spleen tyro- niches are composed of stromal cells ex- sine kinase Sykhigh29 were found. There PCS pressing C-X-C motif chemokine ligand is a possibility that these abnormalities re- 12 (CXCL12) (ligand of CXCR4) and vas- sult from an overly active immune system PCs are responsible for maintaining serum cular cell adhesion protein 1 (VCAM1).36 with enhanced B cell differentiation, but it antibody levels by continuously producing Other cell types such as megakaryocytes,

J Am Soc Nephrol 29: 741–758, 2018 B Cells and Plasma Cells in Glomerular Diseases 743 BRIEF REVIEW www.jasn.org eosinophils, and basophils contribute to and relevant autoantibodies50–52 provide nondividing PC memory is not affected by the production of survival factors such the basis that activation of B cells has taken therapies dependent on proliferation.56 as a proliferation-inducing ligand (APRIL), place. However, the particular role of B B cell-activating factor (BAFF or BLyS), or cells independent of PC producing auto- IL-6, as well as adhesion molecules.37–39 antibodies has only been clearly demon- CORTICOSTEROIDS The number of available niches in the strated in a lupus model.52,53 Tables 1 and BM or its capacity appears to be limited 2 summarize key features, advantages, and Corticosteroids interrupt multiple steps of and serves as a regulatory factor for serum disadvantages of the most instructive an- the immune response with genomic and Ig levels. Recently, it has been debated imal models in which B cell and PC con- nongenomiceffects,but are mainly related if there is a physical or rather cell type– tributions have been studied within AAV, to the inhibition of cytokine transcription dependent functional BM niche.40 lupus nephritis, and ABMR. via blocking transcription factors. This Besides the BM, other tissues can also leads to the inhibition of certain ILs, offer survival niches in states of chronic thereby depleting T cells (IL-2) and eosin- inflammation. These niches disappear TARGETING MEMORY B CELLS ophils (IL-5), interrupting macrophage when the inflammation is resolved.41–43 VERSUS TARGETING MEMORY function (IL-1, TNF-a), and increasing Once it was thought that survival niches PCS IN HUMAN DISEASE neutrophil release from the BM and neu- harbor almost exclusively highly-affinity trophil migration to the sites of inflamma- matured PCs, but other studies revealed Because expression of certain surface tion.57 Less is known about the detailed that immature PCs can access survival markers on memory B cells and PCs are effect of corticosteroids on B cells. It has niches.44,45 Recent data suggest that distinct, selective targeting by using spe- been suggested that B cells are not signif- there is heterogeneity of PCs in human cific agents is a clinical possibility. Mem- icantly inhibited by steroids and Ig levels BM. Here, a stable and highly differenti- ory B cells show the phenotype of mature are only slightly decreased.58 However, 2 ated CD19 PC fraction with a distinct B cells expressing CD19, CD20, and CD22 high-dose glucocorticoids affects PCs phenotype (CD56+,HLA-DRnegative, besides the above discussed surface mark- and has been widely used in myeloma, es- CD44negative etc.)andalessmature ers. PCs differ on the basis of their larger pecially dexamethasone. Recent data from CD19+ PC fraction exist in human sizeandgranularity,aswellaslossofCD20 children with steroid-responsive ne- BM, which suggests that further differen- and CD22 expression, downregulation of phrotic syndrome show that B cell num- tiation even within the BM PCs is a pos- CD19, and expression of CD38 and, to bers decline under corticosteroid therapy sibility.46 These human PC subsets in the large extent, CD138.8 Memory B cells ex- and that especially peripheral memory B BM have been confirmed subse- press three B cell cytokine receptors, cells further decline after corticosteroid 2 quently.47,48 Because CD19 PCs usually BAFF receptor (BAFF-R), transmem- cessations.59 In patients with autoim- enriched in human BM were also found brane activator and CAML interactor mune hemolytic anemia, splenic germinal in autoimmune tissues including kidney (TACI), and B cell maturation antigen center B cells and circulating plasmablasts transplant rejection,46 it needs to be fur- (BCMA), whereas PCs have very dimin- were largely suppressed in patients under ther delineated what factors are involved ished BAFF-R and TACI expression but long-term corticosteroid therapy.60 in their induction and/or maintenance in receive survival signals through BCMA. autoimmunity. Notably, a potential role There is differential signaling of BLyS/ of T cells within the BM has been sugges- BAFF and APRIL through these recep- ANTI-CD20 MONOCLONAL ted recently. Here, regulatory T cells tors. We will briefly summarize certain ANTIBODIES (Treg) cells share a particular niche with agents that have an effect on PCs or PCs in CD11c+ BM cells and appear to (memory) B cells. Anti-CD20 monoclonal antibodies, such as regulate PC survival via CTLA-4.49 This the type 1 antibodies rituximab, ofatumu- suggeststhatTcellshavedistinctbut mab, and ocrelizumab, largely deplete pe- largely unknown functions determining CONVENTIONAL ripheral B cells including memory B cells the lifestyle of PCs and mandates further IMMUNOSUPPRESSANTS from the peripheral blood but not always in studies. the BM,61 lymph nodes,62 or synovium.63 2 Although a number of agents have an effect CD20 pro-B cells and PCs are not targe- on B cell subsets, nonproliferating memory ted by these antibodies (Figure 2A), but ANIMAL MODELS Bcellshavebeenshowntobemoreresistant they lead to impaired generation of plas- to conventional immunosuppressants mablasts and short-lived PCs. These Different animal models for SLE, the two such as cyclophosphamide,54 as well as to monoclonals act by several mechanisms, AAV conditions (myeloperoxidase mycophenolate mofetil55 (Figure 2B). Fur- including antibody-dependent cellular cy- [MPO] or proteinase 3), and ABMR ther, generation of plasmablasts and short- totoxicity, complement-dependent cyto- could provide evidence for the role of lived PCs are sufficiently inhibited by toxicity, and apoptosis induction.64 Novel B lineage cells. Here analyses of T cells conventional immunosuppressants, and type 2 monoclonal anti-CD20 antibodies,

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29: 2 Table 1. Indicators of the presumed pathogenic role of CD20+ B cells and CD20 PCs on the basis of available data of therapeutic responses to different B lineage 741 cell directed agents – 5,21 el n lsaClsi lmrlrDiseases Glomerular in Cells Plasma and Cells B 2018 758, Glomerular Disease AAV SLE ABMR Response to... Anti-CD20 (rituximab) Experience from RCTs leading to approval Experience from two RCTs and Experience from one RCT and several and several observational studies. several observational studies. cohort studies. Effective in remission induction in and RCTs failed to reach primary end points No difference in RCT of acute ABMR.189 noninferior to cyclophosphamide.106,107 in renal140 and nonrenal SLE.188 Superior to azathioprine in maintenance Meta-analysis of published data and EULAR Partial success in retrospective of remission.108 and ERA-EDTA recommendations warrant cohort studies of acute ABMR.171 the use of rituximab.142,144 Meta-analysis of uncontrolled studies support No effect of rituximab in chronic ABMR.171 data from RCTs. Rituximab might be superior in relapsing disease.190 Proteasome inhibition Very limited experience. Limited experience from small case series. Limited experience from small cohort studies. (bortezomib) One patient with AAV refractory to rituximab Report of five patients with lupus nephritis, Bortezomib is able to reduce DSA successfully treated with bortezomib.119 three had complete remission after 6–12 mo.156 in most patients but graft survival remains very poor.181 Report of 12 patients with SLE, six with lupus nephritis. All patients responded to therapy.155 Pathogenic relevance of ... (Memory) B cells Regulatory B cells, but not memory B cells Antibody-independent mechanisms Memory B cells can be reactivated in predict relapse after rituximab therapy.104,105 e.g., autoantigen secondary transplantation upon antigen presentation, costimulation of T cells, re-exposure.191 production of regulatory cytokines.192 Reconstitution of memory B cell subset can predict disease flares after rituximab therapy.136,137 Long-lived PCs/ Materno-fetal transfer of anti-MPO antibodies Involved in the formation of immune complexes Responsible for the maintenance of serum autoantibodies led to vasculitis with pulmonary renal syndrome1 that lead to nephritis.192 DSA that cause transplant glomerulopathy.164 www.jasn.org 12 in neonates and can cause murine necrotizing crescentic GN.193 Pathogenicity of anti-PR3 antibodies is not entirely proven.194

RCT, randomized, controlled trial; EULAR, European League Against Rheumatism; ERA-EDTA, European Renal Association/European Dialysis and Transplant Association. REVIEW BRIEF 745 746 RE REVIEW BRIEF ora fteAeia oit fNephrology of Society American the of Journal

Table 2. Summary of the most relevant animal models of AAV, lupus nephritis, and ABMR with regard to B cell and PC function www.jasn.org Animal Model Kind of Intervention Key Feature Advantages and Disadvantages Reference AAV 2 2 Mpo / mice/ Transfer of anti-MPO antibodies or Induces necrotizing pauci-immune Mainly B cell but not Xiao et al.193 2 2 (Rag2 / ) mice splenocytes, generated by MPO GN and, in some cases, Tcell–dependent, immunization of MPO deficient mice. pulmonary capillaritis. Transfer of splenocytes: more severe neutrophils are required. disease with immune complex deposition in the glomeruli. Transfer of antibody alone: mild Only mild disease without granuloma disease but pauci-immune. formation. Disease induction strongly depends on genetic background.195 Depends on the passive transfer of antibodies. No cellular immunity. Wistar–Kyoto rats Immunization of Wistar–Kyoto rats with Leads to crescentic nephritis and Stable and severe disease induction. Little et al.196 human MPO and adjuvants. lung hemorrhage in all immunized rats. Depends on the passive transfer Chavelel et al.197 of antibodies. No cellular immunity. Disease induction strongly depends on genetic background. Humanized NOD- Transfer of patients’ PR3-ANCA IgG into Induction of hematuria, glomerular Very mild disease. Little et al.198 2 2 SCID-IL-2Rg / mice endotoxin-primed human-hematopoietic hypercellularity, and pulmonary Technically challenging. stem cell (HSC) mice, created using healthy capillaritis in a some of mice. Low level neutrophil reconstitution and donor (PR3) HSC. absence of human T cells due to mixed chimerism. Lupus nephritis New Zealand Black Spontaneous polygenic. Develop severe GN at 5–6 mo of age Difficult to use as a genetically Dixon et al.199 (NZB)/New Zealand and kidney failure at 10–12 mo modified model. Alleles have to Andrews et al.200

mScNephrol Soc Am J white (NZW) mice of age. Animals develop anti-nuclear be matched to NZB and F1 intercross antibodies without anti-Sm antibodies. NZW backgrounds. New Zealand mixes Spontaneous polygenic. Severe GN with an earlier onset No sex difference. Rudofsky et al.201 mice (NZM2328 compared with NZB/NZW F1. Morel202 and NZM2410) 29: 741 – 5,2018 758, mScNephrol Soc Am J

29: Table 2. Continued 741 –

5,21 el n lsaClsi lmrlrDiseases Glomerular in Cells Plasma and Cells B 2018 758, Animal Model Kind of Intervention Key Feature Advantages and Disadvantages Reference MRL/MpJ-FASlpr MRL is a polygenetic mouse model. Production of class-switched autoantibodies Model meets all of the ACR Dixon et al.199 (MRL/lpr) mice FASlpr mutation accelerates the (anti-DNA, Sm), end-organ disease including criteria for SLE. time course of murine disease. dermatitis, GN cardiovascular and lung disease. Mice that expressed a mutant transgene encoding Rapid and stable onset of Cohen et al.203 surface Ig but are unable to secrete Ig developed disease. nephritis in the absence of soluble autoantibodies. B cells with cognate BCR are essential for lupus nephritis via antigen-presentation to cognate T cells or other functions (cytokine, chemokine production, formation of germinal center). Andrews et al.200 Herlands et al.204 Chan et al.53 ABMR Mouse heterotopic Repeated passive transfer Animals develop chronic Depends on the passive transfer Uehara et al.205 cardiac allografts of alloantibodies. transplant arteriopathy. of antibodies. In B cell–deficient mice it was shown that No cellular immunity. chronic allograft vasculopathy was only observed in the presence of alloantibodies. No insights into the mechanism of antibody formation. Humanized CD52Tg Transgenic mouse model in which CD52 Animals show cardiac allograft Offers the possibility to study outcomes Kwun et al.206 (H-2K) mice is only expressed on T cells. vasculopathy, whereas animals of animals with continuous de novo. T cells are depleted by alemtuzumab without DSA show normal grafts.206 (anti-CD52) and de novo allospecific B cells and DSA but not alloreactive T cells arise in some animals. www.jasn.org RE REVIEW BRIEF 747 BRIEF REVIEW www.jasn.org such as obinutuzumab (GA 101), are pri- terminal unfolded protein response causing extrinsic and intrinsic characteristics of marily inducing cell death with a more pro- apoptosis81 and prevention of the activation memory B cell maintenance are far less found and lasting B cell depletion and are of NF-k light chain enhancer of activated B understood. currently under investigation in autoim- cells (NF-kB), which is crucial for PC sur- mune diseases.65 vival.82 Initial data were obtained for mul- tiple myeloma but proteasome inhibitors CLINICAL EXPERIENCES SUGGEST are toxic to non-neoplastic cells as well.83 DISTINCT ROLE OF MEMORY B TARGETING B CELL SURVIVAL Further, cells with high protein production, AND PCS IN DIFFERENT FACTORS such as PCs, are susceptible to proteasome GLOMERULAR DISEASES inhibition.84 Bortezomib is the most widely There are several approaches indirectly used proteasome inhibitor approved for the AAV targeting B cell and PC survival via cyto- treatment of mantle cell lymphoma and Small-vessel vasculitis, which is associated kine targeting. One is blocking BAFF or myeloma.85 The main limitation of borte- with autoantibodies against neutrophil cy- the related cytokine APRIL (Figure 2B). zomib is severe neurotoxicity that occurs in toplasmic antigens, manifests as a necrotiz- These cytokines bind to three different re- up to 30% of all patients, resulting in ther- ing inflammation of vessels with little or no ceptors expressed on B cells: BAFF-R, apy discontinuation,86 which is less with the Igandcomplementdepositioninthevessel TACI, and BCMA. BAFF-R exclusively new generation compounds carfilzomib87 wall. This lack of Ig deposit distin- binds BAFF,66 whereas both cytokines and delanzomib.88 guishes ANCA-associated GN (directed can bind to TACI and BCMA.67 APRIL, against MPO or proteinase 3) from immune binding to BCMA is crucial for the survival complex-mediated GN, e.g., found in lupus of PCs,68 whereas memory B cells do not ANTI-CD38 nephritis.98 In human kidney specimens of 2 depend on these survival factors.69,70 Sev- patients with AAV, B cell clusters with IgD eral biologic drugs targeting the BAFF/ The monoclonal daratumumab targets B cells forming germinal center-like BLyS and APRIL axis have been studied CD38, which is highly expressed on the sur- structures were found, whereas CD138- over the last years, including belimumab, face of short-lived PCs, long-lived PCs, and positive plasma was almost absent.99 T tabalumab, atacicept, and blisibimod. Be- myeloma cells,89 butonlyexpressedatlow cells that are present in the inflamed kid- limumabbindstosolubleBAFFandhas levels on lymphoid or myeloid cells and ney tissue mostly belong to a senescent been approved for the treatment of SLE.71 some other tissues.90 Daratumumab mon- memory T cell population, whereas the Tabalumab is a human mAb whereas bli- otherapy was recently approved for the number of memory T cells in circulation sibimod is a fusion polypeptide protein. treatment of refractory multiple myeloma is decreased, indicating their migration Both block biologically active BAFF72–74 on the basis of two studies.91–93 Also, the as effectors into the kidney.100,101 but development programs of tabalumab addition of daratumumab to standard Disturbances of peripheral B cell sub- in SLE have been cancelled after poor effi- care has shown favorable results,94,95 with sets have been described in patients with cacy results in clinical trials. Atacicept is a an overall acceptable safety profile.96 AAV. Here memory B cells are reduced in 2 TACI Ig fusion protein that blocks both Nonetheless, a high number (71% of patients with active disease,102 possibly BAFF and APRIL.75 So far, the effect of patients) of adverse reactions of cough, by recruiting B cells to the sites of in- these compounds on PCs becomes evident bronchospasm, and dyspnea were observed flammation or their differentiation into by the substantial reduction of all Ig classes upon infusion of daratumumab.93 Patients PCs. During remission memory B cell to different degrees, whereas the effect on with autoimmune diseases have not yet levels are restored.102 An imbalance of memory B cells is largely confined to the been treated with this antibody but it regulatory B cells, a B cell fraction that initial increase in peripheral blood likely appears to lead to a profound depletion of is commonly defined by the production related to their mobilization.76,77 plasma cells. of IL 10, a cytokine able to suppress T cells, has been reported.103 These regu- latory B cells are decreased in patients PROTEASOME INHIBITORS TARGETING PC HOMING AND with AAV. Diminished regulatory B cells SURVIVAL were found to predict relapse after ritux- Proteasome inhibitors are prototypic for imab therapy.103,104 The overall memory their effect on highly differentiated PCs Anumberofrecenteffortshavebeenmade B cell population did not correlate with with substantial endoplasmic reticulum to target certain factors involved in PC disease activity or the time to flare after B stress. They selectively target the 26S homing/migration or interfere with their cell depletion,104 whereas CD38++ pe- proteasome,78,79 which is needed for the survival in order to affect long-lived PCs ripheral PC and B cell activation have degradation of ubiquinated proteins.80 otherwise refractory to treatment (re- been reported to correlate with active Their cytotoxic effect causes accumulation viewed recently2), including autologous ANCA vasculitis.105 of misfolded proteins in the endoplasmic stem cell transplantation.97 Clinical expe- Anti-CD20 therapy with rituximab reticulum, leading to the activation of the riences are very limited. In contrast, the has been approved on the basis of clinical

748 Journal of the American Society of Nephrology J Am Soc Nephrol 29: 741–758, 2018 www.jasn.org BRIEF REVIEW studies for remission induction,106,107 surge seen after rituximab, due to the re- SLE and the expression of programmed and is also a valuable maintenance ther- duction of B cell BAFF-R clearance, pro- death 1 correlates with circulating plasma- apy,108 especially in refractory disease or motes autoreactivity in the reconstituting blasts and anti-dsDNA antibodies.127,128 patients not responding to cyclophos- B cell repertoire. BLyS/BAFF inhibition is The presence of these tertiary lymphoid phamide.109 Because the ANCA titers also effective in IMN, where it signifi- structures is associated with the local for- typically, but not always correlate with cantly reduces anti-PLA2R antibodies ti- mation of autoantibodies and tubular disease activity and are reliably reduced ters within 28 weeks (Clinicaltrials.gov basement membrane immune complexes by rituximab to a greater extent than identifier NCT01610492). in more active disease.124 seen with cyclophosphamide, they ap- There is little experience with agents All these data show that the interac- pear to be the product of short-lived targeting PCs in AAV. Bontscho et al.118 tion of B and T cells is critical in lupus PCs,110 which provides the basis for the reported that bortezomib is able to in- nephritis. In addition to the footprints of key role of autoreactive B cells in AAV. hibit anti-MPO–mediated necrotizing B cell abnormalities (autoantibodies and However, rituximab has also been effec- crescentic GN in mice by depleting immune complexes), continuous activa- tive in ANCA-negative patients with MPO-specific PCs in the spleen and tion of innate and the adaptive immunity granulomatosis and polyangiitis,111 and BM. A favorable effect of proteasome is operative. Here, T cells provide help to the presence of B cells in close proximity inhibition was also reported in one pa- B cells or are cytotoxic to glomeruli or to T cells and macrophages at sites of in- tient with AAV,119 but precludes any tubular cells.129 A key characteristic of flammation indicates alternative roles, firm conclusion in the absence of larger SLE T cells is their reduced IL-2 produc- such as antigen presentation, which sup- experiences. tion, which inversely correlates with port the disease process. The hypothesis enhanced IL-17 regulated by the tran- of the pathogenicity of ANCA is also SLE scription factor CREM-a.Moreover, supported by a case report in which fe- Lupus nephritis is the most common severe IL-2 as an essential growth and survival tomaternal transfer of anti-MPO auto- organ manifestation in SLE, seen in up to factor for Treg cells has been found to be antibodies led to vasculitis with pulmo- 50%ofcases.120 Histologically, it can pre- functionally deficient in patients with nary renal syndrome112 in the offspring. sent with a spectrum of glomerular, vascu- SLE.130 A number of genetic risk alleles Another case, however, did not develop lar, and tubulointerstitial lesions, including and epigenetic modifications altering GN or vasculitis upon transplacental germinal center-like structures in the inter- the gene expression and the function of transfer of MPO-ANCA.113 Amore stitium. Cytokine-mediated activation of certain T cell subsets in SLE appear to be direct correlation of autoantibody titers glomerular mesangial cells and in situ tu- involved.131 These abnormal T cell re- and response to therapy is present bulointerstitial macrophages promotes sponses can result in disturbances of B in IMN, where a fall in phospholipase the deposition of anti-dsDNA, anti-C1q, cellsinSLE.BecauseSLEpathology A2 receptor (PLA2R) antibody titers anti-nucleosome, and anti-glomerular apparently comprises pathogenic contri- exactly predicts reductions in protein- antibodies recognizing glomerular butions of memory B cells and PCs de- uria and correlates with the extent of structures—the formation of immune pendent on T helper cells, abnormal T proteinuria.114 complexes with complement deposition cell activation may represent a critical Circulating BAFF levels correlate with initiating renal damage.121,122 Circulating link.Proofforthisideaisverysmall, disease activity in AAVand therefore this neutrophil activation with neutrophil ex- but a recent phase 2 trial is using voclo- cytokine has been suggested as potential tracellular trap deposition in the glomeruli sporine in lupus nephritis.132 Alterna- treatment target.115–117 An ongoing trial may also be an initiating event in renal in- tively, therapies with an effect on T and is addressing the role of BAFF inhibition flammation. Anti-dsDNA antibodies B cell interaction (Figure 3) are attrac- in patients with AAV: BREVAS is evalu- represent a risk factor for lupus nephritis, tive. In addition, low-dose IL-2 has been ating belimumab in combination with with negative predictive value for renal out- studied in non-renal SLE133 and demon- azathioprine as maintenance of remission come in some studies.123 In addition to the strated some clinical efficacy, leading to after a standard induction regimen (Clin- typical presence of autoantibodies, anti- an increase of Treg cells in vitro134 and in icaltrials.gov identifier NCT01663623). body-independent mechanisms contribute vivo.135 This approach follows the hypothesis to to lupus pathogenesis. Lupus nephritis bi- The contribution of CD20+ and espe- selectively block enhanced BAFF and opsies contain interstitial B cell lymphocyte cially memory B cells became apparent reduce ANCA producing peripheral infiltrates that are organized along with by experience with B cell–depleting PCs and thereby affect AAV activity. A T cells and dendritic cells,124–126 and un- agents, such as rituximab. In several re- further study, COMBIVAS, is address- dergo further differentiation as in germinal ports the reconstitution of the memory ing the combination of BLyS/BAFF centers. Within these aggregates, T follicu- B cell subset after rituximab predicted blockade and anti-CD20 on the basis larhelpercellsareimportantforestablish- recurrence of active disease.136,137 This of two hypotheses: that local BLyS/ ing germinal centers to promote activation phenomenon has not exclusively been BAFF impairs B cell depletion at inflam- and differentiation of B cells.126 T follicular observedinSLEbutalsoinpatients matory sites and that the BLyS/BAFF helper cells are expanded in patients with with rheumatoid arthritis25,138 and

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IMN, and suggests that memory B cells However, there are conflicting data about delanzomib.88 Clinical experiences with contribute to the pathogenesis of these the interrelation of the cytokine levels of proteasome inhibition in lupus nephritis diseases. A reduction in autoantibody ti- BAFF and APRIL with lupus activity.148 rely only on bortezomib. Alexander ters, in contrast to AAV, did not always Notably, these studies found an associa- et al.155 reported 12 patients with predict the effectiveness of rituximab tion between response to belimumab refractory SLE including six patients therapy.139 Rituximab did not meet the and reductions in autoantibody titers, with nephritis. Musculoskeletal and mu- primary efficacy end point in a lupus ne- suggesting successful targeting of PCs. Al- cocutaneous manifestations improved phritis trial (LUNAR),140 partly due to though other compounds targeting BAFF, in all patients, and proteinuria signifi- aspects of the trial design. Clinical expe- such as tabalumab149,150 or atacicept151 cantly decreased in patients with nephri- riences141,142 in otherwise refractory pa- cotargeting APRIL, did not provide con- tis. A recently published study reports a tients support a clinical value that has led vincing clinical data, a more profound ef- beneficial effect with a decrease in creat- to recommendations as a second line fect on PCs reflected by Ig reductions inine in three of five patients with lupus agent by the American College of Rheu- was noted. Selective inhibition of the nephritis.156 A phase 2 study is currently matology143 and European League PC-relevant cytokines without sufficient investigating the safety and efficacy of Against Rheumatism-European Renal treatment of CD20+ memory B cells may bortezomib in patients with SLE (Clini- Association/European Dialysis and hold more promise. In this context, a se- caltrials.gov identifier NCT02102594). Transplant Association.144 Rituximab, quential approach of B cell depletion A phase 1 study in lupus nephritis with in combination with mycophenolate and BLyS/BAFF inhibition to influence the oral proteasome inhibitor ixazomib mofetil, has been reported in newly di- PC activity is being evaluated in lupus is underway (Clinicaltrials.gov identifier agnosed patients with lupus nephritis nephritis, the Rituximab and Belimumab NCT02176486). Although proteasome in- in a UK center,145 with a substantial for Lupus Nephritis (CALIBRATE) study hibition is often considered a PC-targeted rate of patients achieving complete re- (clinicaltrials.gov identifier NCT02260934) therapy, it has the advantage to cotarget PCs mission without use of oral glucocorti- and in extrarenal lupus, the BEAT-LUPUS but also affect other immune cells.155 Apo- coids. This study requires confirmation study.152 tential difference of lupus nephritis versus in treatment-naïve patients, whereas the Efforts to preferentially target the PC AAVisthateffectiveBlineagetherapyre- currently available data suggest that anti- compartment have been undertaken. In a quires cotargeting of memory B cells CD20 depletion alone may not be suffi- murine model of lupus-like nephritis, and PCs. cient in patients with established disease. short- and long-lived PCs were depleted In this population, the additional role of by bortezomib and lupus-like nephritis Kidney Transplantation PCs likely requires cotargeting. improved remarkably.83 These results In the transplant setting, donor-specific Belimumab has been approved for gen- were confirmed by Ichikawa et al.153 antibodies (DSA) are likely the main bi- eralSLEonthebasisofthesuccessfulphase and Seavey et al.,154 using the less toxic ologic reason for allograft injury and 3 studies BLISS-52146 and BLISS-76.147 proteasome inhibitors carfilzomib87 and loss.157 Their detection either pre- or post-transplant increases the risk of graft loss.158,159 DSA directly bind to the grafts and cause local inflammation and tissue damage through complement activation and human Fc gamma-mediated cytotoxicity, and also serve as opsonins that facilitate the activation of alloreactive T cells.160–162 These mechanisms lead to the development of transplant glomerulop- athy, the histologic feature of chronic ABMR.163 Long-lived PCs are responsible for the maintenance of long-term circulat- ing DSA, which are detectable in solid- organ transplant recipients and are associated with worse transplant outcomes.164 Quies- cent memory B cells appear to be reactiva- ted in cases of secondary transplantation in presensitized individuals. The best risk Figure 3. Immune intervention at key nodes of immune interaction in SLE. Targeting key management to avoid transplant glomerul- nodes of T cell and B cellinteraction holds promise to improve abnormal T helper cell activity opathy comprises transplantation without or enhanced regulatory T cell activity (i.e., using low-dose IL-2) that may also have the preexisting DSA159 and avoidance of trans- potential to normalize B lineage cell abnormalities. plantation with HLA mismatches, especially

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NCT02201576), and the Effect of BM- MSCs on Chronic AMR after Kidney Transplantation study (Clinicaltrials. gov identifier NCT02563340), will eval- uate the clinical value of bortezomib on chronic ABMR. Notably, levels of BAFF were found to be associated with the occurrence of trans- plant glomerulopathy183 and enhanced ABMR,184 thus BAFF targeting appeared an attractive option. However, a study of tabalumab for desensitization did not lead to clinically significant reduction of DSA,185 which may be taken as another indicator that outstanding long-lived PCs are a key challenge in this clinical Figure 4. Distinct role of B lineage and plasma cell functions in glomerular diseases. The setting. Studies of belimumab for pre- sites of induction and residence, however, remain to be delineated. transplant desensitization and at the time of transplantation are ongoing (clin- icaltrials.gov identifier NCT01025193). as class 2 HLA mismatches are a strong pre- Kidney transplantation permits com- An innovative approach to reduce HLA dictive biomarker for DSA.165 The induc- prehensive corresponding insights in tis- antibodies in the setting of desensitiza- tion of DSA requires interaction between B sue resident immunology. Just as in other tion of highly sensitized patients is the cells and antigen-specific CD4 T helper glomerular diseases, tertiary lymphoid use of the endopeptidase derived from cells. The presence of memory T cells before structures have been identified in kidney Streptococcus pyogenes (IdeS), which transplantation is associated with a poor grafts.173 Within the tertiary lymphoid cleaves IgG into F(ab9)2 and Fc frag- transplant outcome.166,167 ABMR and the structures an increase of activated mem- ments. IdeS leads to a complete IgG de- underlying importance of pathogenically ory CD4+ T cells and a decrease in T ficiency what makes it less attractive for relevant PCs producing DSA are a key target regulatory subsets (IL-10–producing long-term use in chronic ABMR.186 of immunotherapy to eradicate DSA. These Tr1 cells and Foxp3-positive Tregs) has However, early clinical experiences with strategies include plasmapheresis and im- been observed.174 Also PC-rich infil- IdeS in renal transplants provide addi- munoadsorption for the direct removal of trates have been found in renal allografts tional proof that targeting autoreactive DSA, intravenous Igs for immunomodula- and their occurrence was associated with PCs is key in targeting ABMR. tion,168 rituximab to deplete PC precursors, an increased risk of allograft failure in and targeting PCs by proteasome inhibi- the pediatric population.175 However, tion.169 Combined renal and allogeneic data on PC-rich infiltrates in the adult CONCLUDING REMARKS BM transplantation have also aimed to de- population are limited.176–178 To target pletePCsandinducetolerancewithoutthe the PC compartment, proteasome inhi- A number of preclinical models have need for antirejection therapy.170 bition has been included in the treat- supported the role of B lineage cells in B cell–directed therapy by rituximab ment repertoire. In a model of chronic glomerulopathies, but do not reflect the seems to be partially effective in acute allograft nephropathy, bortezomib re- complexity of human diseases. Interven- ABMRbutineffectiveinchronic duced antibody titers and depleted PCs tions in human disease have inspired a re- ABMR.171 Jackson et al.172 provided in- in the BM.179 The reduction of PCs was vision of the role of B cells and long-lived teresting evidence about long-lived PCs also observed in BM aspirates of two pa- (memory) PCs in these entities. Here, cur- in humans and the capacity of rituximab tients treated with bortezomib for hu- rently available data support a key role of B to interfere with relevant B cells as PC moral rejection.180 Several small case cells (likely memory and activated B cells) precursors when they compared DSA series report the effect of bortezomib in AAVand IMN, and long-lived PCs as a levels in patients who have been desen- treatment on graft survival, kidney func- pathogenic driver in chronic ABMR, sitized with or without rituximab. They tion, and DSA levels. Overall, patients whereas lupus nephritis appears to be un- found a greater reduction of DSA but a responded together with a reduction in der the influence of both B cells and PCs similar rate of DSA persistence, most DSA levels and a stabilization of kidney (Figure 4). As a consequence, the idea that likely explained by refractory long-lived function in refractory patients.181 The distinct immunopathogenic contribu- PCs, whereas the difference in DSA titers BORTEJECT (Clinicaltrials.gov identi- tions by memory B cells and PCs is also can be ascribed to memory B cells un- fier NCT01873157),182 the TRIBUTE probably related to distinct T helper cell dergoing differentiation into PCs. study (Clinicaltrials.gov identifier abnormalities requires consideration.

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ACKNOWLEDGMENTS 11. Bortnick A, Chernova I, Quinn WJ, Mugnier low frequency of somatic mutation. JIm- M, Cancro MP, Allman D: Long-lived bone munol 177: 3728–3736, 2006 marrow plasma cells are induced early in 24. Anolik JH, Barnard J, Cappione A, E.S. is supported by the Charité Junior Clinical response to T cell-independent or T cell- Pugh-Bernard AE, Felgar RE, Looney RJ, Scientist Program (Charité-Universitätsmedizin dependent antigens. JImmunol188: 5389– Sanz I: Rituximab improves peripheral B cell Berlin and the Berlin Institute of Health). Re- 5396, 2012 abnormalities in human systemic lupus er- lated support has been provided by projects 12. Bortnick A, Allman D: What is and what ythematosus. Arthritis Rheum 50: 3580– funded by the German Research Foundation should always have been: Long-lived plasma 3590, 2004 cells induced by T cell-independent antigens. 25. Roll P, Dörner T, Tony H-P: Anti-CD20 (SFB650, 633, CRC “Immunobone,” TR130, JImmunol190: 5913–5918, 2013 therapy in patients with rheumatoid arthri- and individual DFG projects Do491/7-4, 8-1,2, 13. Weisel FJ, Zuccarino-Catania GV, Chikina tis: Predictors of response and B cell subset 10-1, all granted to T.D.). M, Shlomchik MJ: A temporal switch in the regeneration after repeated treatment. germinal center determines differential Arthritis Rheum 58: 1566–1575, 2008 output of memory B and plasma cells. Im- 26. Cagigi A, Du L, Dang LVP, Grutzmeier S, munity 44: 116–130, 2016 Atlas A, Chiodi F, Pan-Hammarström Q, DISCLOSURES 14. Kaji T, Ishige A, Hikida M, Taka J, Hijikata A, Nilsson A: CD27(-) B-cells produce class None. Kubo M, Nagashima T, Takahashi Y, switched and somatically hyper-mutated Kurosaki T, Okada M, Ohara O, Rajewsky K, antibodies during chronic HIV-1 infection. 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