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.