Opinion

Receptor editing and receptor revisionin rheumatic autoimmune diseasesMoncef Zouali

Inserm U606 and University of Paris Diderot-Paris 7, Centre Viggo Petersen, Hopital Lariboisiere, 2 rue Ambroise Pare,

75475 Paris Cedex 10, France

Receptor editing is a key mechanism of B cell tolerancethat modifies the B cell receptor (BcR) specificity ofself-reactive lymphocytes. It acts through initiation ofsecondary immunoglobulin rearrangements, throughgeneration of newly rearranged endogenous l chainsthat displace k chains, or through isotypic and allelicinclusion of dual BcRs (k+/l+ or k+/k+ B cells). Mountingevidence indicates that receptor editing is eitherimpaired or accelerated in patients suffering from rheu-matic autoimmune diseases. Remarkably, both altera-tions can promote the pathogenesis of autoimmunedisorders by favoring the uncontrolled emergenceand/or persistence of autoreactivity. Whereas impairedsecondary rearrangements might result in ineffectivesilencing of B cells, exacerbation of receptor editingcan give rise to autoreactive receptors from clones thatwere initially devoid of autoreactivity.

Accumulating evidence indicates that B cells are keyplayers in the innate and adaptive branches of immunity,and that impairment of some of their functions can lead toa variety of disorders in humans. In autoimmune diseases,such as rheumatoid arthritis (RA) and systemic lupuserythematosus (SLE), several B cell alterations have beenrecognized [1]. This relatively recent insight has led tonovel immunointervention strategies based on specific Bcell targeting, with beneficial effects in a variety of humanautoimmune diseases [2]. Despite this significant thera-peutic progress, the precise mechanisms that lead to loss ofB cell tolerance to self-antigens in autoimmune diseaseremain under scrutiny.

Receptor editing: a key mechanism of B cell toleranceDuring development, recombination and somatic mutationof immunoglobulin (Ig) genes generates heavy (H) and light(L) chains that combine to form B cell receptors (BcR)capable of recognizing a virtually unlimited number ofantigenic determinants. These temporally ordered pro-cesses can also give rise to potentially threatening poly-reactive BcRs able to recognizemore than one epitope, or toBcRs endowed with self-reactivity. The immune systemmust therefore deploy cellular and molecular strategies tokeep autoreactive B cells in check.

In the bone marrow, tolerance to self-antigens in the Bcell lineage is maintained by three important mechanisms

Corresponding author: Zouali, M. (moncef.zouali@wanadoo.fr).

1471-4906/$ – see front matter � 2007 Elsevier Ltd. All rights reserved. doi:10.1016/j.it.2007.12

(Figure 1). First, clonal deletion purges self-reactive B cellsfrom the repertoire by apoptosis [3]. Second, clonal anergysilences autoreactive B cells and renders them unrespon-sive to BcR crosslinking [4]. Third, receptor editingmodifies the BcR specificity of self-reactive cells throughthe initiation of secondary Ig gene rearrangements [5,6].Studies with transgenic and ‘knockin’ mice revealed thatediting is an important mechanism of B cell tolerance thatcan function in the apparent absence of major cell loss.Compared to mature B cells, immature B cells are highlysensitive to receptor editing [7]. Even encounters withultra-low-affinity, membrane-bound autoantigens canreinduce expression of sufficient recombination-activatinggene (RAG)-1 and RAG-2 activities and can extinguishautoreactivity by successive gene rearrangements thatdisplace productively rearranged k chain genes [8]. Re-ceptor editing can also result from the generation of newlyrearranged endogenous l chains that displace k chains,and they can form edited BcRs with no, or reduced, auto-reactivity (Table 1). As a result, 47% of l+ lymphocyteshave evidence for rearrangement in normal mice, andalmost all l+ lymphocytes have undergone k gene assemblyin humans [7]. Another strategy for dealing with autoreac-tive B cells is the expression of two different L chains (k+/l+

and k+/k+ B cells). Such isotypically and allelically includeddual receptor B cells are part of the peripheral repertoire inhumans and mice [9–12].

Inefficient receptor editing in human autoimmunerheumatic diseasesAlthough knowledge about the autoantibodies (autoAbs)produced by patients with rheumatic autoimmune dis-eases is increasing, the molecular basis underlying theirinduction and persistence remains enigmatic. Initially,analysis of B cell clones obtained from patients with idio-pathic lupus and producing pathogenic autoAbs suggestedthat receptor editing might be defective in human SLE[13]. In patients with lupus nephritis, lack of receptorediting in B cells producing anti-double-stranded (dsDNA)Abs has also been suggested to occur [14], leading to theproposal that impaired receptor editing could play a role inthe persistence of threatening autoreactivity [15].

However, these early studies did not take into accountdisease activity, a hallmark of human lupus. Investigationof SLE patients with active disease revealed that maturenaıve B cells express self-reactive Abs that are biased tocontain 30 Vk genes in association with 50 Jk elements [16].Patients in remission, however, exhibited a normalized,

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Figure 1. Negative selection of self-reactive B cells. Shown here are three mechanisms that maintain tolerance to self-antigens in the B cell lineage. In clonal anergy, self-

reactive B cells become functionally unresponsive to BcR engagement, a state that can be reversed. In clonal deletion, the encounter between autoreactive B cells and self-

antigen results in apoptosis and physical elimination of the clonotype. In receptor editing, autoreactive B cells undergo Ig gene replacements to modify their BcR specificity,

extinguishing their potential to recognize self-antigens, and acquire a new specificity. Hence, extinction of autoreactivity by receptor editing changes the fate of B cells and

allows them to persist in the immune repertoire.

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unskewed Ig Vk gene repertoire as well as an overalldecrease in autoreactivity. In lupus-prone mice, in whichimmature B cells in the bone marrow can be accessedand B cell transit followed, this crucial self-tolerancecheckpoint was also found to be reduced [17]. It is there-fore tempting to conclude that active SLE is associatedwith increased expression of unedited self-reactiveB cells.

Consistent with the view that impaired receptor editingmight play a role in the etiology of SLE, defects in second-ary Ig gene recombination have also been reported in otherrheumatic diseases. L chain Ab sequences from threepatients with RA showed an increase in downstream Vk

genes associated with the most upstream Jk element, Jk1,suggesting inefficient secondary recombination and, there-fore, a potential defect in receptor editing [18]. In oligoar-ticular juvenile idiopathic arthritis, there is a decrease inthe frequency of RAG-2-expressing, CD19+CD27+, memoryB cells as well as a lack of secondary rearrangements inperipheral CD27+CD5� B-2 cells when compared tohealthy individuals [19]. This reduced RAG expressionsuggests that impaired editing could contribute to auto-immune pathogenesis in oligoarticular juvenile idiopathicarthritis.

Table 1. Molecular mechanisms of receptor editing that canmodify B cell reactivity

Molecular mechanism Refs

Initiation of secondary Ig L chain rearrangements that lead

to expression of new L chains.

[5,6]

Generation of newly rearranged endogenous l chains that

displace k chains and form edited BcRs with no, or reduced,

autoreactivity.

[6]

Secondary rearrangements of VH genes that give rise to

non–self-reactive receptors.

[26,44]

Isotypic and allelic inclusion leading to the emergence of

dual receptor B cells expressing two different L chains

(k+/l+ and k+/k+ B cells).

[9–12]

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Receptor revision: a diversity-driven process in theperipheryInitially, receptor editing was thought to take place essen-tially in the bone marrow to extinguish self-reactivity.With further investigation, additional facets of thismechanism were uncovered, and in experimental animals,receptor editing did not always completely extinguish self-reactivity and could even generate autoreactivity [7].

In addition to secondary rearrangements, isotypic andallelic inclusion represent another potential mechanismthat can give rise to autoreactivity. Specifically, editing ofautoreactive BcRs could give rise to allelically included Bcells that carry two L chains, one imparting autoreactivityand the other not [9–12]. The emergence of such multi-reractive B cells expressing bispecific receptors, includingpartial autoreactivity, might contribute to autoimmunity[20].

In immature B cells, receptor editing seems to be drivenby the need to maintain tolerance to self-antigens. Inperipheralmature B cells, however, editing, called receptorrevision, might be driven by the need for receptor diversity,and it acts as a mechanism for expanding the B cell reper-toire [21–24]. Examples of receptor revision in the peripheryhave involved RAG expression in germinal centers (GCs) ofnormal mice, suggesting a physiological role of this mech-anism [25]. Key to the view that secondary rearrangementscan contribute to repertoire diversification is a set ofexperiments performed with mice bearing a transgene thatrenders their primary B cell repertoire ‘theoretically’ mono-specific [26]. When infected with different viruses, the miceexhibited V gene replacement, together with hypermuta-tion, and generated protective antiviral antibody specifici-ties, suggesting that both mechanisms could contribute tothediversification of theB cell repertoire of normalmice andthat the expanded repertoire is functional [27].

In humans, the function of receptor revision in theperiphery is not settled. Early studies indicated that

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human B cells that have lost surface Ig re-express RAG-1and RAG-2, suggesting that secondary Ig gene rearrange-ments leading to replacement might occur in human GCand might contribute to the peripheral B cell repertoire[28]. It has also been suggested that secondary recombina-tion in the periphery might participate in repertoire diver-sification by improving very low-affinity receptors [21]. InGCs from human tonsils, RAG expression was upregulatedin activated naıve B cells, but not in centroblasts [29], andin activated mature CD5+ B cells [30]. Further support forthe contribution of receptor revision to the secondaryimmune response comes from the detection of recombina-tion-generated hybrid V genes in normal human tonsils[31].

In addition to diversifying the humoral repertoire andto generating useful pathogen-specific Abs [27], receptorrevision represents a potential source of autoreactive Bcells. For example, anergic B cells from autoimmune-pronemice could be activated to produce pathogenic autoAbsafter somatic mutation and receptor revision [32],suggesting that receptor revision can lead to BcR changesthat overcome anergy. Support for this view also comesfrom the K/BxN mouse model of RA [33]. In this model,animals carry a transgene encoding a self-reactive T cellreceptor that recognizes cells presenting a peptide from theglycolytic enzyme glucose-6-phosphate isomerase (GPI).Knockin targeting of the rearranged H and L chain vari-able gene segments of an anti-GPI hybridoma into thecorresponding germline JH and JL loci revealed that nega-tive selection of B cells expressing high-affinity anti-GPIspecificities operates mainly at the transitional B cellstages in the spleen. Receptor editing allowed significantnumbers of autoreactive cells to escape negative selection,and gave rise to cell precursors that produce, upon T cellhelp, pathogenic autoAbs [11].

Accelerated receptor revision in human autoimmunityThese experimental studies suggested that ongoing B cellstimulation could overwhelm the capacity of receptor edit-ing to prevent autoimmunity. This hypothesis was testedin experimental models of lupus. In NZB mice, B-1 cells,like GC B cells, were found to express RAG-1 and RAG-2and to undergo secondary Ig V(D)J recombination [34]. Inaddition, B cells from autoimmune-prone mice showedhigh levels of RAG mRNA and recombination. Based onaltered somatic VHmutation profiles,Rag gene expression,and circular VHDH gene excision products in mice bearingthe Sle3/5 locus [35], and on a preferred usage ofVH-proximal DH genes and distal JH genes [36], it hasbeen proposed that IgH chain receptor revision mightcontribute to the development of autoreactive antibodies.

In humans, profiling the distribution of Vk and Jk geneelements in individual B cells of a patient with early,untreated SLE led to the conclusion that receptor editingappeared to be greatly enhanced in the SLE patient [23].The authors also found that SLE patients exhibiteda significant increase in the frequency of RAG-1 andRAG-2 mRNA+ B cells in the peripheral blood [37].Analysis of the frequency of RAG-expressing cells in theCD19+IgD+CD5+ and CD5� peripheral blood B cell popu-lations of three juvenile SLE patients and two age-matched

healthy controls also suggested that RAG expression isupregulated in the CD5+ B cell population of certain SLEpatients [38].

Extensive secondary Ig gene recombination has alsobeen reported in B cells from patients with RA, suggestingthat it can be an abnormal mechanism shared by differentrheumatic diseases. In one study of an RA patient, k chainsfrom new emigrant B cells showed an increase in upstreamVk genes associated with downstream Jks, probably reflect-ing extensive secondary recombination in those cells [18]. Arelated investigation identified a group of human B cellsthat coexpress surrogate and conventional L chains(V-preB+L+). Whereas conventional B cells preferentiallyuse Jk1 and Jk2 segments, V-preB+L+ B cells derived fromnormal donors showed decreased Jk1 and Jk2 usage andincreased downstream Jk4 and Jk5 segment usage [39].The V-preB+L+ B cells also exhibited a higher proportion ofunusually long Igk CDR3s (complementarity-determiningregion), a persistent RAG expression, and an overrepre-sentation of the Vk4 family member, B3, suggestingincreased secondary V(D)J recombination and receptorrevision. In addition, the B cells had an unusual Ab reper-toire associated with self-reactivity and were enriched inthe joints of RA patients [39].

Whereas little is known regarding the function ofhuman V-preB+L+ B cells, their murine counterpartsappear to be cells with low-affinity anti-self Abs that failto be edited or deleted, and that survive to enter theperipheral circulation [40–42]. Under normal circum-stances, these B cells are probably anergic [40–43]; how-ever, in autoimmune-prone backgrounds they mightescape tolerance mechanisms and produce autoAbs [32].

SLE and RA are characterized by the expansion ofautoAb-producing B cells that often increase in affinityas the disease progresses and that often correlate withdisease severity. Because it is clear from transgenic mousemodels of autoimmunity that secondary rearrangements ofVH genes can lead to non-self-reactive receptors [26,44], itseemed reasonable that VH replacement of autoreactiveBcR might be occurring in SLE and RA. One study ident-ified four types of secondary VH gene rearrangements thatoccurred among clonally related B cells in the synovialtissues of different RA patients [45]. Whether this highfrequency of VH replacement events represents a feature ofnormal GC reactions or of the ectopic GC reactions presentin RA synovium remains unresolved. Nevertheless, theseVH replacement events might bear significance for theautoreactivity seen in RA, because they could break self-tolerance. The fact that the VH1-69 gene, which appears tobe a preferred donor in VH replacement events detected insynovial tissue B cells [45], is frequently used to encoderheumatoid factors (RFs) might support the notion thatediting can inadvertently lead to autoreactivity. However,the antigenic specificities of the B cell clones involved inthese VH replacement events were not identified.

Signaling pathways recruited in the process of receptoreditingAntigen binding to the BcR can lead to lymphocyteproliferation and differentiation, or to tolerance. Thesedistinct cellular outcomes depend, at least in part, on

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the developmental stage of the lymphocyte and on thecoordinate regulation of BcR-mediated signaling pathways[46]. Initial signaling is triggered by the activation of theSrc-family protein-tyrosine kinases Btk and Syk. In turn,these kinases coordinate the activation of signal trans-duction pathways, including phospholipase C (PLC)-g 1and -g 2, phosphatidylinositol 3-kinase (PI3K), the Vav-and Rho-family pathway, and mitogen-activated proteinkinase (MAPK) pathways. How individual signaling path-ways lead to distinct cell fates remains the focus of muchinvestigation. It appears, however, that theMAPK cascadeis essential for signaling of various extracellular stimulifrom the membrane to the nucleus [47], and evidence hasbeen obtained supporting a role for MEK1 and -2 andextracellular kinase (ERK) in promoting BcR-induced cellcycle entry and proliferation in quiescent splenic B cells[48]. Ras engagement induces activation of the serinekinase, Raf, which, in turn, activates the dual specifickinase MEK-1/2. MEK-1/2 then activates ERK-1 andERK-2, leading to nuclear translocation of various tran-scription factors involved in cell functions.

With regard to receptor editing in B cells, which isstrongly correlated with elevated RAG-1 and RAG-2mRNA levels, it has been demonstrated that the NF-kBand Rel transcription factors regulate RAG-1 and RAG-1expression as well as L chain gene rearrangements innewly formed B cells in vivo [49]. Additionally, the controlof editing seems to require the Raf-MEK-ERK signalingpathway. This conclusion stems from the characterizationof the phenotype of mice deficient in SPA-1, a Rap1-specific GTPase-activating protein (GAP) that negativelyregulates the small G protein Rap1 (Ras-proximate-1). Theactions of Rap1, a molecule that regulates MAPKs andaffects cell survival and function [50], occur in selected celltypes to enhance or diminish ERK signaling, depending onthe expression pattern of the MAPK kinases of the Raffamily (Raf-1 and B-Raf). In B cells, Rap1 is important forseveral processes that are essential for development. AfterBcR ligation, Rap1 is activated via a pathway that involvesPLC-dependent production of diacylglycerol. Remarkably,Spa-1�/�mice exhibit an expansion of autoreactive B cells,produce anti-dsDNA Abs, and develop a lupus-like syn-drome [51]. Importantly, their immature B cells showineffective receptor editing of Vk genes as well as a signifi-cantly altered repertoire, in which the frequency of usage ofthe Vk4 gene, the most frequently utilized Vk gene amongmurine anti-dsDNA and antinuclear Abs [52], is markedlyincreased. This enhanced Vk4 gene utilization might favorthe generation of immature B cells that are reactive withnuclear autoantigens. Further support for the view thatthe control of editing requires the MEK-ERK signalingpathway comes from studies showing that partial blockingof that pathway alters Vk gene repertoire expression,impairs receptor editing in immature B cells, and givesrise to self-reactive B cells in vivo [53].

Like receptor editing, clonal anergy, another processthat requires exposure to self-antigen, also seems to recruitthe ERK signaling pathway. During positive signaling innaıve B cells, continued BcR ligation by antigen stimulatesa biphasic calcium response and activates nuclear signalsthrough nuclear factor of activated T cells (NFAT), NF-kB,

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JNK (c-jun terminal kinase), and ERK [54–56]. By con-trast, BcR stimulation with the same ligand has a negativeeffect in self-reactive tolerant B cells that have beenchronically exposed to a self-antigen, and this is accom-panied by a different calcium pattern and activation of onlythe NFAT and ERK pathways. This differential activationled to the proposal that recurrent activation of the ERKpathway in tolerant B cells might block terminal differen-tiation into autoAb-secreting plasma cells [55].

Implications of accelerated receptor revision in humanautoimmunityPatients with rheumatic autoimmune diseases, includingRA and SLE, fail to efficiently remove autoreactive B cellsat both early andmature tolerance checkpoints, in the bonemarrow and in the periphery [18,57–59]. The alterations ofreceptor editing summarized above have implications con-cerning the etiology of autoimmune conditions. It is easy toenvision that accelerated revision might promote diseaseby an uncontrolled creation of autoreactive Abs. However,the mechanisms contributing to the increased frequency ofRAG-expressing B cells in the peripheral blood of auto-immune patients remain unclear. The apparent exagger-ated degree of receptor editing in an SLE patient has beensuggested to reflect attempts to delete autoreactive Igreceptors that might have developed as a result of somatichypermutation [23]. Because the patient expressed severalautoAbs despite extensive receptor editing, this mechan-ism probably was insufficient to prevent autoimmunity.Another possibility is that the bone marrow emigration ofRAG+ immature B cells was accelerated. The increasedRAG expression in IgD+ peripheral blood B cells in someSLE patients [37,38] might suggest a prolonged receptorediting in B cells that have prematurely left the bonemarrow. Because RAG-1 and -2 expression has beendetected in normal human GC B cells of secondary lym-phoid organs [28,29], it might also be possible that SLEB cells re-express RAG at mature stages of differentiationas a consequence of accelerated receptor revision.

Genetic and epigenetic factors underlying impairedreceptor editingAs other studies indicate, it also is conceivable thatimpaired receptor editing in SLE and RA could result inineffective silencing of B cells that have acquired auto-reactive receptors [13,14,18,19,59]. Further insight intothe molecular basis of inefficient editing as a potentialcause of autoimmunity comes from studies based on differ-ent approaches. First, studies of two lupus-susceptibilityloci suggest that impairment of receptor editing might be amajor mechanism through which antinuclear Abs arise inlupus [60,61]. For example, Sle2z is a NZM2410 mouse-derived locus on mid-chromosome 4 that impacts autoAbproduction and lupus nephritis. When introgressed ontothe normal C57BL/6 background, the Sle2z locus leads toage-dependent hypergammaglobulinemia and generalizedB cell hyperactivity. To understand how Sle2z breachesB cell tolerance, this locus was bred to two anti-DNA Ig Hchain transgenic mouse models, B6.3H9 and B6.56R[61]. The introgression of the Sle2z lupus-susceptibilityinterval onto C57BL/6 mice carrying an anti-DNA H chain

Figure 2. Dysfunctional receptor editing in the bone marrow and receptor revision in the periphery can result in the persistence and the emergence of autoreactive B

lymphocytes. (a) In the bone marrow of healthy individuals, receptor editing potently extinguishes autoreactivity of B lymphocytes generated through the V(D)J

recombination machinery. Autoreactive B cells that might escape from this negative selection process or that emerge in the periphery can also be rendered tolerant to self-

antigens by receptor revision. (b) In patients with rheumatic autoimmune diseases, such as lupus and rheumatoid arthritis, inefficient receptor editing in the bone marrow

results in the persistence of autoreactive B cells that can migrate to the periphery. Additionally, accelerated receptor revision can lead to the emergence of autoreactive B

cells from non-self-reactive B cells present in the periphery. Both impaired receptor editing and accelerated receptor revision have been reported in diseased subjects with

different ethnic backgrounds.

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transgene augmented the breach in B cell tolerance toDNA. Additionally, antinuclear Abs exhibited diminishedreceptor editing and/or revision in the context of thetransgene. The data suggest that the presence of Sle2z

might diminish the pressure to edit an initial BcR thatmight have been autoreactive, and that receptor editingimpairment might be a major mechanism through whichantinuclear Abs arise in lupus.

A second line of evidence comes from investigation of theeffect of hydralazine, an antihypertensive drug that trig-gers lupus, on receptor editing in mice harboring humantransgenic Igs. The studies revealed that, by disrupting theERK signaling pathway, hydralazine reduces receptorediting in B lymphocytes and contributes to the generationof pathogenic autoreactivity [53]. The data also support theview that epigenetic alterations contribute to exacerbatedactivation or deregulation of the mechanisms that main-tain tolerance to self-antigens in patients with lupus, asystemic autoimmune disease that can be triggered bymedications taken to treat a variety of conditions.

Overall, receptor editing seems to contribute to thepathogenesis of rheumatic autoimmune diseases inhumans through at least two different mechanisms.Whereas impaired secondary rearrangementsmight resultin ineffective silencing of B cells, exacerbation of receptorediting can give rise to the emergence of autoreactivereceptors from clones that were initially devoid of auto-reactivity. Both alterations can promote the pathogenesisof autoimmune diseases by favoring the uncontrolled emer-gence and/or persistence of autoreactive B cell clones(Figure 2). Additionally, other mechanisms, such as clonaldeletion or anergy,might be disturbed so as to contribute toautoreactivity formation. The potential roles of molecularprocesses and subsequent selective influences on thegeneration of autoreactive B cells remain the focus ofinvestigation. Because epigenetic mechanisms can affectvarious biological properties – from the eye color of fruitflies to the morphology of flowers [62] – further investi-gation into the impact of epigenetics on lymphocyte toler-ance to self might provide us with unexpected clues that

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will help to elucidate more fully the basis of dysregulatedreceptor editing in autoimmune disease.

AcknowledgementsThis work was supported by Inserm and University of Paris Diderot-Paris7 institutional funding.

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58 Wardemann, H. et al. (2003) Predominant autoantibody production byearly human B cell precursors. Science 301, 1374–1377

59 Yurasov, S. et al. (2005) Defective B cell tolerance checkpoints insystemic lupus erythematosus. J. Exp. Med. 201, 703–711

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