Available online at www.sciencedirect.com

(2007) 149–154www.elsevier.com/locate/autrev

Autoimmunity Reviews 7

The paradox of CD5-expressing B cells in systemiclupus erythematosus

Pierre Youinou, Yves Renaudineau⁎

Brest University Medical School, Brest, France

Available online 20 March 2007

Abstract

The pathophysiological relevance of B cells for systemic lupus erythematosus (SLE), particularly those expressing the T-cellmarker CD5, raises the question as to how they operate upon autoimmune processes. Based on their production of low-affinitymultispecific antibodies (Abs), CD5+ B lymphocytes, also referred to as B1 cells, have originally been endowed with theautoAb making. It has since been established that high-affinity Abs to double-stranded DNA are not generated by these cells,but rather by B2 cells. It does not appear that they have the exclusive rights to the production of pathogenic autoAbs. In the lightof recent findings, CD5 plays a paradoxical role in preventing autoimmunity. Hence, misguided signaling through CD5 couldlead to autoimmunity. This provocative view differs from the naïve interpretation that the increased levels of B1 cells in SLErepresent a direct source of autoAbs responsible for damaging organs.© 2007 Elsevier B.V. All rights reserved.

Keywords: Systemic lupus erythematosus; B lymphocyte; CD5; Chronic lymphocytic leukemia

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1502. The original interpretation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 150

2.1. CD5 B cells and disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1502.2. Separate lineage or activation marker? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1502.3. Function of CD5 in B cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1512.4. CD5+ B cells as the source of autoantibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 151

3. New findings on the CD5 molecule . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1513.1. CD5 revisited . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1513.2. Increased CD5+ B cells in systemic lupus erythematosus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 151

4. Current interpretation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1524.1. Recent clues . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1524.2. The emerging picture . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 152

5. Conclusions and perspectives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 153

⁎ Corresponding author. Laboratory of Immunology, Brest University Medical School Hospital, BP 824, F 29609 Brest, France. Tel.: +33 298 22 3384; fax: +33 298 22 38 47.

E-mail address: youinou@univ-brest.fr (Y. Renaudineau).

1568-9972/$ - see front matter © 2007 Elsevier B.V. All rights reserved.doi:10.1016/j.autrev.2007.02.016

150 P. Youinou, Y. Renaudineau / Autoimmunity Reviews 7 (2007) 149–154

Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 153Take-home messages . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 153References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 153

1. Introduction

Systemic lupus erythematosus (SLE) is a complexillness hallmarked by increased antinuclear antibody (Ab)titers and widespread organ involvement [1]. Investiga-tion into this jumble of immunological disorderscontinues to be an extremely active area of research [2],all the more because the central stage has recently shiftedfrom T to B cells. Although our early concepts focused onthe ability of B lymphocyte to produce autoAbs, it hasbecome clear that they accomplish various other tasks.Any of them may be faulty in nonorgan-specificautoimmune diseases (NOSAIDs). These include [3–5]SLE, rheumatoid arthritis (RA) and primary Sjögren'ssyndrome (SS). Accumulating evidence points to disrup-tion ofB-cell tolerance [6], and offers a rationale for B-celldepletion as a therapeutic strategy [7].

The complexity inherent in the B-cell compartmentdictates a thorough reappraisal of models based on theconcept of a single B-cell population. It has indeed beentwo decades since CD5, first described as a T-cell marker,was identified in malignant human B cells [8] and latershown tomark a minority of B lymphocytes in the normalblood [9]. A new nomenclature has subsequently been setup [10] referring to CD5-negative conventional B cells asB2, and to CD5-positive distinctive B cells as B1. Thelatter subpopulation was further divided into B1a whichexpress CD5, and B1bwhich do not but share many of thecharacteristics of their B1a counterpart. By nature, B1 andB2 lymphocytes mediate different functions.

Those B cells expressing the T-cell marker CD5 havelong been suspected to play a role in the development ofautoimmunity for umpteen years. In the light of recentfindings, they might rather act to prevent this damagingcondition. The interplay between serum interleukin (IL)-6 levels and IL-10-producing B-cell numbers might tunethis cunning balance. Yet, the mechanisms involved inthe loss of B-cell tolerance to nuclear antigens (Ags)remain elusive.

2. The original interpretation

2.1. CD5 B cells and disease

Since T lymphocyte-associated Ags have unexpect-edly been detected in chronic lymphocytic leukemia(CLL) B cells [11], there have been claims that the

CD5+ B-cell subset is expanded in numerous NOSAIDs,such as SLE, RA and primary SS. At that time, thephysiological role of such cells was likely, through aframework of self-reactivities, to be involved in the settingup of the immunoglobulin (Ig) repertoire, including theidiotypic (Id) network. Then, evidence has accumulatedfor a close relationship between CLL and NOSAIDs.Autoimmune traits were observed in more than 8% ofpatients with B lymphoproliferation, compared with lessthan 2% of those with myeloproliferation. Reciprocally,monoclonal Igs have been detected in the serum ofpatients with NOSAID. To come full circle, CLL B cellsare skewed towards the production of multispecificautoAbs [13].

2.2. Separate lineage or activation marker?

A flurry of findings is consistent with the lineagemodel, particularly in the mouse model. For example,irradiated mice could be supplied with B1 cells, pro-vided that the graft contained not only bone marrow(BM) stem cells, but also peritoneal cells. In addition,mice with severe combined immune deficiency failto develop either T or B cells because of a geneticdeficiency in the enzyme required for rearrangements ofB-cell receptor (BCR) genes, and their B1 cells arereconstituted by fetal liver cells, but not by adult BMcells. Recently, a B1 cell-specified progenitor has beenunravelled in the murine BM [13]. The crucial criteriafor determining whether human B-cell subsets arehomologous to the mouse B1a, B1b and B2 lineagesremain, nonetheless, to be met [14].

Arguments against this view support, as a result, thatB1 cells are activated. Human CD5-negative B cells canindeed be turned into CD5-positive by incubation withphorbol-myristic acetate (PMA) or EL4 thymoma cells.For this reason, we have proposed that there may bediscrete B1 populationswhich depend on the consequenceofCD5 ligation on their surface [15]. If proved correct, ourhypothesis would raise the possibility of differences inCD5+ B cells arising during early ontogeny (innate B1acells) and those whereby CD5 expression is induced byvarious stimuli (acquired B1a cells). These two families ofCD5+ B cells would coexist in normal individuals.Endogenously carryingCD5B1 cellsmay have a differentfunction from those B cells induced to express CD5following activation. Consequently, signaling via CD5

151P. Youinou, Y. Renaudineau / Autoimmunity Reviews 7 (2007) 149–154

occurs through different ligands in innate than in acquiredCD5+ B-cell populations.

2.3. Function of CD5 in B cells

CD5 is associated with the BCR, since it co-caps andco-modulates with surface IgM [16]. A number of dataestablish that induction of proliferative or apoptosisresponses to anti-CD5 depends on the activation state ofthe cells.

The physiological relevance of CD5-mediated apo-ptosis mediated is unclear, although it is known that themolecule precludes the production of autoAbs in certainNOSAIDs. In addition, its defective regulation mightfavor the development of CD5+ B-cell tumors.

2.4. CD5+ B cells as the source of autoantibodies

The question as to whether B1a cells are the sourceof autoAbs has been discussed for ages. Some ex-periments have yielded data suggesting that they make anumber of autoAbs, including anti-double-stranded (ds)DNA Abs and rheumatoid factor (RF). Our own studieson CLL showed that cells from 12 out of 14 patientscould be driven by PMA to release multispecific Abs,some of which bound to dsDNA and displayed RFactivity [12]. It has subsequently been proven that high-affinity Abs to dsDNA in SLE [17] and RF in RA [18]derive from B2 cells and not from B1. In addition, CLLpatients' cells express dominant cross-reactive Ids(CRIs) which have been associated with specific geneusage. This might be associated exclusively with CD5+

B cells [19].Earlier experiments had approached this question

using immortalised cord blood clones: 53 clones werederived from CD5+ cells and 49 from CD5− cord bloodB cells. Using mAbs to the mutually exclusive 9G4 Id ofthe Ig products of the 34+VH4 gene, and the LC1 Id ofthe Ig products of the 34−VH4 genes, we found that theformer predominated in CD5+ clones, whereas it was thelatter in the CD5− B-cells clones [20]. This clear-cutdistinction suggested that CD5 skewed the 9G4-encoding gene usage. By re-evaluating the expressionof CRI in sorted CD5+ and CD5− B cells from normalblood, CD5+ cells from CLL patients and CD5− cellsfrom patients with Burkitt's lymphoma, neither of theVH4 CRI appeared to be associated exclusively withCD5+ B cells. Furthermore, it was clear that, when theIgM was tested with 20 Ags, the Abs bound to eithernone, one or two Ags, irrespective of CD5 expression ofthe cells [21]. Consistent with this result is the lack ofCRI with RF activity in CLL patients shared by in RA

patients [17]. Increases in autoAbs in SLE and RAwould thus not be directly due to CD5+ B cells. Still,from the 9G4 CRI studies in the cord blood cells was thespecificity of the positive clones for the carbohydrateerythrocyte Ags Ii (Mageed et al., submitted). Thisobservation indicates that the CD5+ clones had been Ag-driven and, therefore, selected in vivo. Likewise, at leastin the influenza model, innate CD5+ B cells andacquired CD5− B cells are mediated by distinct armsof the immune system [22].

3. New findings on the CD5 molecule

3.1. CD5 revisited

B1a lymphocytes could rather act as Ag presentingcells (APCs). Due to their association with multispecificAbs, they appear to be particularly appropriate to thepresentation ofAgs, and able to present self-components toother B1, B2 or Tcells. It is thus of no surprise that splenicB1a lymphocytes are so potent APCs that they induce two-fold greater levels of lymph-node T-cell interferon-γproduction than that produced by B2 in the NZBM 2410lupus-prone mouse [23]. Interestingly, Roosnek andLanzavecchia have demonstrated that B cells bindingIgGAb complexes viamembrane RF, primarily B1a cells,process and present Ag very efficiently [24].

B cell-derived IL-10 is a common finding in RA, SLEand primary SS [25]. This encourages Ag presentationby B1a cells. Relevant to this issue, we have sorted B1a,B1b and B2 cells from the peritoneal cavity and spleen ofnormal mice and identified the message for IL-10 byreverse transcriptase-polymerase chain transcription,particularly within the peritoneal B1a cells [26].

3.2. Increased CD5+ B cells in systemic lupuserythematosus

Hardly any B cell of the B1a phenotype arises duringBM development in adult animals. Their increasednumbers might thus reflect defective regulation of B-cell function through CD5 itself. Moreover, there is muchevidence that CD5 is essential in modulating signalsdownstream from the BCR. Ligation of CD5 or IgM ontonsil B but not blood T cells results in apoptosis [27],whereas anti-CD5 sustains the proliferation of tonsil Bcells pre-activated with anti-IgM and IL-2 [28]. Thiscontrasts with the finding that cord blood CD5+ B cells donot apoptose in response to anti-CD5 (our unpublishedresults), but reflect the fact that they are continuouslyexposed to autoAg in vivo. CD5 is associated, bothphysically and functionally with the BCR, of which the

Fig. 1. When exon 1A (E1A) is selected (left), the full-length CD5protein is synthesized and translocated to the membrane, along withthe src-homolog 2 domains-containing protein tyrosine phosphatase(SHP-1) to the vicinity of the B-cell antigen receptor (BCR), in order todephosphorylate the CD79a and CD79b chains associated with themembrane immunoglobulin, and, thereby, diminish BCR signalingand raise its threshold. When it is (right) E1B, a truncated CD5 proteinis synthesized and retained in the cytoplasm as well as SHP-1. Theformer scenario leads to anergy, and the latter to (auto)antibodyproduction.

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Igα, Igβ chains are constitutively linked to the NH2-terminal Src-homology 2 domain-containing proteintyrosine phosphatase (SHP-1) through their immunoreg-ulatory tyrosine based inhibitory motif of CD5 [29]. Suchan interaction with CD5 sequesters the SHP-1, and limitsits effects with important molecules in positive signalingthrough the BCR.

The role of CD5 in the maintenance of clonal anergyhas been addressed by the hen egg lysozyme (HEL)-Igtransgenic (Tg) mouse model [30]. Mice Tg for HEL-Igand the membrane-bound form of HEL present withapoptotic anti-HEL B cells, while those Tg for HEL-Igand the soluble form of HEL initiate anergy via SHP-1.Breeding of the latter anergic mice onto a CD5−/−

background results in such a loss of tolerance, that anti-HEL Abs are released. In other words, the presence ofCD5 raises the threshold required for activation of self-reactive B cells, and thereby determines their ultimatefate.

Consistent with this role for CD5 is another recentmodel in which CD5− spleen cells from anti-RNPAb Tgmice were injected into irradiated naïve mice. Theymigrated to the peritoneal cavity (the site where most ofthe CD5+ B cells reside) and began to express CD5which prevented their production of anti-RNP [31].

Other molecules than CD5 are important in theregulation of autoreactive B cells. For example, CD19amplifies BCR signaling by facilitating the activity oftyrosine kinases, such that a modest increase in CD19expression is sufficient to shift the balance betweentolerance and immunity to autoimmunity [32]. In con-trast, CD22 dampens down the signals by recruitingSHP-1, which is the reason why deficiency in CD22induces autoimmunity [33]. In this respect, defectivesignaling through the BCR has been demonstrated for Bcells from patients with SLE [34].

4. Current interpretation

4.1. Recent clues

A novel exon 1 for the CD5 gene has freshly beenidentified [35]. This is exclusively transcribed in Blymphocytes. It has been designated exon 1B (E1B),and the known exon 1 renamed E1A. Interestingly, E1Boriginates from a human endogenous retrovirus, at atime interval between the divergence of New World andOld World monkeys, and the divergence of humansfrom the apes [36]. This explains why E1B does notexist in the mouse. There is a reciprocal expression ofthe two exons 1. The balance might be key in theregulation of membrane expression of CD5.

By raising the threshold of the BCR for the response,CD5 diminishes the signal down to a level [37] thattriggers the expression of recombination activatinggenes (RAGs). Revision of variable genes (which hasbeen shown to be instrumental in the prevention ofautoimmune states) is launched this way.

IL-10 that is synthesized by CD5+ B cells andinvolved in the control of autoimmunity [38], might berelevant to this issue. Also, IL-6warrants to bementioned,which contributes to the expression of RAGs in humanmature B cells (Hillion et al., submitted) is currently beingevaluated in SLE, RA and primary SS [39].

4.2. The emerging picture

A great deal of effort has been made into under-standing the expression of CD5 at intracellular and cellsurface levels. Shedding and internalization of theprotein have been recognized to regulate the membraneexpression level of CD5, and a third mechanism mightoperate through transcription of the gene.

CD5-E1B transcripts are translated into a truncatedvariant of the CD5 molecule; truncated and, therefore,devoid of leader peptide. Hence, E1B tends to preventthe translocation of CD5, and to limit the amount ofSHP-1, whereas E1A promotes its membrane expres-sion (Fig. 1).

When E1A is selected, the full-length CD5 proteinwhich is synthesized carries SHP-1 to the membrane,increases the amount of phosphatase in the vicinity ofthe BCR, and makes tolerance easier in autoreactive B

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lymphocytes. Conversely, when E1B is selected, thetruncated version of CD5 is synthesized, and SHP-1blocked within the endoplasmic reticulum. In that case,the strength of the BCR-mediated signaling increasesup to a level enabling the B lymphocyte expansion.Not only does the truncated CD5 protein not recruitSHP-1, but it also reduces the expression of the full-length molecule in Jurkat T lymphocytes transfectedwith E1B-complementary DNA. As a consequence,folowing their shedding and internalization, CD5molecules would not be replaced, and their mem-brane expression level of CD5 is doomed to decline. Ourongoing studies are focused on analyzing more ac-curately how this mechanism regulates the level ofmembrane CD5 expression.

We know nothing about the basis for the selection ofexons 1 for transcription. One mechanism for silencinga gene is through the transfer of methyl groups tothe cytosine nucleotides of the CpG motifs by DNAmethyl-transferases (DNMTs). These are, themselves,regulated through the ras-dependent pathway of themitogen-activated protein and extracellular-regulatedkinases. Three families of DNMTs have so far beendelineated: DNMT1 which are maintenance methy-lases, DNMT2 of which the specificities are unclear,and DNMT3a and DNMT3b which are generated anew.Although being established during ontogeny andmaintained by DNMT1, the DNA methylation patternsare not fixed forever. The selection of E1A or E1Bmight(also or rather?) be regulated through protein degradation.Consistent with this alternative pathway is the presence oftwo 9-amino acid peptide sequences, called destructionboxes in the N-terminus of CD5. One of these is requiredfor ubiquitination by anaphase-promoting complex andproteasomic proteolysis.

5. Conclusions and perspectives

Conventional therapy, although at times effective inSLE, brings it with a host of severe complications.The current revival of interest in B lymphocytes ascontributors to the cause of NOSAIDs promotes B-celldepleting therapies. Although the last years havewitnessed numerous initially promising drugs thatproved disillusioning, anti-B-cell mAbs should now beused on a routine basis in adults [39] and children [40]with SLE.

Acknowledgements

We are grateful to Simone Forest and Cindy Séné forexpert secretarial assistance.

Take-home messages

• CD5+ B cells are associatedwith autoimmune diseasesand B lymphoproliferative disorders.

• TheseB1 cells do not generate pathogenic autoantibodies.• Due to its association with the B-cell antigen receptor(BCR) and a protein tyrosine phosphatase, CD5raises the threshold of the BCR response.

• A reciprocal expression of two exons 1 for CD5regulates the membrane expression level of the protein.

• These findings offer a rationale for B-cell-targetedtherapies.

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ly diagnosis

s a humoral response to cancer-derived antigens. In this) assessed the diagnostic potential of autoantibodies toal controls, primary breast cancer patients (n = 97) and

nvestigated for the presence of autoantibodies to p53, c-tigens by ELISA. Reproducibility elevated levels of64% of primary breast cancer patient sera and 45% of

ifferences were seen when patients were subdivided byr detection methodology. Autoantibodies against one orhe presence of early-stage breast cancers. Autoantibodymammography in the detection and diagnosis of earlysed risk of breast cancer were mammography is known