ARTHRITIS & RHEUMATISMVol. 62, No. 9, September 2010, pp 2605–2610DOI 10.1002/art.27564© 2010, American College of Rheumatology

REVIEW

Significance of B Cells and B Cell Clonality inSjogren’s Syndrome

Pierre Youinou, Valérie Devauchelle-Pensec, and Jacques-Olivier Pers

Introduction

Sjogren’s syndrome (SS) is a chronic autoimmunedisease in which the exocrine glands become sites ofintense immunologic activity, leading to tissue damagethat is manifested as mucosal dryness (1). This disordercan occur either alone, as primary SS, or on a back-ground of another connective tissue disease, such asrheumatoid arthritis (RA), systemic sclerosis (SSc;scleroderma), or systemic lupus erythematosus (SLE), assecondary SS. One theory of the disease immunopatho-genesis proposes that the syndrome is initiated by epi-theliitis and is sustained by the ensuing influx of lym-phocytes (2). Hence, the disease was referred to by thoseinvestigators as autoimmune epitheliitis.

All affected organs, especially the salivary glands,exhibit a lymphoproliferative sialadenitis. Lymphoprolif-erative sialadenitis in SS is associated with lymphocyteinfiltration, epithelial cell proliferation, and apoptosis(3). Compared with healthy individuals, patients with SSare at greater risk of developing non-Hodgkin’s lym-phoma (4). Lymphocytes are therefore central to thepathophysiology of this autoimmune condition. How-ever, there is controversy about which set of lymphocytesdirects the immunopathologic process.

Examination of the available evidence at a glancesuggests that T lymphocytes play the principal role in theimmunopathogenesis of these diseases. This propositionis based on the numerical predominance of T lympho-

cytes in the cellular composition of the inflamed tissuesand on the restriction of the T cell receptor (5). Onepotential contradiction of this proposition, however, isthat if the T lymphocytes were indeed the principaldriving cells, then no increases in monoclonal Ig and Bcell lymphoma would be seen in primary SS. Therefore,because the numerical predominance of T lymphocytesis not consistent with the clonal expansion of B cells inSS patients, attention has recently focused on the possi-bility that B lymphocytes play the leading role. Further-more, there is good evidence to indicate that B lympho-cytes promote the immune responses to self and non-selfantigens through antibody-dependent and antibody-independent mechanisms (6).

Accumulation of B cells in exocrine glands resultsin their clustering into aggregates (7). There is nonethe-less evidence from phenotype analyses suggesting thatthese aggregates are benign (8). Such findings raisequestions as to why lymphomas frequently develop on abackground of polyclonal proliferation of B cells inpatients with SS (9). The frequent leukemic transforma-tion in these patients with primary SS was first noted byBunim and Talal (10). Subsequent studies by theseinvestigators indicated that the two B cell aberrationswere associated (11). They went on further to show awhole range of benign-to-malignant B cell proliferationsin patients with primary SS, but not in those withsecondary SS (12). Lymphoma in these patients has thuschanged from an all-or-nothing phenomenon to one of acontinuous spectrum of disease. This concept fits in with,but does not explain, the high frequency of lymphoma inpatients with primary SS.

In this review, we venture into the area of theambiguous relationship between primary SS and B celllymphoma. This analysis is focused in part on highlight-ing the centrality of B lymphocytes to the pathogenesisof primary SS and on exploring the likely processes thatunderpin the polyclonality or monoclonality of B cells inthe disease. Our paradigm does not exclude a key role of

Supported by the Association Francaise du Gougerot-Sjogrenet des Syndromes Secs, the French Ministry for Education andResearch, and the Institut Francais pour la Recherche Odontologique.

Pierre Youinou, MD, DSc, Valerie Devauchelle-Pensec, MD,PhD, Jacques-Olivier Pers, DDS, PhD: EA2216 Immunology andPathology, IFR 148 ScInBioS, European University of Brittany, andBrest University Medical School Hospital, Brest, France.

Address correspondence and reprint requests to Pierre Youi-nou, MD, DSc, Laboratory of Immunology, Brest University MedicalSchool Hospital, BP824, F29609 Brest, France. E-mail: youinou@univ-brest.fr.

Submitted for publication March 19, 2010; accepted May 11,2010.

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T cells in the pathogenesis of the disease, since some Tcell responses are overtly deleterious. However, it isclear that B cell lymphoma transformation is not instan-taneous, but seems to proceed from antigen-drivenhyperactivity. Some insight into the process has beengained from studies of the pathophysiology of primarySS, yet much uncertainty remains.

B cells are central to the pathophysiology of Sjogren’ssyndrome

B cell–induced serum anormalities. Autoanti-bodies to a range of self antigens, including the 52-kd (or60-kd) protein of the SSA particle, the SSB particle, andthe Fc portion of IgG (i.e., rheumatoid factors [RFs]),have been identified in patients with SS (13). Some ofthe autoantibodies found in patients with primary SShave even been suggested to be involved in the patho-genesis of the disease. For example, there is evidencethat antimuscarinic autoantibodies (14), anti–carbonicanhydrase II antibodies (15), and possibly antifodrinautoantibodies (16) can induce harmful autoimumnity.In addition, IgA-RF, IgA-containing immune com-plexes, monoclonal Ig (17), and mixed cryoglobulins (18)are frequently found in the serum of patients with SS.

The hyperactivity of B lymphocytes in patientswith SS is also reflected in the anomalous expression ofCD72, a transmembrane lectin that is expressedthroughout the period of B cell maturation. This canboth positively and negatively modulate B cell receptor(BCR)–mediated signaling. The expression of the co-stimulatory molecule has been found to be up-regulatedin B lymphocytes from patients with primary SS ascompared with patients with RA or SLE (19). Therelevance of this observation to the pathogenesis of SS,however, is largely unknown.

In addition to these anomalies in B lymphocyteresponses, there is good evidence of perturbation in thedistribution of B cell subsets in primary SS. The regu-lated and sequential expression of the membrane pro-teins IgD and CD38 distinguishes mature B cells (Bm)through their maturation from Bm1 to Bm5 cells (20). Inthe secondary lymphoid organs, as a consequence oftheir selection outside germinal centers (GCs) in thepresence of short-lived plasma cells, naive CD38–IgD–Bm1 cells progress to become activated CD38�IgD�Bm2 cells, some of which are primed as GC founderCD38��IgD� Bm2� cells. They then differentiate intolong-lived plasma cells or IgD–CD38� early Bm5(eBm5) cells and late-memory IgD–CD38–Bm5 cells. Afew cells of each subset escape from the formed GCs

into the circulation. Patients with primary SS exhibitincreased percentages of circulating Bm2-plus-Bm2�cells and decreased percentages of eBm5-plus-Bm5 cellsas compared with healthy controls and with patients withRA, SSc, or SLE (21). Interestingly, this disturbance in Bcell subsets is associated with a decrease in the percent-age of circulating memory B cells (22). Among them, theproportion of memory autoreactive B cells remains to bedetermined.

Intrinsic B cell defects. The cause of B lympho-cyte hyperactivity in primary SS is not known, but atleast 3 different intrinsic abnormalities have been iden-tified. First, preswitch Ig transcripts are abnormallyretained in circulating memory B cells, regardless of theadvent of postswitch Ig transcripts (23). Second, thekinetics of BCR translocation to lipid-rich membranesignaling microdomains, called lipid rafts, is altered inprimary SS. Thus, there is evidence of prolonged trans-location of the BCR into lipid rafts in B cells, resultingin inappropriately enhanced signaling (24). Third, pa-tients with primary SS have elevated serum (25) andsalivary (26) levels of BAFF. This cytokine is a memberof the tumor necrosis factor family, which plays a keyrole as a survival factor for B lymphocytes (27,28), andits excessive production in primary SS is thought to beinvolved in the B cell hyperresponsiveness.

Histopathologic features of the salivary glands inSjogren’s syndrome

Local features of an ongoing autoimmune re-sponse. A B cell–mediated autoimmune response devel-ops locally in salivary glands in a milieu that favors Blymphocyte proliferation. For example, plasma cellsproducing autoantibodies to the 52-kd protein of SSA,the 60-kd protein of SSA, and/or the SSB particle wereclearly identified in the salivary glands of 8 of 10 primarySS patients who were tested (29). Support for theparadigm also comes from studies showing surface ex-pression of the SSA 52-kd, SSA 60-kd, and SSB proteinsduring apoptosis of salivary gland epithelial cells (30).However, in contrast to neonatal lupus, where patho-genic roles of the autoantibodies have been established,no substantial evidence of a pathogenic role of theseantinuclear autoantibodies in primary SS exists. To gainfurther insights into this phenomenon, the earliestevents that follow the binding of the B cell to antigenshould be delineated. Thus, B lymphocytes may act asantigen-presenting cells to the neighboring T lympho-cytes.

Their accumulation in exocrine glands suggests

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that plasma cells differentiate in ectopic GCs that de-velop in nonlymphoid sites, rather than from genuineGCs in secondary lymphoid organs (31). Initial clustersof B cells require the presence of multiple factors toevolve to GCs. The fact that GCs are involved ingenerating high-affinity antibodies in secondary lym-phoid organs suggests that local salivary gland antigensare crucial for these ectopic clusters. The influence oflocal antigens is evident from the high rate of Igheavy-chain variable-region gene mutations in lympho-proliferative sialadenitis clones and from the nonran-dom distribution of these mutations (32). Accumulationof replacement mutations in the complementarity-determining regions of the Ig genes and the restrictednature of the generated antibody repertoire serve asindicators of antigen-driven selection in the salivaryglands.

Intriguingly, however, we have shown that realGCs are less common in patients with SS than waspreviously suggested. Notably, we found that these B cellaggregates in salivary glands lack the GC B cell–associated CD10 and CD38 markers (Figure 1) (33). Wewere unable to find transcripts for activation-inducedcytidine deaminase in most of the microdissected GC-like cell aggregates from the salivary glands of SSpatients (33), although they have been associated with

follicular dendritic cell networks and interfollicular largeB cells (34). Thus, the mere finding of B cell aggregatesin the salivary glands does not necessarily imply that theyare functional GCs (35). However, immature pre-GC Bcells have been identified in these salivary gland B cellaggregates (36).

Due to the dependency of newly formed B cellson BAFF for survival, it is a prerequisite that thiscytokine be produced in the nearby tissue in order forthe cell aggregates to form. Indeed, we have shown thatBAFF is detectable in the salivary glands of patients withprimary SS (24). Analyses by 3 different reversetranscription–polymerase chain reaction methods ofmessenger RNAs from single cells eluted from thesalivary glands (37) confirmed the anomalous expressionof BAFF by B lymphocytes in the salivary glands ofpatients with primary SS (36). This locally producedBAFF is thought to rescue autoreactive B lymphocytesin an autocrine manner. This observation is all the moreimportant, given the data showing that transgenic ex-pression of the human BAFF gene is sufficient to inducean SS-like disease in normal mice (38).

Autoreactivity-driven B lymphocyte prolifera-tion. Autoreactive transitional type 1 (T1) and type 2(T2) B lymphocytes can accumulate in an area reminis-cent of the splenic marginal zone (MZ). This can serveas a fast track to autoimmunity. Based on our ownstudies of salivary glands, this event is likely to happen,since salivary gland cell aggregates appear to primarilyinclude T2 B cells and MZ-like B cells (34). Theseclusters of MZ-like B cells act as reservoirs for autore-active B lymphocytes. Because of the permanent avail-ability of autoantigens, a clone can thus be transformedand become dominant (Figure 2). Autoantibodies pro-duced in BAFF-transgenic mice cause nephritis andsialadenitis, but very interestingly, mice that lack MZ Bcells develop nephritis but not sialadenitis (39). Theimplication of these observations is that the develop-ment of autoimmune epitheliitis requires the presenceof MZ B cells.

The development of overt lymphoma may thusarise secondary to the autoimmune response. This islikely to be due to the fact that sustained stimulationpromotes the expansion of scarce clones and results inthe outgrowth of monoclonal aggregates of B cells (40).Consequently, the initial antigen-driven lymphoprolif-erative sialadenitis may shift to low-grade mucosa-associated lymphoid tissue (MALT) lymphomas (41), atransitional event that is difficult to stop (42). It isgenerally recognized that SS patients with lymphoprolif-erative sialadenitis often produce monoclonal Ig that

Figure 1. Two-color immunofluorescence staining of B cells from thesalivary glands of patients with primary Sjogren’s syndrome. B lym-phocytes were identified by their expression of CD20 (top) or IgD(bottom). Germinal center (GC)–like structures, called “real GCs,”are CD10� and CD38� (left), whereas structures called “aggregates,”which resemble marginal zone B cells, are devoid of CD10 (right) andCD38 (left). Reproduced, with permission, from ref. 33.

B CELLS AND B CELL CLONALITY IN SJOGREN’S SYNDROME 2607

may not reflect a malignant transformation. The illus-tration in Figure 3 presents the continuum of B celltransformation from the naive stage to a mature prolif-erating single clone and through to a nonmalignantpseudolymphoma stage. In practice, the distinction be-tween the transformation of lymphoproliferative sialad-enitis from low-grade lymphoma is nevertheless chal-

lenging. This dilemma leads ultimately to a failure toproperly treat the resulting neoplasia.

The transcription factor p53 is central to theregulation of B cell growth, and mutations in its gene areinvolved in the development of lymphoma in patientswith primary SS (43). Pathogenic salivary gland B cellsare purported to infiltrate MZ-like areas and invadeinterfollicular regions. The subsequent differentiation oflymphocytes into plasma cells is seen in a high propor-tion of cases of monoclonality (44). This was originallydemonstrated by membrane Ig staining and more re-cently by Southern blotting and by polymerase chainreaction analyses. Although a diagnosis of lymphopro-liferative sialadenitis can be mistaken in the presence ofa monoclonal population of B cells, the clonality of theB cells has never been shown to correlate with morpho-logic evidence of lymphoma. Indeed, the significance offinding monoclonal B cells remains unclear. Secondarytransformed clones, or subclones, as evidenced by iden-tical or similar Ig variable-region gene rearrangements,may also be seen (45). The propensity of lymphoprolif-erative sialadenitis–associated monoclonal B cells tolimit their expansion reflects an indolent characteristic.Initially, low-grade MALT lymphoma cells are retainedin the salivary glands for years, with no evidence ofexpansion. Dissemination of lymphoma cells outside thesalivary glands, however, may occur in a stepwise man-ner, resulting in their spreading to the lymph nodes and

Figure 2. Absence of clonal expansion of B lymphocytes eluted fromthe salivary glands of 9 of the 10 patients with primary Sjogren’ssyndrome who were tested. Clonal expansion (arrow) was identifiedonly in B lymphocytes from the salivary glands of patient 16. Daudicells were used as a control for monoclonality (arrow) and normal Bcells were used as a control for polyclonality in V–D–J polymerasechain reaction analyses.

Figure 3. Schematic depiction of the continuous maturation of B cells, from polyclonal cells to monoclonal proliferative cells, originallynonmalignant but ultimately becoming malignant.

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extranodal sites, such as the stomach, skin, and lungs(46).

The coexistence of leukemic B cell aggregateswith reactive GCs is well-established for MALT, but notfor nodal-associated lymphomas. The emergence oflymphocytes derived from a parental clone within nodalstructures is explained by the elegant concept of coloni-zation that was proposed by Falzon and Isaacson (47).The implication of this progression is that differentrearrangements in adjacent B cell clusters reflect addi-tional mutations specific for their novel microenviron-ment.

Conclusion

B lymphocytes are major contributors to thepathogenesis of SS. With the advent of biologic responsemodifiers, these data may be used in the development ofnovel approaches to therapy. Thus, B cell depletion (48)may hold significant promise for the treatment forpatients with primary SS.

ACKNOWLEDGMENTS

This article is dedicated to the memory of Yvon-LouisPennec. Many thanks to Simone Forest and Genevieve Michelfor typing the manuscript, and all our gratitude to ProfessorRizgar Mageed (Barts and the London Queen Mary School ofMedicine and Dentistry, London, UK) for his editorial helpwith the manuscript.

AUTHOR CONTRIBUTIONS

All authors were involved in drafting the article or revising itcritically for important intellectual content, and all authors approvedthe final version to be published.

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