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REVIEWS

B cells in the pathogenesis of primary


Sjögren syndrome
Gaëtane Nocturne and Xavier Mariette*
Abstract | Primary Sjögren syndrome (pSS) is a prototypical autoimmune disease. The
involvement of B cells in the pathogenesis of pSS has long been suspected on the basis of clinical
observations that include the presence of serum autoantibodies, hypergammaglobulinaemia,
increased levels of free light chains and increased risk of B cell lymphoma. Moreover, the
composition of the B cell subset is altered in pSS. In this Review, we discuss the mechanisms that
support the increased activation of B cells in pSS, including genetic and epigenetic factors and
environmental triggers that promote B cell activation via the innate immune system. B cell
activating factor (BAFF, also known as TNF ligand superfamily member 13B) is at the crossroads of
this process. An important role also exists for the target tissue (exocrine glands, namely the
salivary and lachrymal glands), which promotes local B cell activation. This continuous stimulation
of B cells is the main driver of lymphomatous escape. Identification of the multiple steps that
support B cell activation has led to the development of promising targeted therapies that will
hopefully lead to the development of an efficient therapeutic strategy for pSS.

Primary Sjögren syndrome (pSS) is a systemic auto- lymphoid tissue (MALT) lymphomas, which develop
immune disease that predominantly affects women in in the salivary glands, the target organ of the disease.
midlife and has an estimated prevalence of 0.3–3 per Moreover, disease activity is an important risk factor
1,000 of the general population1,2. Lymphocytic infil- for lymphoma, which indicates that B cell lymphomas
tration of salivary and lachrymal glands leads to ocular represent the ultimate stage of chronic B cell activation
and oral dryness, and systemic complications develop in pSS8.
in one-third of patients. pSS is prototypical among The past few years have witnessed major advances in
systemic autoimmune diseases, and a number of lines our understanding of the mechanisms involved in B cell
of evidence support the involvement of B cells in its activation in the pathogenesis of pSS. The aim of this
pathogenesis. Review is to provide an update concerning the drivers of
Patients with pSS exhibit biological signs of B cell activation in pSS. First, we describe advances in our
B cell activation, including serum polyclonal hyper­ understanding of the genetics involved, focusing on data
gammaglobulinaemia, increased levels of free light involving B cells and plasma cells. We also discuss the
chains and positivity for autoantibodies such as rheu- role of environmental factors, the molecular and cellu-
matoid factor (RF), anti-Sjögren-syndrome-related lar mechanisms that support B cell activation and newly
antigen A (SSA; also known as Ro) antibodies (in described pathogenic pathways involved in lymphoma-
Department of 60–80% of patients) and anti-Sjögren-syndrome-­related genesis. Finally, we attempt to link pathogenic pathways
Rheumatology, Université antigen B (SSB; also known as La) antibodies (in 30–40% involving B cells in pSS with new treatments that target
Paris-Sud, INSERM U1184:
Centre for Immunology of
of patients)3. As in rheumatoid arthritis (RA) and sys- the activation of B cells, which are currently or soon to
Viral Infections and temic lupus erythematosus (SLE), auto­antibodies spe- be evaluated in pSS.
Autoimmune Diseases, cific for pSS can develop long before symptoms emerge,
Assistance Publique-Hôpitaux highlighting a key early role for B cells in pSS4,5. B cells Genetics and epigenetics
de Paris (AP‑HP), Hôpitaux
are also found within the target organ of pSS, the sal- Genome-wide association studies
Universitaires Paris-Sud
Bicêtre, Le Kremlin-Bicêtre, ivary glands, and can occasionally form ectopic ger- Genetic studies give the unique opportunity to highlight
France. minal centres (GCs)6. In addition, patients with pSS new pathogenic pathways. Previously, genetic studies
*e-mail: xavier.mariette@ have an increased risk of developing B cell lymphoma; in pSS were based on a gene candidate approach that
aphp.fr comorbid lymphomas actually occur in patients with was inspired by studies in the field of SLE research. The
doi:10.1038/nrrheum.2018.1 RA, SLE or pSS, but those with pSS have the highest results of these studies confirmed the involvement of
Published online 8 Feb 2018 risk7. These lymphomas are mainly mucosa-­associated key pathways, such as the interferon signalling pathway

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Key points Overall, these GWAS highlight the involvement


of B cell stimulation in pSS via B cell receptor (BCR)
• Genetic risk factors associated with primary Sjögren syndrome (pSS) can promote activation (BLK), follicle organization (CXCR5) and
B cell activation, as can epigenetic changes, which can sometimes affect the same plasma cell activation (PRDM1). Beyond implicating
disease-associated genes. B cells in the pathogenesis of pSS, these genetic studies
• BAFF (also known as TNF ligand superfamily member 13B) is central to the crosstalk highlight three other major pathogenic pathways in this
between early activation of the innate immune system and the stimulation of disease: activation of the innate immune system, nota-
autoreactive B cells. bly through type I interferons (IRF5); T cell activation
• CD27+ memory B cells, marginal zone B cells, plasmablasts and plasma cells are the (HLA and MHC associations, STAT4, IL12, KLRG1,
key subsets of B cells involved in the pathogenesis of pSS. SH2D2A and NFAT5); and control of NF‑κB activation
• Target organs (salivary and lachrymal glands) are involved in B cell activation, notably (TNIP1 and TNFAIP3).
via the formation of germinal centre-like structures within the epithelium and plasma
cell niches.
DNA methylation
• Continuous stimulation of autoreactive B cells by immune complexes is the first step Gene expression is regulated not only by DNA sequences
towards lymphomagenesis associated with pSS. but also by epigenetic modifications, which include the
• Continuously activated autoreactive B cells need to be tightly controlled by genetic covalent modification of DNA (methylation) or proteins
factors and by the tissue microenvironment as subtle defects in these controls might (histone acetylation) and the splicing of RNA, as well as
promote clonal escape and lymphomagenesis.
the action of microRNAs (mi­RNAs). Again, the implied
involvement of B cells is supported by data from epige-
netic studies. The first genome-wide DNA methylation
in pSS9. However, in the past few years, three large- study of naive CD4+ T cells from the blood of patients
scale genome-wide association studies (GWAS) have with pSS was performed in 2014, in which interferon-­
revealed the involvement of new loci in pSS. regulated genes were found to be hypo­methylated15. In
The first GWAS involved 396 patients with pSS and 2016, the methylation of circulating B cells was assessed
1,980 healthy individuals of European ancestry and was in two separate studies16,17. In both studies, the number
followed by a replication study of 22,350 gene variants of genes that were differentially methylated in patients
in 1,263 patients with pSS and 3,987 healthy individu- with pSS compared with controls was higher for B cells
als10. The HLA region at 6q21 was the HLA region most than T cells. Again, interferon-regulated genes were
significantly associated with pSS (P < 5 × 10−8). Moreover, hypomethylated in patients with pSS, and in B cells,
disease associations were noted with polymorphisms this hypomethylation was associated with an increase
located at six independent loci: IRF5, BLK, STAT4, in gene expression17. The regulation of genes by methyl­
IL12A, CXCR5 and TNIP1 (REF. 10). In addition to these ation mostly affected genes containing pSS-associated
loci, associations with 29 other regions were discovered, polymorphisms, which suggests that the same key genes
including TNFAIP3 (which encodes TNFα-induced are controlled by genetic and epigenetic modifications16.
protein 3; also known as A20), a key negative regulator Abnormalities in DNA methylation occurred mainly
of the nuclear factor‑κB (NF‑κB) pathway, and PRDM1 in patients with active disease and in those who were
(which encodes PR domain zinc finger protein 1; also autoantibody positive18. The association between auto­
known as BLIMP1), an important transcription factor antibody status and methylation profile could be linked
in plasma cell differentiation10. to the hypomethylation of SSB gene promoters, which
A second GWAS examined a cohort of patients with was associated with an increased expression of the
pSS of Han Chinese descent and included 597 patients auto­antigen SSB/La. Inhibition of methylation using
with pSS and 1,090 healthy individuals11. In addition to 5‑­azacytidine increased the mRNA level of SSB in a
MHC class II genes, three other genes were identified human salivary gland cell line18. Methylation in the tar-
as being associated with pSS11. The most strongly asso- get organ of the disease has been directly assessed19,20, but
ciated gene in the Chinese cohort was GTF2I, located the study of tissue samples from minor salivary glands
at 7q21. The two other polymorphisms associated with might have some limitations as such samples contain a
pSS were in STAT4 and again in TNFAIP3, which was mixture of epithelial and immune cells. However, these
only weakly associated with pSS in the European descent studies revealed some interesting findings. Alterations
cohort 10 but is strongly associated with pSS in patients to the epigenetic machinery mainly affected cellular
with lymphoma12,13. responses driven by interferons and antioxidants and
In 2017, another GWAS was conducted using the could thereby deregulate mi­RNAs as well as a large
SICCA (Sjögren’s International Collaborative Clinical range of genes involved in cellular activation, antigen
Alliance) cohort, which included 1,513 patients with presentation and autoantigen production19. In fact,
pSS14. This study focused on the effect of ancestry on sus- a study of the global methylation profile of salivary
ceptibility to pSS and compared individuals of European glands revealed a lower level of methylation in sali-
or Asian descent. In addition to finding associations in vary gland epithelial cells from patients with pSS than
established regions of the MHC, the results of this study 14 in those from healthy individuals20. DNA demethyla-
confirmed the previously identified associations with IRF5 tion is associated with lymphocyte infiltration, notably
and STAT4 (REFS 10,11). New regions associated with pSS B cell infiltrates, as demonstrated by co-culture of the
included KLRG1 in Asian individuals and SH2D2A and human salivary gland cells with B cells18, and the protein
NFAT5 in all ethnicities studied. kinase Cδ–­extracellular-signal-regulated kinase–DNA

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methyltransferase 1 pathway is likely to be involved in Latent EBV infection and EBV reactivation were specific
this phenomenon20. These results emphasize the role of features of the salivary glands of patients with pSS that
dysregulated methylation in pSS, especially in B cells. contain GC‑like structures, which seemed to provide a
protective niche for EBV. Nuclear egress protein 2, a sign
MicroRNAs of EBV reactivation, was detected in peri-follicular plasma
mi­RNAs are key epigenetic regulators. Differential cells, and plasma cells infected with EBV were reactive
miRNA expression patterns can be seen in the blood21–23 to antibodies to 52 kDa SSA/Ro antigen (Ro52, also
and salivary glands24 of patients with pSS. These stud- known as TRIM21)34. Another study performed in mice
ies should be interpreted with caution as they are based demonstrated that the expression of EBV latent mem-
on the analysis of heterogeneous populations of cells brane protein 2A (LMP2A) in B cells promoted plasma
(peripheral blood mononuclear cells or cells from sal- cell differentiation; conditional expression of LMP2A in
ivary glands) that might differ in their composition B cells from the GC caused lupus-like disease in mice35.
between patients and healthy individuals. However, In addition, EBV-encoded small RNA (EBER) complexes
a 2017 study using purified circulating T cells and with SSB/La and can activate the innate immune system
B cells revealed a role for miR‑30b‑5p in B cell biology via Toll-like receptor 3 (TLR3), leading to the production
through its regulation of B cell activating factor (BAFF, of type I interferons and pro-­inflammatory cytokines30.
also known as TNF ligand superfamily member 13B), a In 2017, response to the H1N1 influenza vaccine
key B cell cytokine25. Notably, miR‑30b‑5p expression was assessed in patients with pSS, who produced higher
was inversely correlated with the expression of BAFF- vaccine-specific antibody titres than matched controls
encoding transcripts. Moreover, functional experiments and showed a general increase in nonspecific anti-
showed an increased expression of BAFF after inhibition bodies, including an anti-EBV response and increased
of miR‑30b‑5p25, providing support for the emerging auto­antibody levels, as well as having higher numbers of
role of this miRNA in B cell regulation. circulating CD19dimCD138+ plasmablasts than matched
controls36. This finding might be the result of a hyper-
Environmental factors responsiveness of B cells to viral stimulation via TLR
Viral triggers of B cell activation stimulation in patients with pSS.
The triggering of disease by viruses, including hepatitis C
virus, T lymphotropic virus type I and coxsackie­viruses, Endogenous retroviruses
has long been suspected in pSS, but data remain contro- Looking beyond exogenous viruses, the over­expression
versial9. Close attention has been paid to the Epstein–Barr of some endogenous retroviral sequences (such as occurs
virus (EBV), perhaps owing to the tropism of this human when epigenetic abnormalities are present) could be
DNA herpesvirus to B cells26 and epithelial cells27. Most involved in B cell activation37. Retroelements are non-­
of the literature revealed an increased prevalence of the coding DNAs that make up about half of the human
EBV genome and proteins in the salivary glands of genome. These DNA molecules epigenetically regulate
patients with pSS28. Notably, the absence of detected gene expression by providing new promoters for genes or
virus does not negate a possible role for a virus at an by generating mi­RNAs. Moreover, when overexpressed
early stage of the disease. This assertion is supported by (for example, during epigenetic dysregulation) retro­
evidence using the experimental model of Fas-deficient elements might induce an interferon response and be a
C57Bl/6‑lpr/lpr mice, which develop systemic auto­ driver of the type I interferon signature seen in patients
immunity and glomerulonephritis without salivary gland with pSS.
involvement. Three months after infection with murine Endogenous retroviral sequences participate in a
cytomegalovirus (a sialotropic virus), these mice showed T cell-independent B cell response that mainly involves
salivary gland infiltrates, but no virus was detectable marginal zone (MZ) B cells38. This finding is of particu-
within the glands29. lar interest because MZ B cells have a key role in pSS;
EBV could be stimulating B cells by a variety of BCR crosslinking induced by T cell-independent antigen
mechanisms. First, EBV could be stimulating the innate recognition leads to a signalling cascade that results in
immune system30, which, in turn, can activate B cells, the transcription of endogenous retroviral DNA38. The
notably via BAFF. Second, the virus is well known to transcribed viral RNA molecules can then activate the
mimic key pathways in B cell activation, including sig- RNA sensor pathway via retinoic acid-inducible gene I
nalling via the BCR and CD4031. EBV can also stimu- (RIG‑I; also known as probable ATP-dependent RNA
late B cells by inducing the production of key cytokines: helicase DDX58) and mitochondrial antiviral signalling
EBV-encoded latent membrane protein 1 induces B cells protein (MAVS). Alternatively, the viral RNA molecules
to express a proliferation-inducing ligand (APRIL, can be reverse-transcribed into DNA and go on to stim-
also known as TNF ligand superfamily member 13)32. ulate the DNA sensor pathway via cyclic GMP-AMP
Moreover, EBV might participate in autoantibody pro- synthase (cGAS) and stimulator of interferon genes pro-
duction. In mice, EBV activates caspases, which promote tein (STING). The stimulation of this pathway enables
the accumulation of α‑fodrin (also known as spectrin α a second wave of signalling that promotes the produc-
chain, non-­erythrocytic 1), and reactivation of EBV leads tion of specific IgM molecules and complete MZ B cell
to the production of anti‑α‑­fodrin auto­antibodies33. In activation38.
Among the retroelements, long interspersed
the past few years, a link between EBV and GC‑like struc- nuclear element 1 (LINE‑1) and Alu might be implicated
tures within salivary glands has also been suspected34. in the pathogenesis of pSS. LINE‑1 participates in the

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production of type I interferons, which leads to B cell the stratification of patient subsets with distinct levels of
activation39,40. In fact, levels of LINE‑1 are increased in disease activity 50. Notably, increased numbers of plasma-
patients with pSS and are associated with increased blasts in the blood and plasma cells in the salivary glands
production of type I interferons39. By contrast, Alu tran- positively correlated with serum IgG levels, disease activ-
scripts are induced by type I interferons and participate ity and positivity for auto­antibodies. In addition, almost
in the amplification of the immune response associated half of the infiltrating B cells in the peripheral inter-
with infection41. Notably, Alu retroelements can be tar- stitium of the glandular lobules of salivary gland tissue
geted by Ro60 (the 60 kDa SSA/Ro antigen), and thus can samples were fully differentiated plasma cells. Within
also participate in the formation of immune complexes the CD38+CD27+ B cell subset, a substantial fraction was
in the presence of anti‑Ro60 autoantibodies. Overall, CD19 negative50; this phenotype is likely to be associated
endogenous retroviruses might have a protective role in with long-lived plasma cells involved in the maintenance
the context of infection, which explains their persistence of humoral immunity 51. Thus, antibody-producing
in the human genome, but as a consequence, could also B cells can be thought of as consisting of two subsets:
favour the development of autoimmunity. short-lived plasmablasts that might recirculate from the
tissue and long-lived plasma cells that differentiate and
Drivers of B cell activation in pSS accumulate within the salivary glands, which represent
B cell subpopulations in pSS a real niche for these cells (Fig. 1).
B  cell subpopulations have been assessed in the In 2017, a specific subset of circulating plasmablasts
peripheral blood and salivary glands of patients with with a mucosal phenotype was described in patients with
pSS. Increased numbers of mature IgD+CD38+ and SLE52. This plasmablast subset was able to produce IgA
IgD+CD38++ B cells (described as GC founder cells) are and IgG autoantibodies and to home to mucosal sites via
found in patients with pSS42. These subsets of B cells the expression of CC-chemokine ligand 28 (CCL28) and
express high levels of CD19, which could increase the might have a key role in plasmacytosis in SLE. Regarding
strength of BCR signalling in these cells43. In 2017, high the mucosal tropism of pSS and the analogies between
levels of tyrosine-protein kinase BTK were described pSS and SLE, suggests these IgA plasma cells might also
in B cells from patients with pSS, which might also be involved in pSS; however, this specific subset has
increase survival signals from the BCR44. However, the not yet been assessed in pSS. A 2017 study of patients
best-­characterized change in the peripheral blood cells with pSS who had renal involvement also highlighted
of patients with pSS is a decreased number of circulating the importance of the plasma cell infiltrate in pSS-­
CD27+ memory B cells42,45–48. One explanation for the associated interstitial nephritis53. Overall, these studies
decreased number of these B cells is the migration to or highlight the importance of plasmablasts in the blood
retention of this subset within target organs, as suggested and plasma cells in the target organs of pSS and identify
by the increased number of memory B cells seen in the the latter as probably being long-lived plasma cells that
salivary glands of patients with pSS49. secrete anti-SSA/Ro and anti-SSB/La autoantibodies54.
These findings might have important therapeutic con-
Plasmablasts and plasma cells. In addition to detecting sequences and highlight the need to target plasmablasts
increased numbers of memory B cells, an increased num- and plasma cells in this disease.
ber of CD27highCD19dimCD20− plasmablasts was found
in a subgroup of patients with pSS who had a history Marginal zone B cells. The involvement of MZ B cells
of lymphoma49. A 2016 unbiased immuno­phenotyping in pSS has been supported by the results of studies using
study that used cytometry by time‑of‑flight (CyTOF) mouse models of pSS, including Tnfsf13b‑transgenic
provided fresh insights into the involvement of B cell mice55, NOD‑Aec1Aec2 mice56 and Txlna-transgenic
subsets, including CD27+ memory B cells and plasma- mice57,58. In these murine models, depletion of MZ B cells
blasts, in pSS50. This study included blood samples from alleviated pSS manifestations: salivary function was pre-
49 patients with pSS and 45 healthy individuals, which served, and animals were negative for autoantibodies and
were quantified for 34 protein markers by mass cytome- had normal histology of salivary and lacrimal glands. In
try. This approach enabled the definition of a blood pSS contrast to data from mouse models, no human data have
signature comprising 6 unique cellular phenotypes that formally demonstrated the involvement of MZ B cells in
included decreased numbers of CD27+ memory B cells, pSS. However, assessment of B cells from the salivary
CD4+ T cells and plasmacytoid dendritic cells (pDCs) and glands of patients with pSS revealed that a high propor-
an increased representation of activated CD4+ and CD8+ tion of CD27+ memory B cells were IgM+ cells, which
T cells and plasmablasts50. CyTOF immunophenotyping raised the question of whether T cell-independent B cell
of salivary gland tissue samples from patients with pSS selection was taking place and whether these cells could
confirmed the presence of B cells, including terminally have an MZ phenotype59. The fact that most instances
differentiated plasma cells, as well as high numbers of of pSS-associated B cell lymphoma develop from MALT
activated CD8+ T cells and activated epithelial cells. (meaning from MZ B cells)60 supports a role for this
Analysis of paired blood and salivary gland tissue sam- subset in pSS.
ples enabled the researchers to correlate variations in cell
populations in the blood and tissue and to correlate these Regulatory B cells. B cells are not only effector cells but
findings with clinical and biological parameters. Taken can also have regulatory properties, which have been well
together, the identified blood and tissue signatures led to studied in the field of autoimmunity 61. These regulatory

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Virus
Endogenous
retroviral
Salivary epithelial cells elements

Immune
DC complex
BAFF IFNα

Autoantibody
production

T cell B cell Germinal


rich area rich area centre

IL-21
FDC
TFH cell Plasma cell
ICOSL
ICOS
• CXCL12
• IL-6
Stromal
CD40 cells
TFH cell B cell Activation
CD40L and migration B cell

↑ CXCL13
Plasma cell niche

Figure 1 | B cell activation in salivary glands. Salivary glands are the target organ of primary Sjögren syndrome (pSS),
an autoimmune epithelitis, and epithelial cells have an active role in the pathogenesis of this disease. 
Nature Salivary
Reviews epithelial
| Rheumatology
cells express co-stimulatory molecules and can present autoantigen to immune cells. Epithelial cells also participate in
B cell activation by secreting B cell activating factor (BAFF, also known as TNF ligand superfamily member 13B) following
stimulation by viruses or IFNα. T follicular helper (TFH) cells, which secrete IL‑21, and the expression of chemokines such
as CXC-chemokine ligand 13 (CXCL13) lead to the formation of germinal centre-like structures that support B cell
activation. Moreover, epithelial and stromal cells might participate in the formation of a plasma cell niche, for example,
through the production of survival factors such as CXC-chemokine ligand 12 (CXCL12) and IL‑6, which enables
long-lived plasma cells to perpetuate in the tissue, thereby fulfilling an important role in the pathogenesis of pSS. DC,
dendritic cell; FDC, follicular dendritic cell; ICOS, inducible T cell co-stimulator; ICOSL, ICOS ligand.

B cells are likely to function mainly via the secretion of production by pDCs. In patients with SLE, this regu-
IL‑10, which has immunosuppressive properties (Box 1). latory feedback is disrupted. Exposure to high levels of
Regulatory B cells are able to control T helper 1 (TH1) type I interferons leads to the hyperactivation of pDCs,
cell proliferation by producing IL‑10 and inducing the which activate plasmablasts that secrete pathogenic anti-
expansion of regulatory T (Treg) cells62,63. This specific bodies and fail to induce IL‑10‑producing regulatory
action of IL‑10‑producing regulatory B cells on TH1 B cells. Although this study 65 was performed in patients
cells does not seem to be impaired in pSS64,65; how- with SLE, the cells and cytokines being studied are also
ever, other suppressive functions of regulatory B cells involved in pSS, so these defects might also participate
could be involved. The crosstalk between pDCs and in the pathogenesis of pSS.
IL‑10‑producing regulatory B cells has been assessed Effective suppression by regulatory B cells is likely
in patients with SLE65. In healthy individuals, pDCs not to be exclusively mediated by IL‑10 production;
can drive the maturation of IL‑10‑producing regula- cell–cell contact and other cytokines might also par-
tory B cells and control plasmablasts via IFNα produc- ticipate in the regulatory functions of B cells63. Several
tion, and in turn, regulatory B cells can restrain IFNα studies have shed light on IL‑35, a new cytokine with

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Box 1 | Regulatory B cells region of the spleen61, which is likely to have two negative
effects. First, MZ B cells interact with T follicular helper
In addition to effector cells, subpopulations of immune cells with regulatory functions (TFH) cells and can promote the maturation of the B cell
have been described. The first regulatory cells to be described were regulatory T (Treg) response within GCs, thereby leading to auto­antibody
cells, but research over the past few years has identified new cells with regulatory secretion. Second, migration of MZ B cells leads to dis-
functions, including tolerogenic dendritic cells, M2 macrophages and
ruption of the interactions between these B cells and
regulatory B cells.
Regulatory B cells have inhibitory properties and can target effector cell subsets, MZ macrophages, which inhibits the phagocytosis of
including TNF-producing monocytes, IL‑12‑producing dendritic cells, T helper (TH) 17 apoptotic cells by these macrophages. Apoptotic cells are
cells, TH1 cells and cytotoxic CD8+ T cells. In addition, regulatory B cells promote the then able to form complexes with autoantibodies, and
differentiation of Treg cells61. However, the definition of what constitutes a regulatory these immune complexes can in turn stimulate pDCs
B cell has been controversial. In mice, transitional 2 (T2) marginal zone precursor to produce interferon, thereby leading to a vicious cir-
cells, CD5+CD1dhigh B cells and Tim1+ B cells have all been described as potential cle of activation of the immune system. The role of MZ
subsets of regulatory B cells148. In humans, CD19+ CD24high CD38high CD1dhigh and macrophages has not yet been assessed in patients with
CD19+CD24high CD27+ populations of regulatory B cells have been identified148. pSS, but their possible role could be important given
A consensus has been reached on the capacity of regulatory B cells to produce IL‑10, the potential for these cells to interact with TFH cells
an immunoregulatory cytokine, and IL‑10 production is currently the best way to
and B cells.
define regulatory B cells. Thus, IL‑10‑producing regulatory B cells are sometimes
referred to as B10 cells64. Besides secreting IL‑10, some subsets of regulatory B cells Another example of interaction between the innate
also secrete IL‑35, an anti-inflammatory cytokine of the IL‑12 family66. These immune system and B cells is via neutrophils. A novel
IL‑35‑producing regulatory B cells are likely to be mostly plasma cells, giving rise to population of neutrophils localized within human
the concept of regulatory plasma cells. Defects in regulatory B cells have been splenic MZ promoted B cell activation and differen-
described in patients with autoimmune diseases149. In primary Sjögren syndrome, an tiation via the production of BAFF, APRIL and IL‑21.
imbalance between IL‑12 and IL‑35 could participate in perpetuating the activation These new cells were termed B helper neutrophils69.
of the immune system68. Innate lymphoid cells were also suggested to promote
the B helper phenotype in neutrophils; B helper neutro-
phils increased antibody production by MZ B cells in the
potential regulatory functions that is part of the IL‑12 human spleen70. Precise assessment of neutrophils has
family of cytokines. IL‑35 is a heterodimer comprising not been performed in patients with pSS, but increased
p35 and EBI3. Two murine studies have demonstrated numbers of granulocytes have been described71, and a
that IL‑35 could drive regulatory functions in B cells. deep characterization of the subsets involved would be
In the first study 66, IL‑35 induced B cells that secreted of interest. Altogether, these studies support the idea that
IL‑10 and IL‑35. IL‑35+ B cells probably directly inhib- B cell activation might be promoted at an early stage by
ited TH1 cells and T helper 17 (TH17) cells and induced the innate immune system.
Treg cell proliferation. Together, these actions led to a
reduction in inflammation in a murine model of uvei- BAFF
tis66. In the second study 67, IL‑35+ B cells were protective BAFF is a key cytokine for B cells and promotes their mat-
in the context of autoimmunity in a murine model of uration, proliferation and survival. Tnfsf13b‑transgenic
experimental autoimmune encephalomyelitis but had mice, which overexpress BAFF, illustrate the role of this
deleterious effects in the context of Salmonella infec- cytokine in pSS. Tnfsf13b‑transgenic mice first develop
tion. IL‑35‑producing B cells were mainly plasma cells, a lupus-like phenotype and then acquire features of pSS,
which gave rise to the concept of regulatory plasma including sialadenitis. As these mice age, lymphoma
cells. In 2017, dysregulation of the balance between pro-­ develops spontaneously (at around 1 year of age)72. A
inflammatory IL‑12 and anti-­inflammatory IL‑35 was role for BAFF has been suspected in pSS on the basis of
described in patients with pSS68. Serum levels of IL‑35 elevated BAFF levels in the serum of patients with pSS
were lower in patients with pSS than in healthy indi- and the correlation of BAFF levels with levels of anti-
viduals, whereas IL‑12 was highly expressed in patients SSA/Ro and anti-SSB/La antibodies and RF73. Moreover,
with pSS. In addition, increased IL‑35 levels were associ- increased BAFF levels have been detected in the salivary
ated with low disease activity in pSS, and this IL‑35 was glands of patients with pSS74.
probably produced by B cells, which supports a defective Usually, BAFF is produced by monocytes, macro­
function of IL‑35+ regulatory B cells in pSS. phages and dendritic cells. In patients with pSS, T cells
and B cells are also able to secrete BAFF74,75. Notably,
B cells and the innate immune system salivary epithelial cells (the target of autoimmunity) are
The interferon signature that is characteristic of pSS has able to secrete BAFF75,76. This finding strongly supports
been demonstrated by genetic studies, transcriptomic the idea that epithelial cells have an active role in the
analysis and the results of studies into pDCs, profes- pathogenesis of pSS via the promotion of B cell activa-
sional producers of type I interferon, within the salivary tion. In addition, BAFF might also promote epithelial cell
glands9. Several studies have provided support for the survival via TNF receptor superfamily member 13C (also
interaction between the interferon signalling pathway known as BAFF receptor), which supports an autocrine
and B cells in autoimmunity and, notably, SLE (the effect of BAFF on these target cells77.
pathogenesis of which shares similarities with pSS). In As previously mentioned, BAFF could provide a link
a murine model of SLE, type I interferon promoted the between activation of the innate immune system and the
translocation of MZ B cells from the MZ to the follicular adaptive immune system (mainly via B cell stimulation).

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In reality, BAFF is released mainly by cells of the innate Germinal centre-like structures
immune system78. The production of BAFF is induced The presence of B cells within salivary glands is a key fea-
by type I and II interferons76,79, and TNFSF13B (encod- ture of pSS. This B cell infiltrate could potentially follow
ing BAFF) can therefore be considered an interferon-­ a continuum that leads from discrete infiltration to foci
stimulated gene. Interferon regulatory factors (IRFs) to aggregates and even on to more organized structures
control the transcription of TNFSF13B: IRF1 and IRF2 that eventually share morphological features with GCs
are inducers of TNFSF13B transcription, whereas IRF4 (termed ectopic GCs or GC‑like structures; BOX 2). These
and IRF8 act as repressors80. A clear correlation has been structures are not specific to pSS but have been described
demonstrated between the type I interferon signature at many tissue sites that have been exposed to chronic
and the secretion of BAFF by monocytes81. Moreover, inflammation. GC‑like structures share morphological
viruses can promote the production of BAFF by epithelial features with classic GCs and are involved in somatic
cells via stimulation of TLRs by double-stranded RNA82 hypermutation, BCR editing and immuno­g lobulin
(FIG. 1). The induction of BAFF by viruses is not specific to class switching.
epithelial cells, but the type of virus and the mechanisms Such GC‑like structures are likely to be involved in
that lead to BAFF secretion do differ depending on the the pathogenesis of pSS via the promotion of chronic
cell type involved83. B cell stimulation. Several lines of evidence support this
Increased levels of BAFF could preferentially support role: these GC‑like structures are present within the sal-
a pathogenic subset of B cells that have an MZ B cell-like ivary gland epithelium of 10–30% of patients with pSS6;
phenotype within exocrine glands84. A role for BAFF in an association exists between polymorphisms within
ectopic GC formation has also been proposed. To test the CXCR5 locus (encoding a key receptor for TFH hom-
this hypothesis, overexpression of BAFF in NOD mice ing) and pSS10; and these structures might participate in
was induced by the hydrodynamic delivery of a plas- autoantibody production. In a murine model of salivary
mid85. BAFF overexpression increased lymphocytic infil- gland inflammation, glandular inflammation is associ-
tration and B cell differentiation; however, BAFF was not ated with the production of antinuclear antibodies86.
able to efficiently promote ectopic GC formation in these B cells producing autoantibodies are located at the mar-
mice85. Thus, the formation of these GC‑like structures gin of such GC‑like structures87, making these structures
might be driven by other molecular and cellular players. likely to be involved in promoting chronic activation of
autoimmune B cells. In addition to these characterized
GC‑like structures, aggregates made of MZ B cell-like
cells and type 2 transitional B cells have been described
Box 2 | Germinal centre-like structures in the salivary glands of patients with pSS88. Interestingly,
Ectopic lymphoid structures that resemble germinal centres (GCs) can be observed in
B cells from such aggregates can be distinguished from
the chronically inflamed tissues of patients with a variety of autoimmune diseases, GC B cells by their lack of expression of activation-­
including primary Sjögren syndrome (pSS), and are termed GC‑like structures89. The induced cytidine deaminase (AICDA; also known as
expression of specific homing molecules, such as the chemokines CXC-chemokine AID) and CXC-chemokine receptor 5 (CXCR5); however,
receptor 5 (CXCR5) and CXC-chemokine ligand 13 (CXCL13), promotes the these cells are likely to support autoreactivity, similar to
organization of GC‑like structures by recruiting T follicular helper (TFH) cells cells from GC‑like structures.
and B cells. Mechanisms involved in the neogenesis of GC‑like
TFH cells are characterized by IL‑21 secretion and expression of B-cell lymphoma 6 structures differ from those involved in secondary GC
protein (BCL6) and inducible T cell co-stimulator (ICOS), and participate in GC formation89. Three factors are of great importance: the
formation150. Once GCs have been formed, TFH cells help to maintain these structures
CXC-chemokine ligand 13–CC-chemokine receptor 5
as well as to regulate the differentiation of B cells into plasma cells and memory B cells.
In 2017, a T cell population termed TFH-like cells was described as being similar to
(CXCL13–CCR5) axis, IL‑22 and T FH cells. These
classical TFH cells in its production of IL‑21 and expression of ICOS and BCL6; however, cytokines and chemokines are involved in the initiation
TFH-like cells did not express CXC-chemokine receptor 5 (CXCR5) but instead and maintenance of GC‑like structures, whereas TFH
expressed CC-chemokine receptor 9 (CCR9), the ligand for which is CC-chemokine cells are mediators of GC‑like function.
ligand 25 (CCL25)101. This new subset is likely to be an efficient driver of B cell
stimulation because these cells secreted higher levels of cytokines, including IFNγ, IL‑4 The CXCL13–CCR5 axis. Two cell types are involved
and IL‑21, and were able to induce IgG production more potently than CCR9−CXCR5− in the genesis of GC‑like structures: lymphoid tissue
T helper cells. In the same year, a related population of ICOS+ PD1high BCL6+ T cells that inducer cells and lymphoid tissue organizer cells. The
do not express CXCR5 (called T peripheral helper cells) and that are able to stimulate recruitment of lymphoid tissue inducer cells is driven by
B cell activation was discovered in the synovium and blood of patients with
the expression of CXCL13 and IL‑7 because these cells
rheumatoid arthritis102.
Functions normally associated with secondary lymphoid organs, such as somatic
express their respective receptors, CXCR5 and CD127
hypermutation, B cell receptor editing and class switching, take place within GC‑like (REF. 89). CXCL13 is central to the formation of GC‑like
structures. The involvement of GC‑like structures in pSS is supported by several lines structures: mice lacking CXCR5 have no inguinal lymph
of evidence. First, GC‑like structures are present within the epithelium of salivary nodes and possess very few abnormal Peyer’s patches90.
glands and are associated with increased levels of circulating autoantibodies and By contrast, overexpression of CXCL13 is associated
systemic manifestations, including an increased risk of lymphoma120. Second, with the formation of ectopic lymphoid tissue composed
genome-wide association studies identified a polymorphism within the CXCR5 locus primarily of B cells91.
associated with pSS10. Finally, TFH cells have been identified as a key cellular player in In patients with pSS, CXCL13 levels are increased
the pathogenesis of pSS100, indicating that these structures might be a promising in the serum and saliva and are associated with dis-
therapeutic target in the disease.
ease activity 92. CXCL13 is also associated with GC‑like

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structures in patients with pSS93. In addition, non-­ disease development. Notably, these cells participate in
immune cells resident in salivary glands, including B cell activation via their ability to secrete cytokines such
ductal epithelial cells and endothelial cells, can produce as BAFF and IL‑21 (REFS 82,100). In addition, the presence
CXCL13 (REF. 89). In a murine model of virus-induced of circulating short-lived plasmablasts and accumulation
lymphoid neogenesis, the production of CXCL13 was of long-lived plasma cells within the glands are key fea-
induced by IL‑22 (REF. 94). Il22−/− mice are protected tures of pSS50. Under normal conditions, plasma cells are
against ectopic GC development and show reduced not present in salivary glands but are found in the bone
signs of autoimmunity and reduced B cell recruitment marrow. The survival of plasma cells is dependent on
to salivary glands. In this model94, the main producers of signals received through adhesion molecules and a series
IL‑22 were likely to be classical αβ T cells. Natural killer of soluble factors such as CXC-chemokine ligand 12
(NK) cells that express the NKp44 receptor could also (CXCL12), IL‑6 and APRIL, a requirement that triggers
be a source of IL‑22 within the salivary glands of patients the formation of haemato­poietic stem cell niches. In
with pSS95. This subset of NK cells, termed NK22, has addition, under normal circumstances, the gut mucosa
been found within MALT and might participate in BAFF harbours a high level of IgA+ plasma cells that constitute
production96. IL‑18 is also likely to promote IL‑22 receptor a first-line barrier against pathogens. These IgA+ plasma
production; high levels of IL‑22 receptor were detected cells are located within the gut-associated lymphoid tis-
in tissue and circulating myeloid cells from patients with sue (GALT), where they have access to survival factors
pSS and have been proposed to be a specific immunologic such as BAFF, APRIL and IL‑6 (REF. 104). In the murine
signature of the disease97. model of virus-induced GC‑like structure formation,
IL‑22 induced the secretion of CXCL12 by epithelial
TFH cells and IL‑21. TFH cells are specialist providers of cells94. Similarly, in salivary glands from patients with
B cell help, notably by the secretion of IL‑21. These cells pSS, CXCL12 expression and IL‑6 were associated with a
have an important role in the maintenance of GC‑like high focus score and a high degree of infiltration by
structures, and their involvement in pSS is supported by CD138+ plasma cells105. High levels of CXCL12 have
several lines of evidence. IL‑21 was detected at increased also been detected in the ductal epithelial cells of salivary
levels in the serum and salivary glands of patients with glands with GC‑like structures from patients with pSS93.
pSS compared with disease controls (RA and SLE plasma
and sicca salivary glands) and correlated with auto­ Pathogenic role of autoantibodies
antibody titres in these patients98. B-Cell lymphoma 6 B cells can participate in the pathogenesis of auto­
protein (BCL6), a transcription factor associated with TFH immune diseases via several mechanisms: as cytokine
cells, was also detected in salivary glands from patients producers, antigen-presenting cells or autoantibody
with pSS that contained GC‑like structures99, and salivary secretors. The presence of autoantibodies is one of the
epithelial cells from patients with pSS directly induce the key features of pSS; in fact, the presence of anti-SSA/Ro
differentiation of IL‑21‑secreting TFH cells100. autoantibodies in the serum is one of the items with the
In 2017, a subset of T cells with a TFH-like phenotype highest weight (3 points) in the 2016 joint ACR–EULAR
was described101. This TFH cell subset shares some char- pSS classification criteria106. No direct pathogenic role
acteristics with classic TFH cells, including IL‑21 produc- has been described for anti-SSA/Ro auto­antibodies
tion, inducible T cell co-stimulator (ICOS) and BCL‑6 except for a role in the pathogenesis of congenital heart
expression, and expression of CC-chemokine receptor 9 block107. In addition to anti-SSA/Ro and anti-SSB/La auto­
(CCR9) but not CXCR5. These cells are likely to partic- antibodies, other autoantibodies have been described in
ipate in the pathogenesis of pSS. Interestingly, increased pSS, such as anti-salivary gland protein 1, anti-carbonic
levels of CC-chemokine ligand 25 (CCL25) have been anhydrase 6 and anti-parotid secretory protein, which
detected in salivary glands from patients with pSS101 recognize salivary gland and lacrimal gland-specific
and might participate in attracting such TFH-like cells, antigens, although their specificities and functional
which in turn can produce pro-inflammatory cytokines, activities remain unclear 108. Autoantibodies directed
including IFNγ, IL‑17, IL‑4 and IL‑21, and very effi- against IFNγ-inducible protein 16 (IFI16) have also been
ciently activate B cells to promote the production of detected in pSS and are likely to be associated with active
IgG. In 2017, a very similar population of ICOS+ PD1high disease109. Although IFI16 was detected in the salivary
BCL6+CXCR5- cells, called T peripheral helper cells, was glands of patients with pSS109, the specificities and role
described in the synovium and blood of patients with of this autoantibody await elucidation. Autoantibodies
RA and was found to be able to stimulate B cell activa- can also have a pathogenic role via their participation in
tion102. These cells have also been described in patients immune complex formation, a vital step in the stimulation
with pSS, and treatment with abatacept is associated with of RF+ B cells110.
a reduction of these T peripheral helper cells in patients The identification of the B cell epitopes involved in
with pSS103. pSS helps in the understanding of the pathogenic mech-
anisms that lead to the diversification of the autoimmune
Salivary glands as a plasma cell niche response during this disease. A public clonotypic auto­
Salivary glands can be considered to constitute a spe- antibody has been identified in the serum of patients with
cific microenvironment that supports B cell activation pSS111. This antibody is directed against Ro60 and is char-
(FIG. 1). Salivary epithelial cells are not only the victims of acterized by a VH3‑23 heavy chain paired with a Vκ3‑20
the autoimmune process but also have an active role in light chain111. By studying serum from patients with

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pSS over several years, the same group demonstrated low-grade, MZ histological type60. Mucosal localization
that the persistence of anti‑Ro humoral autoimmunity is predominant for these lymphomas, which are usually
resulted from a dynamic process of clonal succession112. MALT lymphomas, and they often develop in organs
This finding supports the idea of a constant replacement with active disease, such as the salivary glands60.
of dominant clonotypes by new clonal variants rather
than a single event in which long-lived plasma cells are Predictors of lymphoma development
generated and highlights the fact that chronic activation The main clinical predictors of pSS-associated lym-
of autoimmune B cells is a dynamic process in pSS. phoma are permanent swelling of the salivary glands,
splenomegaly, lymphadenopathies and skin involvement
pSS-associated lymphomas (in particular, a palpable purpura), and the main bio-
Epidemiology of comorbid lymphomas logical predictors are cryoglobulinaemia, lymphope-
Although the risk of lymphoma is increased in three nia (especially CD4+ T cell lymphopenia), low levels
systemic autoimmune diseases (RA, SLE and pSS), of complement proteins and detectable monoclonal
the highest risk is associated with pSS. Previously, two immunoglobulins in the serum or urine60. Disease
studies had estimated this relative risk as being between activity assessed by a composite score (EULAR Sjögren
15 and 20 (REFS 7,113); however, later studies estimated syndrome disease activity index; ESSDAI) also predicts
this relative risk to be 6 in Denmark and Sweden114, 7 lymphoma development with a dose effect 8. In addi-
in Taiwan115 and 9 in Norway 116. Lymphomas asso- tion to these predictors, four major advances have been
ciated with pSS have specific features, being mostly made in understanding the mechanisms leading to the
B cell non-Hodgkin lymphomas, predominantly of the transformation of the B cell clone into lymphoma. These
predictors are discussed in further detail in this section
and enable a better understanding of the pathogenesis of
Salivary gland pSS-associated lymphoma (FIG. 2).

1 Loss of regulators Rheumatoid factor reactivity and chronic antigenic


• Oncogenes
Unknown • NF-κB pathway stimulation. Mixed cryoglobulinaemia is a cold-­
antigen precipitable immune complex that is recognized by RF
Increase in activators and is a well-established predictive factor of lymphoma
• BAFF
• GC-like structures development in patients with pSS. RF itself has also
• Immune complexes been identified as a putative predictor of lymphoma in
4
patients with pSS8. Hence, in some patients with pSS,
2
lymphoma cells could be RF+ B cells that have been stim-
Immune complex Lymphoma ulated by immune complexes. For example, lymphoma-
formation escape
tous B cells from two patients with pSS who had salivary
gland lymphoma expressed an IgMκ with RF activity117.
Similarly, the BCR repertoire from mature B cell lym-
phomas has been studied; 41% of MALT lymphomas
occurring in salivary glands expressed BCRs with strong
RF-reactive CDR3 homology to RF, whereas only 18% of MALT lym-
Autoreactive
3 B cell expansion phomas occurring in the stomach and 0% of pulmonary
B cell
MALT lymphomas displayed this homology 118. The role
of immune complexes in stimulating these RF+ B cells is
likely to be crucial in the lymphomagenesis process in
Nature Reviews | Rheumatology
Figure 2 | The pathophysiology of primary Sjögren syndrome-associated lymphoma. autoimmune diseases. Therefore, the first step of lym-
The development of lymphoma in primary Sjögren syndrome (pSS) is a multistep process phomagenesis in pSS might be the chronic stimulation of
that is centred on chronic antigenic stimulation.  The first step of this process is the autoimmune B cells, leading to the formation of immune
formation of immune complexes consisting of IgG and an unknown antigen, which complexes and the continuous stimulation of RF+ B cells
occurs mainly at the site of autoimmunity, in this case the exocrine glands (steps 1 and 2). by these immune complexes, which if not completely
The presence of these immune complexes at high concentrations at epithelial sites controlled might lead to the evolution of these B cells
stimulates the expansion of rheumatoid factor (RF)-reactive B cells, first polyclonally and into lymphomatous cells. Notably, control of these con-
then monoclonally (step 3). The activation of these autoreactive B cells is amplified by tinuously stimulated RF+ B cells might not be as efficient
different factors, including B cell activating factor (BAFF, also known as TNF ligand in epithelial mucosal tissue as it is in the lymph nodes
superfamily member 13B) via paracrine and/or autocrine secretion, the presence of or bone marrow.
germinal centre (GC)-like structures supporting the continuous activation of B cells, the
formation of immune complexes, the expression of oncogenes and the overactivation of
Germinal centre‑like structures. GC‑like structures pro-
the nuclear factor-κB (NF‑κB) pathway. Lymphomatous escape occurs when there is
insufficient immune control of these continuously stimulated autoreactive B cells mote B cell activation in pSS. Polymorphisms in CXCR5
(step 4). This defect in immune control might be extrinsically linked to the environment are associated with pSS but have also been associated
(occurring at a mucosal site as opposed to a lymph node or in the bone marrow) or with non-Hodgkin lymphoma in independent studies
intrinsically linked to innate or acquired genetic defects that affect genes coding for outside of the context of autoimmunity 119. In addition,
proteins involved in the control of NF‑κB activation, such as TNFα-induced protein 3 these structures seem to predict lymphoma development
(also known as A20). in patients with pSS120. In a study of tissue samples from

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minor salivary gland biopsies taken from 175 patients with pSS compared with those of healthy individuals,
with pSS at diagnosis, GC‑like structures were found and cells with reduced A20 expression have increased
in 86% of the patients who subsequently developed NF‑κB activity 130. Absent or weak immunostaining for
non-Hodgkin lymphoma and in 22% of patients who A20 has also been described in salivary glands from
did not develop non-Hodgkin lymphoma (P = 0.001)120. patients with pSS and lymphoma131. Germline abnor-
However, the way in which these structures are defined malities in TNFAIP3 are associated with different auto-
is controversial. In addition to the presence of GC‑like immune diseases132, and somatic mutations or deletions
structures, the degree of lymphocyte infiltration in the of this gene have been observed in several lymphoma
salivary glands might predict lymphoma; a focus score subtypes, including MALT lymphoma, which is fre-
of ≥3 independently predicts lymphoma in patients with quently associated with pSS60. A coding single nucle-
pSS121. Thus, chronic stimulation of B cells within the otide polymorphism (rs2230926) located on exon 3 of
glands might drive lymphomagenesis. However, these TNFAIP3, which is responsible for a missense muta-
findings were challenged by the results of a 2017 study tion, was specifically associated with pSS-­associated
that found that neither GC‑like structures nor a high lymphoma, in which functional abnormalities of
salivary gland focus score predicted lymphoma occur- TNFAIP3 were present in 31% of germline and 50% of
rence122. The role of GC‑like structures in the transfor- lymphoma DNA12,13. Interestingly, the results of these
mation of B cells therefore requires further studies in studies12,13 show that in the context of autoimmunity
larger populations. Nevertheless, lymphomatous B cells with continuous stimulation of autoimmune B cells,
are not derived directly from GC‑like structures, as fol- a subtle germline abnormality of genes controlling
licular lymphomas are not the classic subtype of lym- NF‑κB activation (present in all cells because of its
phoma that occurs in pSS. The role of GC‑like structures germline nature) might have specific consequences in
could be to favour the formation of immune complexes, B cells. Thus, lymphomagenesis associated with pSS
which are then exported to the MZ where they stim- exemplifies the development of antigen-driven B cell
ulate MZ RF+ B cells, which thereafter might become lymphoma.
lymphomatous.
B cell-targeting therapies in pSS
B cell cytokines. BAFF has also been shown to partici- Given the key role of B cells in the pathogenesis of pSS,
pate in the development of lymphoma in patients with there was a great deal of hope for B cell-targeted ther-
pSS3,123. BAFF levels were increased in the sera of patients apies. Unfortunately, despite promising results in the
with pSS and either lymphoma or a history of lymphoma first two small sample size trials133,134, the following two
compared with levels in the sera of patients with pSS larger randomized controlled studies failed to demon-
who had never had lymphoma. Moreover, BAFF levels strate the efficacy of B cell depletion with rituximab in
correlated with disease activity and were associated with pSS135,136. Methodological explanations (including the
clonal B cell expansion in the salivary glands123. BAFF selection of patients and choice of outcome measures)
levels are still increased in patients with pSS years after have been discussed to explain these controversial
treatment and remission of lymphoma3, suggesting that results 137. Nevertheless, rituximab is probably effi-
serum BAFF levels are not directly related to lymphoma cient in some situations, such as purpura or symptoms
but could instead be linked to genetic factors. In con- linked to mixed cryoglobulinemia138, and inhibition
junction with this theory, polymorphisms in TNFSF13B of BAFF by belimumab seemed to be promising in an
have been associated with increased BAFF levels124,125; open-label trial139.
however, the evidence supporting a possible associ- The combination of rituximab and belimumab
ation between a single nucleotide polymorphism in could be synergistic; indeed, belimumab prevented the
TNFSF13B and/or TNFRSF13C (encoding BAFF recep- elevation in BAFF levels that occurs after B cell deple-
tor) and pSS remain controversial125–128. Other cytokines, tion induced by rituximab, which could drive B cell
such as Fms-related tyrosine kinase 3 ligand129 or IL‑14, repopulation with autoreactive B cells140–142. Moreover,
might also participate in chronic B cell activation and because the number of CD27+ IgD− switched memory
lymphoma emergence57. B cells increases very quickly following administration
of belimumab, rituximab could be administered at this
A20 in the control of B cell activation. As previously stage to achieve robust B cell depletion. Notably, in the
stated, lymphomagenesis in pSS could be considered to TEARS study, which examined the links between B cell
be a multistep process, beginning with the chronic stim- markers and response to rituximab in patients with pSS,
ulation of polyclonal B cells by immune complexes at at baseline, BAFF levels were higher in non-responders
the site of the disease. A consequence of this polyclonal than in responders143. Moreover, baseline levels of BAFF
activation of autoimmune B cells might be an increased are inversely correlated with the duration of B cell deple-
frequency of oncogenic mutations. In the context of tion144. Another way of combining the two pathways
chronic stimulation, dysfunction of any checkpoint would be to use an antibody inhibitor of TNF superfam-
of autoimmune B cell activation could steer autoimmune ily receptor 13B (also known as TACI), a BAFF receptor.
B cells towards a malignant transformation. This strategy would deplete B cells expressing this recep-
The role of TNFAIP3 (encoding A20, a central gate- tor and inhibit the BAFF pathway. Preliminary results of
keeper of NF‑κB activation) illustrates this concept. using atacicept to achieve this approach in patients with
A20 is downregulated in the salivary glands of patients SLE are promising 145.

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Table 1 | Ongoing trials of B cell-targeted therapies in primary Sjögren syndrome


Type of therapy Name Target of therapy Trial identifier Refs
Anti‑CD40 mAb CFZ 533 B cell activation NCT02291029 151
Anti-ICOSL mAb AMG 557 (also known as Ectopic GC formation NCT02334306 152
MEDI5872)
Anti‑IL‑6R mAb Tocilizumab IL‑6 axis NCT01782235 (ETAP) 153
Anti-BAFFR mAb VAY736 • BAFF axis NCT02149420 154
• B cell depletion
PI3K inhibitor UCB5857 BCR signalling NCT02610543 155
Co-administration of Belimumab and rituximab • BAFF axis NCT02631538 156
anti-BAFF mAb and • B cell depletion
anti‑CD20 mAb
CTLA4 Fc fusion protein Abatacept Co-stimulation of T cells NCT02067910 and 157,158
NCT02915159
Anti-pDC mAb MEDI7734 Type I interferon NCT02780674 159
secretion
BAFF, B cell activating factor; BAFFR, BAFF receptor; BCR, B cell receptor; CTLA4, cytotoxic T lymphocyte protein 4; GC, germinal
centre; ICOSL, inducible T cell co-stimulator ligand; IL‑6R, interleukin 6 receptor; mAb, monoclonal antibody; pDC, plasmacytoid
dendritic cell; PI3K, phosphoinositide 3‑kinase.

Novel targets currently under investigation include sev- Conclusions


eral of the specific pathways of B cell activation discussed B cells are central in the pathogenesis of pSS, and the
in this Review: IL‑6, BTK, phosphoinositide 3‑kinase overactivation of B cells is the result of a multistep
(PI3K), CD40–CD40L, GC formation (ICOS–ICOSL process. Environmental triggers occurring in the pres-
(ICOS ligand)) and B cell–T cell interaction (TABLE 1). On ence of genetic and epigenetic dysregulation lead to the
the basis of the key role of plasmablasts and plasma cells in stimulation of specific B cell subsets, particularly MZ
this disease, treatments that deplete plasma cells should be B cells, plasmablasts and plasma cells. The targets of
investigated. The most promising of such treatments are this disease, salivary epithelial cells, maintain crosstalk
the proteasome inhibitors that are already under investi- with these B cell subpopulations, which in turn par-
gation in SLE146 and an anti‑CD38 antibody that seems to ticipate in the intratissular activation of autoimmunity
be promising in multiple myeloma147. There is hope that via the formation of autoantibodies and subsequent
advances in our understanding of the mechanisms lead- immune complexes. Overall, the emergence of B cells
ing to B cell and plasma cell activation will lead to effi- in pSS pathogenesis supporting the development of
cient treatment in patients with pSS and prevent severe B cell-targeted therapies offer new hope for patients
complications, including B cell lymphoma, in the future. with pSS.

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816–821 (2013). 526–531 (2015). claims in published maps and institutional affiliations.

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