NATURE REVIEWS | RHEUMATOLOGY VOLUME 6 | SEPTEMBER 2010 | 529

Department of
Pathophysiology,
Medical School,
National University of
Athens, 75 Mikras
Asias Street, 11527
Athens, Greece
(M. Voulgarelis,
A. G. Tzioufas).
Correspondence to:
M. Voulgarelis
mvoulgar@med.uoa.gr
Pathogenetic mechanisms in the initiation
and perpetuation of Sjgrens syndrome
Michael Voulgarelis and Athanasios G. Tzioufas
Abstract | Sjgrens syndrome (SS), a chronic autoimmune disorder, particularly compromises the function
of exocrine glands. The involvement of these glands is characterized by focal, mononuclear cell infiltrates
that surround the ducts and replace the secretory units. The pathogenetic mechanisms of this autoimmune
exocrinopathy have not been fully elucidated. Immunologically-activated or apoptotic glandular epithelial
cells that expose autoantigens in genetically predisposed individuals might drive autoimmune-mediated
tissue injury. Alterations in several immune mediators, such as upregulation of type I interferon-regulated
genes, abnormal expression of B-cell-activating factor and activation of the interleukin-23type 17 T-helper
cell pathway, have been reported. Extension of the pathological process that affects the exocrine glands into
periepithelial and extraepithelial tissue can cause a considerable percentage of patients to exhibit systemic
findings that involve the lungs, liver or kidneys. These manifestations develop as a result of lymphocytic
invasion or an immune-complex-mediated process, or both, and present as skin vasculitis coupled with
peripheral neuropathy or glomerulonephritis (or both). Patients with systemic extraepithelial manifestations
display low serum levels of the complement component C4 and mixed type II cryoglobulins, and show an
increased risk of developing non-Hodgkin lymphoma, thereby reflecting an overall worse prognosis with higher
mortality rates than those without extraepithelial manifestations.
Voulgarelis, M. & Tzioufas, A. G. Nat. Rev. Rheumatol. 6, 529537 (2010); published online 3 August 2010; doi:10.1038/nrrheum.2010.118
Introduction
Sjgrens syndrome (SS) is a chronic inflammatory disease
that affects the exocrine glands, particularly the salivary
glands. Focal, mononuclear cell infiltrates surround the
ducts and replace the secretory units (Figure 1). Primary
SS is a common systemic auto immune disorder, affecting
approximately 0.10.4% of the general population with a
female to male ratio of 9:1, a prevalence that is comparable
to that of rheumatoid arthritis.
16
Although the patho-
genetic mechanisms of this autoimmune exocrino pathy
are not yet fully known, SS ariseseither as the primary
disease or occurring secondary to other autoimmune
rheumatic diseasesas a result of infiltration of the func-
tional glandular epithelium by autoreactive lymphocytes.
7

During the past 15 years, the importance of the epi thelial
cell in the pathogenesis and evolution of SS has been
highlighted and has prompted the use of the term auto-
immune epithelitis as an alternative name for the disease.
8

In its early stages, SS can also affect other organs, leading
to extraglandular manifestations, including interstitial
nephritis, liver disease and obstructive bronchitis.
911
Although the disease is limited to the exocrine glands
in the majority of patients, clinical and prognostic cri teria
demand that these patients be distinguished from the
approximately 10% of those who develop extra epithelial
manifestations secondary to the deposition of immune
complexes at extraglandular sites, including small or
medium-sized vessels, renal glomeruli and peripheral
nerve microvessels.
1214
A number of studies have docu-
mented an ongoing B-cell hyperactivity in SS, which
might be associated with an increased incidence of lym-
phoid malignancies in the presence of palpable purpura,
glomerulonephritis and peripheral neuro pathy.
1517
Such
serious immune-complex-mediated manifesta tions,
which usually present later in the course of the disease,
define a distinct group of SS patients who show an
increased risk of mortality owing to lymphoproliferative
hematologic malignancies.
15,17,18
In this Review, we aim to
describe important pathogenetic mechanisms involved in
the initiation and perpetuation of SS.
Pathogenesis of SS
As previously mentioned, the pathogenetic mecha-
nisms responsible for SS are not yet fully known, but in
the presence of a susceptible genetic background, both
environmental and hormonal factors are thought to be
capable of triggering this autoimmune exocrinopathy.
Salivary, lacrimal, and other exocrine glands become
infiltrated with CD4
+
T cells, but substantial numbers
of B cells and plasma cells are also present in inflamed
tissues. Moreover, glandular alteration in cell migration
can also lead to the formation of germinal center-like
structures that contain follicular dendritic cells (DCs)
and proliferating B cells.
19,20
Competing interests
The authors declare no competing interests.
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Genetic factors
The observed aggregation of autoimmune diseases in
families of SS patients is supportive for a genetic pre-
disposition to the disease. Alleles within the major
histo compatibility complex (MHC) class II gene region,
mainly HLA-DR and HLA-DQ, are involved in the
pathogenesis of SS. Patients of different ethnic origin
carry different HLA susceptibility alleles. By way of
illustration, white patients from Northern and Western
Europe and from North America show a high prevalence
of B8, DRw52 and DR3 genes, whereas Scandinavian and
Greek patients with SS display strong linkages to the DR2
and DR5 genes.
21
However, it has been shown that HLA
class II alleles are associated with the presence of specific
subsets of autoantibodies, rather than with the disease
itself.
22,23
For example, the production of anti-Ro52
autoantibodies is linked with the presence of the MHC
class II alleles DRB1*0301, DRB3*0101, DQA1*0501 and
DQB1*0201. A genome-wide association study has con-
firmed the genetic association of the interferon (IFN)
regulatory factor 5 (IRF5) rs2004640 T allele with a pre-
disposition to the development of SS (odds ratio, or OR,
1.93 [95% CI 1.153.42]).
24
Another study has revealed
a correlation between polymorphisms in IRF5 (CGGGG
indel, SNP rs10488631) and STAT4 (SNP rs7582694),
genes that encode transcription factors involved in
IFN signaling, and SS development in a Swedish and
Norwegian cohort.
25
Interestingly, the OR for SS in car-
riers with two risk alleles was 1.43, whereas those with
three risk alleles had an OR of 6.78. These findings indi-
cate that a genetic susceptibility conferring an increased
IFN response to different innate stimuli could promote
disease progression.
Hormonal factors
Sex hormones seem to influence humoral and cell-
mediated immune responses, and estrogen is considered
to be one of the factors responsible for gender immuno-
logic dimorphism. Apart from the predominance of
SS in postmenopausal women compared with men,
the results from several experiments in animal models
have indicated a role for estrogen deficiency in SS.
Key points
At the molecular and cellular levels, epithelial cells have an important role in the
initiation and perpetuation of autoimmune lesions in Sjgrens syndrome (SS)
Antigen presentation, apoptosis, chemokine production or germinal center
formation lie at the center of SS pathogenesis; epithelial cells have a key role
in all these processes
Alterations in a number of immune mediators contribute to chronic immune
dysregulation
These changes include: upregulation of type I-interferon-regulated genes;
abnormal expression of B-cell-activating factor; and activation of the
interleukin-23T-helper type 17 cell pathway
Among autoimmune diseases, SS displays the highest incidence of malignant
lymphoproliferative disorders
Severe involvement of exocrine glands, vasculitis, low C4 levels and
cryoglobulinemia at diagnosis identify specific SS patients with a high risk of
lymphoma development and therefore high mortality rates
Mice that lack aromatase (and therefore have an estro-
gen deficiency) develop a lymphoproliferative disease
that resembles SS; the disease is characterized by B-cell
infiltration of the kidney and the spleen.
26
In another
SS mouse model, overexpression in the exocrine glands
of retinoblastoma- associated protein 48 (also known
as histone-binding protein RBBP4), which induces
estrogen-deficiency-dependent apoptosis, caused an
age-dependent SS-like autoimmune exocrinopathy.
27

The sali vary epithelial cells of retinoblastoma- associated
protein 48 transgenic mice functioned as antigen-
presenting cells that directly upregulated the expression
of MHC class II molecules, secreted IFN- and inter-
leukin (IL)-18 and led to the activation of CD4
+
T cells
and glandular inflammation.
27
These findings strongly
suggest that estrogen deficiency stimulates

salivary epi-
thelial cells, via the upregulation

of RBBP4, to present an
autoantigen to the CD4
+
T cells, which

induces lesions in
the salivary glands that resemble

those of

human SS.
Environmental factors
Environmental factors, such as glandular viral infec-
tion, could prompt epithelial cells to activate the HLA-
independent innate immune system through Toll-like
receptors (TLRs); TLRs recognize conserved molecu-
lar patterns shared by large groups of micro-organisms
and products of apoptosis, and induce signaling path-
ways that lead to the production of inflammatory cyto-
kines and upregulation of co-stimulatory and adhesion
mol ecules.
28
Although a number of infectious agents
have been implicated in the pathogenesis of SS, such
as EpsteinBarr virus (EBV), human T-lymphotropic
virus type 1 and hepatitis C virus, their association with
SS appears weak.
29,30
Despite the association between SS
and viral infections being unclear, a high incidence of
EBV reactivation in SS patients has been reported; this
reactivation could contribute to the initiation or per-
petuation of an immune response in target organs.
3134

Interestingly, EBV is a common virus that infects both
salivary epi thelial cells and B cells.
35
Nonetheless, it
remains to be clarified exactly how reactivation of EBV
is induced in lesions of patients with SS, and which speci-
fic molecular mechanisms are involved in the process of
viral reactivation.
Evidence that the coxsackievirus might infect minor
salivary gland cells has also been reported in Greek
patients.
36
Furthermore, epithelial cells of SS patients
have been reported to show high constitutive expression
of several TLRs, which implicates innate immunity in the
autoimmune dysregulation.
37
These findings suggest that,
through an as yet unknown mechanism, the presence of
enteroviral RNA (in the form of the coxsackievirus) that
persistently escapes immune surveillance, activates the
epithelia and leads to chronic immune dysregulation.
However, another study failed to confirm this finding
in French patients.
38
Variations in the genetic poly-
morphisms of virus receptors and HLA among the two
study populations, as well as differences in the prevalence
of enteroviral infections in Greece compared to other
European countries could explain the discrepancy.
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Mild lesion
T cell infltrates B cell infltrates
Severe lesion
Altered glandular homeostasis
Salivary glands of the nonobese diabetic mouse model of
SS are characterized by abnormalities of glandular epi-
thelial cells that occur before infiltration by auto reactive
lymphocytes. Such abnormalities include disturbed cell
proliferation at birth, increased apoptosis of acinar tissue,
breakdown of secreted proteins and increased expression
of IFN-.
39
Altered glandular homeo stasis has also

been
reported in patients with SS. Biopsy samples from patients
with SS, compared to normal controls, showed a notable

increase in the expression of laminin messenger RNA and
protein before

lymphocytic infiltration, suggesting that
altered synthesis of the basement membrane of glandu-
lar epithelial cells is an early event that is associated with
salivary gland pathology in

SS.
40
Furthermore, acinar
and ductal cells from the salivary glands of patients with
SS have a molecular repertoire that is likely to confer an
increased capacity to dis organize their extracellular matrix
environment.
41
The increased gelatinolytic activity medi-
ated by matrix metallo proteinases of acinar and ductal
cells in the salivary glands of SS patients could allow the
subsequent invasion of cytotoxic T lymphocytes.
42,43
Although these findings suggest a primary intrinsic
homeostatic problem in the glands of SS patients, it is not
yet clear whether or not such a defect is an initial event in
the pathogenesis of SS. A special focus on early changes
in this disease could help the understanding of the specif ic
biologic events that lead to clinical signs of SS.
Perpetuation of inflammation
Critical to the initiation and perpetuation of SS patho-
genesis are the upregulation of adhesion molecules and
the production of chemokines and cytokines, which
together promote the migration of lymphocytes and
DCs into the glands, maintaining their cycle of homing
(Figure 2).
The role of epithelial cells
Despite the fact that endothelial cells in the salivary
glands of SS patients express adhesion molecules and
are morphologically similar to high endothelial venules
that might draw lymphocytes and DCs into the glands,
their role in mediating the local immune response has
not been clearly defined.
44
By contrast, evidence exists
that epithelial cells in SS lesions are active participants
in the induction and perpetuation of the inflamma-
tory process.
45
Although salivary gland epithelial cells
have never been directly shown to function as antigen-
presenting cells, they possess all the features needed to
do so.
4649
Their capacity to show enhanced expression
of CD40 and adhesion molecules, as well as to produce
lymphoid chemokines, cytokines and B-cell-activating
factor (BAFF, also known as BLyS and tumor necro-
sis factor ligand superfamily member 13b), indicates
their potential role in the accumulation of DCs, T cells
and B cells in the inflamed salivary glands and in the
formati on of lymphoid tissue.
45,5053
Figure 1 | Lesions in the salivary glands of patients with Sjgrens syndrome. The histopathological hallmark of SS is
periductal cellular infiltration of the salivary glands. In mild lesions, activated T cells predominate, whereas B cells prevail
in severe histologic lesions. Immunohistochemical analysis of minor salivary gland tissue from patients with SS; rabbit-
polyclonal antibodies to human CD3 and mouse-monoclonal antibodies to human CD20 were used to analyze the presence
of T and B cells respectively, original magnification 200. Abbreviation: SS, Sjgrens syndrome.
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The fact that the activation status of epithelial cells
derived from patients with SS remains unaltered
in vitro for a long period of time prompts the hypo-
thesis that they become activated intrinsically.
54
After
their migration to the glands, lymphocytes interact with
epithelial cells.
55
The latter are further activated by pro-
inflammatory cytokines such as IL-1, IFN- and tumor
necrosis factor (TNF) produced by neighboring T cells
and DCs.
56
Studies have shown that SS salivary acinar
epithelial cells express elevated apoptosis regulator BAX
and undergo apoptosis, which causes dysregulation of
the hosting organ.
57
By contrast, infiltrating lympho-
cytes express elevated apoptosis regulator Bcl-2 and are
resistant to apoptosis, which prolongs their survival.
Furthermore, through apoptosis and the formation of
membrane-bound vesicles known as exosomes, epi-
thelial cells present intracellular autoantigens, a process
that contributes to the breakdown of immune tolerance.
58

Ro/SSA and La/SSB are translocated from the nucleus
to apoptotic blebs, where they trigger the production,
by infiltrating B cells, of autoantibodies against these
autoantigens. Given that BAFF can be secreted by human
salivary gland epithelial cells following stimulation by
type I IFN and that viral infection directly induces
BAFF secretion by epithelial cells, it has been suggested
that epithelial cells might not only express and present
autoantigens but also concomitantly activate B cells by
the local secretion of BAFF.
59,60
The role of DCs
Interestingly, the action of type I IFN could orchestrate
all of the above described autoimmune mechanisms,
thereby linking the innate and adaptive immune systems
in SS. In this regard, analysis of minor salivary gland
tissue from patients with SS revealed enhanced levels
of IFN-inducible gene expression;
61,62
plasmacytoid
DCs were detected in the human SS salivary glands
by immuno histochemistry, indicating that the persis-
tence of the type I IFN signature could be related to an
inflammatory cycle that is associated with an inappro-
priate maturation of DCs, stimulation of autoreactive
T cells, production of autoantibodies and increased
production of endogenous IFN-.
61,62
The early appear-
ance of DCs in the salivary glands and the produc-
tion by these cells of type I IFNs could be important,
as they can cause abnormal retention and subsequent
activation of lympho cytes in these tissues, also result-
ing in increased metalloproteinase activity.
63
It has been
hypothesized that viral infections or RNA-containing
immune complexes acting through TLRs are responsible
for the activation of plasmacytoid DCs.
61
Interestingly,
a 2009 study demon strated that when NZB/W F1
mice were repeatedly injected with the TLR3 ligand
polyinosiniccytidylic acid, a rapid induction of type I
IFN and proinflammatory cytokines within the salivary
glands was observed, resulting in a considerable and
rapid loss of glandular function.
64
It has been suggested
that the salivary epithelial cells activated by TLR3 ligand
are the major source of type I IFNs within the gland.
64

This study further reinforces the notion that glandu-
lar epithelial cells have an important and active role in
the pathogenesis of SS and, moreover, that chronic viral
infection of salivary epithelial cells confers the potential
for initiation of salivary gland inflammation.
Resting epithelium Deregulated epithelium
BAFF
Type I IFNs
IL-1, IFN-, TNF
Effector T-cell cytotoxicity
Viral infection
Genetic predisposition
Estrogen defciency
Lymphoid chemokine production
Upregulation of adhesive molecules
Properties of antigen-presenting cells
Increased apoptosis and autoantigens expression
BAFF production
Activation of self reactive T cells
Aberrant homing
Breakdown of B-cell tolerance
Local production of autoantibodies
Production
T cell
B cell
pDCs
Figure 2 | Cellular and molecular pathways implicated in the pathogenesis of Sjgrens syndrome. Environmental (viral
infection) and hormonal factors (estrogen deficiency), in concert with an appropriate genetic background, are believed to
trigger SS, which dysregulates epithelial cells and allows the aberrant homing and activation of DCs, T cells and B cells.
Following the migration of lymphocytes into the glands in response to chemokines and specific adhesion molecules, T cells
interact with epithelial cells. Epithelial cells are further activated by proinflammatory cytokines (IL-1, IFN- and TNF), which
are produced by adjacent T cells. The early accumulation of pDCs in the target tissues, which produce high levels of type I
IFNs, seems to be important, as these cells can further dysregulate the immune response through abnormal retention of
lymphocytes in the tissues and their subsequent activation. IFN- is a powerful stimulator of the production of BAFF by
epithelial cells, DCs and T cells. BAFF stimulates aberrant B-cell maturation, leading to the emergence of self-reactive
B cells, which locally produce autoantibodies. Abbreviations: BAFF, B-cell-activating factor; DCs, dendritic cells; IFN,
interferon; IL-1, interleukin 1; pDCs, plasmacytoid DCs; SS, Sjgrens syndrome; TNF, tumor necrosis factor.
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The role of cytokines
Both proinflammatory and anti-inflammatory pathways
could be driven by this immune response. The inability to
suppress inflammation can lead to chronic tissue damage
and impaired salivary gland function. On examination of
cytokine mRNA expression in the salivary glands of SS
patients and animal models of the disease, an increase in
proinflammatory cytokines, including IL-1, IL-6, IL-7,
IL-10, IFN- and TNF, was noted.
6567
Cytokines pro-
duced by type 2 T-helper (T
H
) cells (T
H
2 cytokines) have
been found to dominate the early phase of SS, whereas
T
H
1 cytokines are associated with a later stage of the
disease.
68
Although such observations suggest that func-
tions associated with T
H
1 and T
H
2 cells are implicated in
the pathogenesis of clinical disease, CD4
+
T
H
17 memory
cells have also been reported within the lymphocytic
foci of the salivary and lacrimal glands of SS-susceptible
C57BL/6.NOD-Aec1Aec2 mice, indicating that the issue
is more complicated than previously thought.
69
In C57BL/6.NOD-Aec1Aec2 mice, the impairment of
exocrine gland tissue resulting from the autoimmune
attack is characterized by the reduced function of regula-
tory CD4
+
cells (T
REG
1 cells) and IL-27-producing DCs,
which would normally downregulate CD4
+
T
H
17 cells,
thus inducing their aberrant activation.
70
The involve-
ment of the IL-23T
H
17 pathway in the pathogenesis of
SS has been supported by data from studies of mice that
lack Ro52, an E3 ubiquitin ligase that is likely to regulate
the levels of several IRFs by ubiquitinyla ion. Ro52
/
mice
develop systemic autoimmunity that is characterized by
the enhanced production of pro inflammatory cytokines
regulated by IRFs, including cytokines involved in the
IL-23T
H
17 pathway.
71
Interestingly, loss of IL-23 and
IL-17 by genetic deletion of the p19 subunit of IL-23
in the Ro52
/
mice conferred protection from systemic
autoimmunity, suggesting that a defect in Ro52 func-
tion can lead to tissue inflammation and systemic auto-
immunity through the IL-23T
H
17 pathway. Likewise,
increased serum levels of IL-17 in SS patients, along with
increased levels of T
H
17 cells and related cytokines, are
dominant in salivary glands and strongly correlate with
the histological focus score.
72
Although compensatory
control of T
REG
1 cells against T
H
17 cell expansion seems
to occur in early and moderate infiltrations, in advanced
lesions T
REG
1 cells fail to control immune-mediated
tissue injury.
73,74
Dysregulation of B cells
As the lymphoid infiltration in the salivary glands is
established, CD4
+
T cells and DCs locally produce B-cell
targeted cytokines and other survival factors, including
BAFF and APRIL (a proliferation-inducing ligand, also
known as TNF ligand superfamily member 13).
52,56
B-cell
dysregulation in SS patients (Figure 3) can be demon-
strated by the presence of circulating immune complexes,
hypergammaglobulinemia, alterations in sub populations
of peripheral B cells, oligoclonal B-cell expansion and
a well-described increased risk of developing non-
Hodgkin lymphoma (NHL).
75,76
An ectopic germinal-
center-like structure found in one-fifth of patients with
SS represents the histologic hallmark of this abnormal
B-cell proliferation.
76
Ectopic germinal centers
Newly formed ectopic germinal centers have been
proposed to be sites of autoantibody production as
well as being involved in lymphomagenesis in patients
with SS.
77
Ectopic germinal centers represent a micro-
environment in the salivary glands in which B cells that
have bypassed the peripheral checkpoint against auto-
reactivity proceed to proliferation and incomplete dif-
ferentiation through T-cell-dependent pathways into
memory B cells and plasma cells.
78
Interestingly, the
formation of germinal centers in salivary glands of SS
patients correlates with increased glandular inflamma-
tion, elevated titers of rheuma toid factor (RF), increased
Risk of non-Hodgkin lymphoma
B-cell hyperactivity and monoclonality
Ectopic lymphoid tissue formation
Circulating immune complexes
Impaired censoring
Disturbed selection
Persistence of RF-expressing B cells
Oligoclonal B-cell expansion
p53 mutations
Malignant transformation
B-cell dysregulation
Perpetuation of SS pathogenesis
Figure 3 | B-cell hyperactivity, monoclonality and lymphomagenesis. The transition from a lymphoepithelial sialadenitis to
malignant lymphoma is a multistep process that is poorly understood. Chronic antigenic stimulation has an essential role
in the development of SS-associated lymphoproliferation by driving the proliferation of specific B cells and by increasing the
frequency of their transformation. B cells expressing cell surface RF are frequently detected in the salivary glands, which
suggests that clonal expansion in these glands might arise from antigen selection of RF-expressing B cells. Large amounts
of IgG produced in the salivary glands of SS patients could result in uncontrolled antigenic stimulation of RF-expressing
B cell clones in the ectopic germinal centers. Additional molecular oncogenic events, such as microsatellite instability, loss
of B-cell cycle control, inactivation of tumor suppressor genes and the forced overproduction of specific biological
stimulators of B cells (such as BAFF) seem to contribute to the emergence and progression of the malignant overgrowth.
Abbreviations: BAFF, B-cell activating factor; RF, rheumatoid factor; SS, Sjgrens syndrome.
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levels of auto antibodies and increased IgG levels com-
pared with SS patients without germinal centers.
79,80

These findings suggest that local selection and pro-
liferation of autoreactive B cells occur in ectopic germi-
nal centers. Additionally, increased levels of circulating
auto antibodies might reflect local autoantibody produc-
tion in the salivary glands. Szodoray et al.
81
identified
reliable biomarkers that detected the presence of germi-
nal centers in SS patients, among which CC-chemokine
ligand (CCL)-11, BAFF and IFN- have the strongest
discriminatory capacity.
81
The role of BAFF
Accumulating evidence has identified BAFF as an impor-
tant mediator in the neogenesis of germinal centers in
SS patients. BAFF can be secreted not only by salivary
epithelial cells but also directly by B cells, which high-
lights the important effect of this factor in the initiation
and perpetuation of B-cell dysregulation in SS.
82
The
reduced level of apoptosis among BAFF-expressing cells
in the salivary glands from SS patients potentially leads
to abundant BAFF expression, thereby amplifying B-cell
signal ing, promoting the regional proliferation of B cells
and their differentiation into autoantibody-producing
plasma cells.
83,84
Plasma levels of BAFF in SS patients are
strongly associated with autoantibody titers, including
those of RF and anti-Ro/SSA.
84
BAFF-transgenic mice
develop a disease that resembles human systemic lupus
erythematosus (SLE), and subsequently show infiltration
of salivary glands predominantly by activated B cells.
The occurrence of SS-like disease in BAFF-transgenic
mice could feasibly be explained by the excessive sur-
vival signals that are received by autoreactive B cells,
causing these cells to bypass the critical tolerance check-
point while maturing in the spleen.
85
In addition, it has
been suggested that the role of BAFF overexpression in
the impairment of self-tolerance in this animal model
further relies on the suppression of the protective effects
of DCs against the emergence of autoreactive T cells.
85
In
the salivary glands of patients with SS, the combination
of apoptotic bodies from epithelial cells and anti-Ro/
SSA antibodies could induce the production of IFN-
by infiltrating cells, which, in turn, could induce BAFF
expression by epithelial cells, leading to the stimulation
of autoreactive B cells.
5961
Interestingly, high levels of
infiltration by macrophages have been related to type II
cryoglobulinemia, parenchymal-organ involvement,
glandular inflammation and, most importantly, NHL,
suggesting the potential involvement of these cells in
disease severity and NHL development.
20
Together,
these data suggest that the sustained survival of auto-
reactive B cells, production of autoantibodies or later
development of NHL could be attributed to local BAFF
expression.
78
B-cell transformation
Patients with SS display severe B cell abnormalities com-
pared to that observed in other autoimmune diseases
such as SLE, with an increased concentration of serum
levels of BAFF.
86,87
The numbers of CD19
+
CD27

naive
B cells are decreased and the numbers of CD19
+
CD27
+

memory B cells are increased in patients

with active SLE,
in contrast with patients with SS, who display a consider-
able reduction in the number of peripheral CD27
+
memory B cells as a result of their migration from periph-
eral blood to the inflamed salivary glands.
88,89
The lym-
phoid population acquired secondary to the autoimmune
process (known as the mucosa-associated lymphoid
tissue [MALT] component) surrounds and infiltrates the
salivary ducts, and represents the substrate from which
B-cell lympho matous proliferation occurs.
90
The transition of reactive lymphoepithelial sialadeni-
tis from monoclonality to monoclonal lymphoma is
generally considered to represent a multistep process,
yet is poorly understood. Speculation exists that
chronic stimulation by exoantigens or autoantigens has
an essential role in the development of these tumors,
by driving the pro liferation of specific B cells and by
increasing the frequency of their transformation.
91
In
view of the intense modification of immunoglobulin

genes during immune responses, a number of criti-
cal transforming events, such as the inactivation of
tumor suppressor genes (for example, p53 mutations)
or chromosomal rearrangements, might result from the
intense cellular activity occurring within ectopic germi-
nal centers in SS.
92
Accordingly, SS patients who have
a high risk of developing NHL exhibit splenomegaly,
lymphadeno pathy,

type II cryoglobulinemia and parotid
swelling, all of which are indicators of extensive lympho-
proliferation.
17,9294
In addition, the occurrence of type II
cryoglobulinemia is thought to represent the transition
from polyclonal B-cell hyperactivity, a hallmark of SS,
to monoclonal expansion of B cells producing an IgMk
immunoglobulin with RF activity, suggesting that some
SS-derived NHLs originate from precursors that bear a
functional autoreactive B-cell receptor.
95
The persistence
of self-reactive RF-expressing B cells in SS might reflect
abnormal antigen selection, altered stimulation and
compromised censoringall mechanisms that magnify
the risk of malignant B-cell transformation.
78
Disease outcome and mortality
Published studies on the survival of SS patients are
limited in varied respects, most probably owing to rela-
tively small sample sizes (Table 1). However, results from
a number of studies indicate that, compared to other
autoimmune diseases, SS is associated with a notably
Table 1 | Studies of mortality in patients with Sjgrens syndrome
Study No. of
patients
Overall deaths
(lymphoma-related)
Standard
mortality ratio
Skopouli et al. (2000)
15
261 11 (3) 2.07
Ioannidis et al. (2002)
18
723 39 (7) 1.15
Petrovara et al. (2001)
106
110 17 (2) 1.20
Theander et al. (2006)
99
484 34 (6) 1.17
Alamanos et al. (2006)
102
422 47 (3) 1.02
Brito-Zern et al. (2007)
103
266 25 (2) 1.22
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high incidence of malignant NHL.
16,75,93,96100
A severe
involvement of the exocrine glands, and the presence of
vasculitis, low C4 levels and cryoglobulinemia at diag-
nosis can be used to identify patients with SS who are at
a high risk of developing lymphoma.
15,18,101104
Apart from this notably higher incidence of malignant
NHL, SS patients typically show only modest or clini-
cally insignificant deterioration in specific organ-related
symptomatology and function, which, together with the
low frequency of systemic effects, is likely to provide
an explanation for why mortality rates are only slightly
increased in patients with SS in comparison with the
remainder of the population.
105,106
This slight increase
in mortality rates in SS patients are mainly because of
the increased incidence of lymphoproliferative disease.
These largely unaffected mortality rates also contrast
with those of other connective tissue diseases such as
rheumatoid arthritis, scleroderma and SLE, which are
increased, mainly owing to cardiovascular disease.
107
Comorbidities have the capacity to influence the
prognosis of primary disease; the greater the number of
comorbidities, the greater the risk of patient hospitaliza-
tion and mortality. Comorbidities might be associated
with SS itself (for example, nephritis, interstitial lung
disease and peripheral neuropathy) or with its treatment
(such as immunosuppressive therapy). Unfortunately,
no published data on the incidence of these comorbidi-
ties and their mortality risk among SS patients exists.
Published data on the risk of accelerated athero sclerosis,
another comorbidity in SS, are lacking. Subclinical
athero sclerosis (intimamedia thickening of the large
vessels) was reported in about 50% of a cohort of young
women with SS.
108
Interestingly, these vascular changes
were not associated with the presence of cardiovascular
risk factors or any drug-induced effect, suggesting that
certain immune system characteristics of the disease
trigger early atherosclerosis. However, the presence of
early subclinical atherosclerosis does not always correlate
with an increased risk of cardiovascular-related death.
Consequently, further studies are needed to determine
the risk of atherosclerosis and cardiovascular-related
mortality among patients with SS.
Conclusions
The etiology and pathogenesis of SS are not clearly
understood. The hallmark of this disease is an immuno-
logically mediated inflammatory exocrinopathy that
is initially characterized by periductal infiltration of
the salivary tissue by lymphocytes and plasma cells.
The auto immune response in SS could ultimately be
driven by cellular proteins acting as autoantigens follow-
ing epi thelial cell apoptosis. In this context, it is feasible
to consider the epithelium as the main orchestrator of
the pathogenesis of SS. Dysregulation of sex hormones,
abnormalities in glandular homeostasis, deficiency in
T
REG
1 cells and dysregulation of plasmacytoid DCs con-
tribute to the disruption of peripheral tolerance and the
stimulation of autoreactive immune cells. Eventually,
these lymphocytes promote autoantibody

production
and damage the epithelium through their cytotoxicity.
SS is characterized by a slightly increased mortality
rate compared to the general population. However, the
develop ment of NHL is associated with an increased
overall disease mortality. The transition of reactive
lympho epithelial sialadenitis to malignant NHL is gen-
erally considered to be a multistep process. Chronic
antigenic stimulation, abnormal B-cell activation in the
inflamed tissues, somatic hypermutations and onco-
genic events in germinal centers are usually implicated
in malignant transformation. Severe involvement of the
exocrine glands, vasculitis, hypo complementemia and
cryoglobulinemia, which characterize a high-risk popu-
lation of patients, all highlight the paramount importance
of closer monitoring, as well as the need for tailored and
robust therapeutic management.
Review criteria
We searched for original articles published between
1968 and 2010 focusing on pathogenesis and mortality
in Sjgrens syndrome using MEDLINE and PubMed.
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Acknowledgments
We would like to thank Professor H. M. Moutsopoulos
for his inspiration and guidance.
Author contributions
M. Voulgarelis researched the data for the article,
provided a substantial contribution to the discussion of
content and wrote the article. A. G. Tzioufas reviewed
and edited the manuscript before submission.
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