Download Primary Sjo¨gren`s syndrome: current and emergent

Rheumatology 2005;44:1354–1367
Advance Access publication 14 June 2005
doi:10.1093/rheumatology/keh714
Review
Primary Sjögren’s syndrome: current and emergent
aetiopathogenic concepts
M. Ramos-Casals and J. Font
Sjögren’s syndrome (SS) is a systemic autoimmune disease that
mainly affects the exocrine glands and usually presents as
persistent dryness of the mouth and eyes due to functional
impairment of the salivary and lacrimal glands [1, 2]. The
common histolopathological feature of all organs affected is a
potentially progressive lymphocytic infiltration. Salivary glands
are the most studied organs because they are affected in almost
all patients and are easily accessible. Microscopic examination
of the salivary glands reveals a benign lymphoepithelial lesion,
characterized by lymphocytic replacement of the salivary
epithelium and the presence of epimyoepithelial islands composed of keratin-containing epithelial cells. The predominant
cells in the minor labial salivary gland infiltrates are T cells, with
a bias towards CD4þ cells rather than CD8þ suppressor cells
(CD4/CD8 ratio of 3:1–5:1). B cells constitute approximately
20% of the total infiltrating population, while natural killer
(NK) cells are observed less often (5%) [3].
The aetiopathogenesis of primary SS is probably a sequential,
multistep process that leads to selective damage of the exocrine
glands, with consequent target organ dysfunction. Although the
exact mechanisms involved in this aetiopathogenic process
are not well known, the autoimmune origin of the disease
(autoimmune epithelitis [4]) is probably the aetiopathogenic
hypothesis most commonly postulated in primary SS. In this
review we have summarized the current concepts on autoimmune
aetiopathogenesis of primary SS and reviewed alternative
aetiopathogenic mechanisms that have recently been postulated.
Autoimmune aetiopathogenesis
The autoimmune aetiopathogenic model of primary SS is based
on the existence of an altered immune system incapable of discriminating between ‘foreign’ and ‘self’ molecules (Figure 1).
This induces an abnormal autoimmune response against altered/
abnormal self antigens expressed by the epithelium of the exocrine
glands. This process may be initiated by a specific combination
of intrinsic (individual predisposition) and extrinsic (exogenous
agents) factors. The abnormal responses of both T and B cells
against autoantigens contribute to the histopathological lesions
characteristically observed in primary SS, and to alterations in
the synthesis of numerous intermediate molecules (cytokines
and chemokines), thereby helping to perpetuate the autoimmune
lesion. Later activation of mechanisms of tissue damage (such as
apoptosis) leads to chronic inflammation of the exocrine glands,
with fibrosis and loss of physiological function. Various recent
studies have contributed to a better understanding of these
autoimmune aetiopathogenic processes (Table 1).
Genetic background
Primary SS is a polygenic disease with multiple SS-related genes
probably involved in its aetiopathogenesis [5]. A genetic predisposition has been suggested on the basis of familial aggregation,
animal models and candidate gene association studies [6].
In experimental studies, genetic susceptibility to autoimmune
exocrinopathy developed by the NOD mouse has been associated
with certain alleles on chromosomes 1 (ldd5) and 3 (ldd3) [7–9].
In human studies, the polymorphic MHC genes have been the
most studied genetic risk factors in primary SS, and a close
association between specific HLA alleles and the synthesis of
anti-Ro/La autoantibodies has been described [10, 11]. Recent
studies have focused on polymorphic genes that encode molecules involved in the different mechanisms of the normal immune
response (immune recognition process, innate immune mechanisms, acquired immune mechanisms and regulation of the
immune response [12]) (Table 2).
Polymorphisms of cytokine genes. There is growing interest
in the possible role of functional polymorphisms of cytokine
genes in the aetiopathogenesis of primary SS (Table 2).
Hulkkonen et al. [13] were the first to study cytokine polymorphisms in patients with SS, describing an increased frequency
of the IL-10 gene GCC haplotype in Finnish patients, a finding
confirmed by subsequent studies [14–16]. Some of these studies
also found clinical associations. Anaya et al. [17] described
more episodes of cutaneous vasculitis in Colombian SS patients
carrying the IL-10 G9 allele. Font et al. [15] found an earlier
onset of primary SS in Spanish patients carrying the IL-10 GCC
haplotype, while Origuchi et al. [18] described a younger age
at onset in Japanese patients carrying the IL-10 GCC and,
especially, the ATA haplotype.
Studies of the tumour necrosis factor-alpha (TNF) gene
polymorphisms have also shown contrasting results. Studies
in France [19] and Tunisia [20] found no significant differences
in the polymorphic distribution of this gene between SS patients
and controls. In contrast, other reports described a higher frequency of the TNF-308A (TNF2) allele in patients with primary
SS, associating its presence with some clinical and immunological features. Gottenberg et al. [16] described a close association
between the TNF2 allele and the presence of anti-La/SS-B
antibodies in French SS patients, while Pertovaara et al. [21]
found a higher prevalence of renal involvement (proteinuria,
distal renal tubular acidosis) and positive anti-Ro/La antibodies
in SS patients carrying the TNF2 allele.
The clinical significance of the interleukin-4 receptor alpha
chain gene (IL4R) haplotypes in SS has also recently been
studied. Two studies in Caucasian patients described a similar
Department of Autoimmune Diseases, IDIBAPS (Institut d’Investigacions Biomèdiques August Pi i Sunyer), Hospital Clinic, Barcelona, Spain.
Submitted 30 March 2005; accepted 17 May 2005.
Correspondence to: M. Ramos-Casals, Department of Autoimmune Diseases, Hospital Clı́nic, C/Villarroel, 170, 08036-Barcelona, Spain.
E-mail: [email protected]
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Aetiopathogenesis of primary Sjögren’s syndrome
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1.1.ETIOPATHOGENIC
ETIOPATHOGENICBACKGROUND
BACKGROUND
Genetic
background
3.3.ESTABLISHMENT
ESTABLISHMENT
+
Neurohormonal
factors
T-cell dysfunction
B-cell hyperractivity
2.2.INITIATION
INITIATION
Autoantigens
+
Viruses
4.4.PERPETUATION
PERPETUATION
↑cytokines
+
↑chemokines
5. EPITHELIAL DAMAGE
Apoptosis
Altered epithelial repair
Proteolysis
FIG. 1. Autoimmune aetiopathogenesis of primary SS: aetiopathogenic background, initiation of the autoimmune process,
establishment of epithelitis, perpetuation of the autoimmune response and epithelial damage. This figure is available in colour as
supplementary data at Rheumatology Online.
TABLE 1. Aetiopathogenesis of Sjögren’s syndrome: altered immune responses
1. Altered immune recognition
1.1. Intrinsic factors
1.2. Extrinsic factors
Molecular mimicry (self antigens)
Triggers of the autoimmune response (viruses)
2. Abnormal acquired immune responses
2.1. T-cell dysfunction
2.2. B-cell dysfunction
3. Altered regulation of the immune response
3.1. Cytokines
Altered TCR repertoire of infiltrating T-cells
Increased circulating plasma cells
Retention of CD27þ memory B cells in salivary glands
Abnormal selection in editing Ig receptors
Prominent Jkappa2 gene usage
Lack of targeting of the hypermutation mechanism
Peripheral enhanced Th2 expression
Predominant local Th1 response
Increased frequency of IL-10 gene GCC haplotype
Increased expression of B-cell attracting chemokines
(CXCL-12 and CXCL-13)
Increased expression of T-cell attracting chemokines
(CXCL-9 and CXCL-10)
Increased levels of circulating BAFF/Blys
3.2. Chemokines
TABLE 2. Altered distribution of genotypes and haplotypes and clinical association of the different polymorphic genes in patients with primary SS
Polymorphic gene
Altered polymorphic distribution
Clinical associations
Interleukin genes
IL10
IL4R
TNF
IL6
IL1RA
TGF1
" GCC haplotype (13,16)
No differences [22, 23]. " Q551 haplotype [24]
No differences [19, 20]. " TNF2 allele [16, 21]
No differences [16, 27]
No differences [28]
No differences [16]
Earlier SS onset [15, 18]. " vasculitis [17]
" Parotidomegaly [23]. # Raynaud’s [25]
" Renal involvement [21]. " Anti-Ro/La antibodies [16, 21]
–
–
–
" Codon 54 (Japan [29, 30]). No differences
(Caucasian [31, 32])
No differences [20]
# Delta 32 genotype [28]
No differences [34]. Altered Fas alleles [33]
–
Other genes
MBL
CTLA4
CCR5
Fas/FasL
distribution of IL4R genotypes and haplotypes in patients with
primary SS and healthy controls [22, 23], although Youn et al.
[24] found a higher frequency of Q551 in 45 Korean patients.
These differing results underline the importance of taking
–
–
–
ethnicity into account when analysing the polymorphic distribution of genes. However, a higher frequency of parotidomegaly
was observed in SS patients carrying the ARSPRV haplotype
[23], while Lester et al. [25] found a protective effect of the
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M. Ramos-Casals and J. Font
R551 allele for Raynaud’s phenomenon. With respect to the
interleukin-1 (IL-1) gene, Muraki et al. [26] detected a lower
frequency of three specific polymorphisms of this cytokine gene
in 101 patients with primary SS compared with systemic lupus
erythematosus (SLE) or controls.
Finally, other studies have found no significant differences
in the polymorphic distribution of cytokine genes between SS
patients and controls, including studies of the IL-6 gene in
Finland [27] and France [16], the IL-1 receptor antagonist gene
(IL-1Ra) gene in Slovakia [28] and transforming growth factor
beta-1 (TGF1) in France [16]. The current data on polymorphic
cytokine genes suggest that IL-10 and TNF genes should be
considered as the most promising genetic markers in the
aetiopathogenesis of primary SS.
Other polymorphic genes. Four recent studies have analysed
the clinical significance of mannose binding lectin (MBL) gene
polymorphisms in patients with primary SS, with different results
according to the ethnicity of patients studied. In two studies
of Japanese SS patients, a higher frequency of the wild type of
MBL codon 54 was detected [29, 30], while other studies found
no significant differences between Finnish or Australian SS
patients and controls [31, 32]. In another study, Petrek et al. [28]
analysed polymorphisms of the receptor CCR5, which binds
the mononuclear cell-attractant chemokines CCL3, CCL4
and CCL5, and found that the frequency of the CCR5-delta
32/CCR5 genotype is significantly decreased in Slovak SS
patients, suggesting a protective role for the development of SS.
Two studies have analysed the clinical significance of Fas
gene polymorphisms in patients with primary SS. Bolstad et al.
[33] analysed Fas and FasL gene polymorphisms and detected
altered prevalence of three Fas alleles in SS patients compared
with controls, while Mullighan et al. [34] found no significant
differences. Finally, genes that encode transporters associated
with antigen processing (i.e. TAP genes) have also been associated with susceptibility to SS [35]. Other reports have suggested
a putative role for the cysteine-rich secretory protein 3 (CRISP-3)
gene as an early response gene that may participate in the
pathophysiology of the autoimmune lesions of SS [36]. The
current data support a tenuous aetiopathogenic role for these
polymorphic genes, which encode chemokine receptors, transporters associated with antigen processing, molecules of the
innate immune system and apoptosis-related molecules (Table 2).
Altered immune recognition
In the aetiopathogenesis of SS, the immune response of the host
probably cross-reacts with self antigens from the exocrine tissue
through a mechanism of molecular mimicry, with a triggering
factor (infectious agents?) playing a key role in the initiation of
this local autoimmune response.
Autoantigens. Some exogenous agents may trigger an
abnormal autoimmune response in patients with a specific
genetic susceptibility for primary SS, inducing a breakdown in
self tolerance that leads to an abnormal/altered exposure of
autoantigens on the surface of epithelial cells. This suggests that
these autoantigens are capable of initiating and sustaining the
autoimmune epithelial damage [37], with Ro/La ribonucleoproteins and fodrins being, at present, the main self molecules
implicated in SS aetiopathogenesis.
Autoantibodies to the ribonucleoprotein particles Ro/SS-A
and La/SS-B are usually found in sera of patients with primary
SS. Their presence is associated with longer disease duration,
increased frequency of non-exocrine manifestations and a higher
intensity of lymphocytic infiltrates invading the minor salivary
glands [38, 39]. The Ro/La ribonucleoprotein complex is
composed of the Ro 60 kDa, Ro 52 kDa and La 48 kDa proteins
that are associated with one small cytoplasmic RNA (Y-RNA).
The Ro/SS-A antigen is a ribonucleoprotein particle composed
of hY-RNAs and two protein components (60 kDa and 52 kDa)
conforming a ribonucleoprotein complex. These two proteins
are probably coded by different genes, with recent reports
showing that the gene coding for the 60 kDa Ro autoantigen is
located on the short arm of chromosome 19 near the low-density
lipoprotein receptor (LDLR). The La/SS-B antigen is also a
ribonucleoprotein particle associated with all RNA polymerase
III transcripts, including the hY-RNAs. The human La/SS-B
gene is located on chromosome 2 and encodes a protein
composed of 408 amino acid (aa) residues with a calculated
molecular weight of 47 kDa. Previous studies suggest that
the Ro/La autoimmune response is antigen driven because the
autoantibodies are produced in the immunopathological lesion
[40–42] and subjected to intra- and intermolecular epitope
spreading [43]. Serum samples of patients with anti-Ro/SSA and
anti-La/SSB reactivity recognize multiple different conformational and linear epitopes. Among them, the sequences
aa145–164, aa289–308, aa301–320 and aa349–364 of La/SSB as
well as aa169–190 and aa211–232 of Ro 60 kDa have been
extensively studied, exhibiting high sensitivity and specificity
for autoantibody detection [44–48]. There are recent studies on
specific epitopes residing in Ro/La ribonucleoproteins. Routsias
et al. [49] showed that the zinc finger domain of Ro 60 kDa
contains a B-cell epitope with a high specificity for primary SS,
while Staikou et al. [50] found that calreticulin (a chaperase
protein) induces conformation-dependent recognition of the
Ro 60 kDa epitopes. With respect to the La ribonucleoprotein,
Davies et al. [11] have identified three regions of the La sequence
likely to contain T-cell epitopes.
It is not known how tolerance breakdown and autoantibody
response to Ro/SSA and La/SSB is generated. The ribonucleoproteins are endogenous proteins that are normally hidden from
the immune system, and should subsequently not give rise to
abnormal B-cell responses. However, stresses, such as ultraviolet
radiation, viral infections and apoptosis, have been suggested
to lead to undesirable cell surface exposure of autoantigens to
the immune system [51]. Ro/SSA and La/SSB have been demonstrated in surface blebs of apoptotic ultraviolet-irradiated
keratinocytes, implying a role in SLE [52]. Not much is known
from a genetic point of view, but a single nucleotide polymorphism in intron 3 of the Ro52 gene was found to be strongly
associated with the presence of anti-Ro52 autoantibodies in
primary Sjögren’s syndrome [53]. This is interesting, because
alternative mRNA is made by deleting exon 4, which encodes
a putative leucine zipper domain, to generate a shorter version
of the Ro52 protein [54].
Fodrin is a major component of the cortical cytoskeleton of
most eukaryotic cells, composed of and subunits. Recent
studies have analysed both the molecular contribution of
fodrins to the pathogenesis of SS and the clinical significance
of antifodrin antibodies. A close association between fodrin and
apoptotic mechanisms has recently been described, with the
detection of an abnormal location of -fodrin on the surface of
apoptotic-induced cells [55]. Nagaraju et al. [56] demonstrated
the specific cleavage of -fodrin by granzyme B during cytotoxic
lymphocyte granule-induced cell death, and Inoue et al. [57]
found that Epstein–Barr virus (EBV) reactivation induces
an increase in apoptotic protease activities leading to progression of -fodrin proteolysis. Maruyama et al. [58] described a
150 kDa cleaved product of -fodrin that is exposed as a
neoepitope to the immune system. These studies suggest that
an abnormal proteolysis of -fodrin may lead to an altered
location of this autoantigen in the external surface of apoptotic
epithelial cells, triggering the autoimmune process in the salivary
glands.
Several authors have analysed the prevalence and clinical
significance of anti--fodrin antibodies in SS (Table 3) [59–65].
Witte et al. [60] detected anti--fodrin antibodies in 55–64% of
adult patients with primary SS and in 40–86% of those with
Aetiopathogenesis of primary Sjögren’s syndrome
TABLE 3. Prevalence of anti--fodrin antibodies in patients with primary
SS (in adult and childhood patients), SS associated with other systemic
autoimmune diseases, SLE and RA
Disease
Primary SS
Associated SS
SLE
RA
Systemic sclerosis
Inflammatory myopathies
Prevalence
Adults
IgA
IgG
Childhood
Adults
IgA
IgG
Adults
IgA
IgG
Childhood
IgA
IgG
Juvenile
IgA
IgG
IgA
IgG
25/63
80/165
64/165
25/25
9/15
13/22
9/22
28/97
17/100
14/100
8/29
16/42
9/42
5/9
4/20
3/20
1/10
3/10
(40%)
(48%)
(39%)
(100%)
(60%)
(59%)
(41%)
(29%)
(17%)
(14%)
(28%)
(38%)
(21%)
(56%)
(20%)
(15%)
(10%)
(30%)
References
59,
60,
60,
61, 62,
59,
60,
60,
61, 62,
60,
60,
63
66
66
64
59
60
60
63
66
66
64
66
66
64
66
66
66
66
secondary SS (depending on the Ig isotype). Other authors
detected anti--fodrin antibodies in child/juvenile SS patients
[61, 62], and de Seze et al. [65] have recently suggested a possible
role for anti--fodrin antibodies in the differential diagnosis of
multiple sclerosis and SS patients with neurological manifestations. However, the most recent studies have also detected these
antibodies in other systemic autoimmune diseases such as adult
or childhood SLE and juvenile rheumatoid arthritis [62–64], and
Ruffatti et al. [66] have described a sensitivity of IgA and IgG
anti--fodrin antibodies for the diagnosis of primary SS of 32%
and 21%, respectively. This suggests that anti--fodrin antibodies seem to reflect non-organ-specific autoimmunity, and
probably have a limited discriminatory value for the diagnosis of
primary SS.
Viruses. Hepatic viruses. The hepatitis C virus (HCV) is one
of the most likely candidates as a potential pathogenic agent
causing SS. The association of SS with HCV has given rise to an
intense debate in the last decade. In 1992, Haddad et al. [67]
found histological evidence of SS (Chisholm–Mason classification grade 3 or 4) in 16 of 28 patients with chronic HCV
infection. Since then more than 250 cases of SS-HCV have been
reported, making SS one of the systemic autoimmune disease
most closely associated with HCV, and the systemic autoimmune
disease with the highest prevalence of chronic HCV infection
[68]. In addition, clinical studies have shown sicca symptomatology, positive ocular tests, lymphocytic infiltration of salivary
glands and autoantibodies in patients with HCV infection [69].
These findings have recently led to HCV infection being
considered as an exclusion criterion for the diagnosis of primary
SS in the 2002 American–European criteria [70]. Furthermore,
recent experimental and human studies have found evidence
supporting the sialotropism of HCV [71–73]. Thus, HCV may be
considered as an important aetiopathogenic agent for SS, with
SS-HCV being indistinguishable in most cases from the primary
form using the most recent sets of classification criteria. For
these patients, we propose the term ‘SS secondary to HCV’ when
they fulfil the 2002 classification criteria for SS [74]. Chronic
HCV infection should be considered an exclusion criterion for
the classification of primary SS, not because it mimics primary
SS but because it may be implicated in the aetiopathogenesis of
SS in a specific subset of patients. However, this aetiopathogenic
role probably varies according to the geographical prevalence of
HCV infection found in the general population.
Other viruses. Retroviruses, herpesviruses and enteroviruses
are also considered as potential aetiopathogenic agents for
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primary SS. Patients infected by retroviruses such as HIV-1 and
human T-lymphotropic virus type I (HTLV-I) quite often present
sicca features. In patients with HIV infection, the histological
analysis of salivary glands demonstrates a similar aetiopathogenic mechanism to that observed in primary SS (lymphocytic
infiltration), although the immunophenotypic analysis shows
that the predominant cells are T CD8þ (and not T CD4þ)
lymphocytes. This specific immunophenotypic pattern has lead
to HIV-related sicca syndrome being defined by the specific name
of diffuse infiltrative lymphocytosis syndrome (DILS). Two
recent studies have analysed sicca features in HIV patients,
suggesting a prevalence of HIV-related sicca syndrome of 3–8%
in HIV patients [75, 76]. With respect to HTLV-I infection, its
clinical significance in patients with SS should be analysed
according to the geographical area of the study. In Japan, an
endemic area for HTLV-I, a prevalence of nearly 25% [77, 78]
was detected in patients with primary SS, suggesting a specific
role of this retrovirus in the aetiopathogenesis of Japanese
patients with SS in contrast to other geographical areas. In
contrast, Caucasian patients do not show the same levels of
HTLV-I infection. Mariette et al. [79] have detected the tax gene
of HTLV-I in salivary glands from 15/50 (30%) of patients
with SS, but also in specimens from 9/32 (28%) patients with
salivary glands affected by other inflammatory processes, suggesting a non-specific role of HTLV-related genes in European
SS patients.
Herpes viruses, especially EBV, have also been studied
recently [80]. Dawson et al. [81] detected EBV DNA in one of
six SS patients with lymphoma, and Inoue et al. [57] suggested
a possible role for EBV reactivation in increased apoptotic
protease activity in SS. With respect to other herpes viruses,
Klussman et al. [82] isolated sequences and antigens of HHV-8
in one patient with SS and MALT lymphoma. In addition,
recent evidence suggests a possible role for other viruses such as
parvovirus B19 [83–85] or coxsackieviruses [86] in the aetiopathogenesis of primary SS. Triantafyllopoulou et al. [86] have
detected the presence of the coxsackievirus genome and the
main antigenic capsid protein VP1 in 11 of 12 patients with
primary SS, 1 of 13 patients with secondary SS, and none of 16
controls, suggesting a latent coxsackievirus infection in salivary
glands of some patients with primary SS. Due to the high
seroprevalence of some of these viruses in the healthy adult
population, a discriminative aetiopathogenic role is usually
difficult to demonstrate, limiting the significance of isolating
sequences of ubiquitous viruses in patients with primary SS.
Abnormal immune responses
Acquired immune responses involve the proliferation of the
cellular components of the immune system (antigen-specific
B and T cells) and occur when the surface receptors of these cells
bind to antigen [12]. After the initiation of the autoimmune
process in primary SS, autoantigens are expressed on the surface
of epithelial cells, with T lymphocytes migrating to exocrine
tissue and being activated in situ and B cells producing
autoantibodies locally [87]. Several studies have recently analysed
the role of T- and B-cell dysfunctions in the pathogenesis of
primary SS.
T-cell dysfunction. The few studies of T-cell dysfunction
in primary SS have centred on the role of the cytotoxic
T-lymphocyte-associated antigen 4 (CTLA-4) and possible
alterations in the T-cell receptor (TCR). Recent evidence
suggests that CTLA-4, an immune attenuator, contributes significantly to the homeostatic control of T helper cell proliferation,
and has a critical immunoregulatory role in the down-regulation
of T-cell activation. Only one study has been performed in
patients with primary SS, and this found no significant
differences in the CTLA-4 polymorphisms of Tunisian patients
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M. Ramos-Casals and J. Font
with SS compared with the control group [20]. However, several
studies have analysed the TCR repertoire of infiltrating T cells
in the salivary glands of SS patients. Sumida et al. [88] found
that TCR V gene usage seems to be relatively restricted, while
Pivetta et al. [89] found scattered T-cell clonotypes within
different V beta families, with a differentiated pattern from
patient to patient. Matsumoto et al. [90] found that the TCR
BV2þ of the infiltrating T cells recognize restricted epitopes and
function as CD4þ Th0 type T cells. Finally, Manavalan et al.
[91] found that SS patients producing autoantibodies have a
lower frequency of T cells expressing TCRs with V(beta)7.2.
As there are few current reports, additional studies are needed
to better define the specific aetiopathogenic role of T cells in
primary SS.
B-cell hyperreactivity. Primary SS represents a pathological
model of the evolution from polyclonal B-lymphocyte activation
to oligo-monoclonal B-cell expansion, which may culminate in
the development of a malignant lymphoproliferative disease.
A significant polyclonal activation of B lymphocytes in the
exocrine tissue is frequently observed in patients with primary
SS, with these B cells using the VKIIIb subgroup of the kappa
light chain. However, several studies have shown that the
exocrine glands are also a major site of monoclonal B-cell
proliferation, demonstrated by both immunophenotyping (an
increased proportion of kappa:lambda light chains in the B-cells
infiltrating the salivary glands) and immunogenotyping studies
(monoclonal or oligoclonal light chain gene rearrangements in
the salivary glands). The permanent stimulation of autoreactive
B cells favours oncogenic events and could finally lead to the
development of B-cell lymphoma. Two aspects of B-cell abnormalities in the pathogenesis of SS have recently generated a lot
of interest. Several studies have focused on analysing the altered
distribution of circulating B-cell subpopulations, while others
have investigated the existence of possible disturbances in the
usage of the Ig-variable region genes from B cells.
Analyses of B cells in the bone marrow and secondary
lymphoid tissues have shown a broad range of cell surface
markers defining different B-cell subpopulations. Some studies
have investigated the role of B-cell subpopulations in the pathogenesis of SS, and found various disturbances in B-cell trafficking and differentiation. Bohnhorst et al. [92] found an altered
proportion of Bm1–Bm5 cell subpopulations in SS patients, with
a higher percentage of circulating activated B cells. Hansen et al.
[93] found a depletion of memory B cells in peripheral blood,
with accumulation (or retention) of these cells in the parotid
glands. Bohnhorst et al. [94] also found a diminished percentage
of peripheral memory B cells, and suggested that an abnormal
differentiation of B cells to plasma cells might result in a reduction of the circulating memory B-cell pool together with the
release of significant amounts of soluble CD27 and IgG. In
addition, Hansen et al. [95] have detected multiple Ig heavy-chain
transcripts in peripheral CD27þ memory B cells in patients with
primary SS. Other studies have analysed possible disturbances
in the usage of the Ig variable-region genes from B cells of
patients with primary SS. Kaschner et al. [96] found a disturbed
regulation of B-cell maturation with abnormal selection, defects
in editing Ig receptors and abnormal mutational targeting in
peripheral B cells from SS patients. Heimbacher et al. [97]
described disturbances of B-cell maturation during early B-cell
development, marked by prominent Jkappa2 gene usage, and
also during germinal centre reactions, marked by the lack of
targeting of the hypermutation mechanism.
These studies indicate the possible existence of multiple disturbances in the differentiation and maturation of B cells and in
the Ig gene usage of B cells in primary SS, including an altered
B-cell trafficking (with retention of CD27þ memory B cells in
salivary gland tissue) together with a disturbance in B-cell
differentiation (with a greater presence of circulating activated
plasma B cells). These B-cell alterations might play an important
role in the autoimmune/lymphoproliferative processes involved
in the pathogenesis of primary SS.
Cytokines and chemokines. A large number of soluble
molecules control the interaction and trafficking of cellular
components of both the innate and acquired immune systems.
In SS, investigation of intermediate molecules such as cytokines
and chemokines and their receptors has contributed to a better
understanding of the migration of inflammatory cells in the
exocrine glands, contributing to the establishment and perpetuation of the autoimmune glandular damage.
Cytokines have been investigated in primary SS at three
different levels: analysing the peripheral patterns of circulating
Th1/Th2 cytokines, investigating the cytokine mRNA expression
in salivary gland tissue and analysing the genetic expression of
polymorphic cytokine genes. Peripherally, patients with primary
SS have a predominant Th2 response, with high levels of circulating IL-6 and IL-10 [98] and a significantly higher number of
circulating cells secreting IL-6 and IL-10 [99]. Perrier et al. [100]
found that IL-10 levels correlated with IgG1 levels and with
focus score, while Tishler et al. [101] found a positive correlation between salivary IL-6 levels and the focus score of labial
biopsies in SS patients. In contrast, mRNA expression of
Th1/Th2 cytokines in the salivary glands of SS patients suggests
an opposite pattern with a predominant local Th1 response.
Although lymphocytes infiltrating salivary glands of patients
with primary SS are capable of producing both Th1 and Th2
cytokines, the Th1/Th2 balance shifts in favour of Th1 in the
exocrine tissue, especially in those glands with the highest
infiltration score [102, 103]. Kolkowski et al. [104] also described
a predominant Th1 pattern (but irrespective of biopsy classification) and a significant increase of Th1 cytokine expression
associated with a longer disease evolution.
The role of B- and T-cell-attracting chemokines in the
exocrine damage of patients with SS has recently generated
increasing interest. To elucidate the mechanism of the development of T-cell infiltrates in the salivary glands of patients with
SS, Ogawa et al. [105] studied the expression of T-cell-attracting
chemokines, such as CXCL9 (Mig) and CXCL10 (IP-10) in
salivary glands from SS patients, and found that these
chemokines are involved in the accumulation of T cells in the
salivary gland tissue. Other studies have analysed the role of
B-cell-attracting chemokines. Amft et al. [106] studied CXCL12
(SDF-1) and CXCL13 (BCA-1) in salivary gland tissue, and
found ectopic expression of CXCL13 on endothelial cells
and germinal centre-like structures, together with a strong
expression of CXCL12 on ductal epithelial cells. Salomonsson
et al. [107] demonstrated the expression of CXCL13 in
epithelial cells from acini and ducts of salivary glands, while
its receptor CXCR5 (BLR-1) was expressed on the infiltrating
mononuclear cells, contributing to the recruitment of B cells
and activated T cells. Thus, these B-cell-attracting chemokines
(CXCL12 and CXCL13) might contribute to create a local
microenvironment supportive of focal B-cell aggregation and
differentiation, with structural features that are remarkably
similar to the germinal centre (GC). In these GC-like
structures, Salomonsson et al. [108] have demonstrated the local
production of anti-Ro/La antibodies and an enhanced apoptotic
activity.
The study of BAFF/Blys, a new member of the TNF family
of cytokines, has also generated a great deal of interest in
autoimmune diseases such as SS and SLE. BAFF specifically
regulates B-lymphocyte proliferation and survival, and is made
in both membrane-bound and soluble forms by myeloid cells
and dendritic cells, as well as by some T cells [109]. Recent
studies describe a higher expression of BAFF/Blys in SS. Groom
et al. [110] found elevated levels of circulating BAFF, as well
as a dramatic up-regulation of BAFF expression in salivary
glands, suggesting an altered differentiation and tolerance of
Aetiopathogenesis of primary Sjögren’s syndrome
B cells induced by excess of BAFF. Szodoray et al. [111] found a
reduced level of apoptosis among BAFF-expressing cells that
might lead to a longer BAFF expression in these cells, which
maintained positive signals for the infiltrating B cells to proliferate and mature. Clinically, Mariette et al. [112] demonstrated
a correlation in SS patients of BAFF levels with circulating levels
of autoantibodies (IgG, RF, anti-Ro and anti-La). High levels
of BAFF/Blys seem to be directly associated with the B-cell
hyperactivity/proliferation usually observed in patients with
primary SS. BAFF-blocking agents may be a promising therapy
for primary SS.
Apoptotic mechanisms
A role for altered apoptotic mechanisms has been strongly
suggested in the pathogenesis of SS-related glandular damage
in SS [113] (Table 4), although some experimental studies have
shown conflicting results [114]. On the one hand, infiltrating
mononuclear cells seem to be resistant to apoptosis (blocked
apoptosis), a phenomenon that may result in longer survival with
an increase in production of Th1 cytokines and autoantibodies.
On the other hand, the predominance of activated T lymphocytes
among the infiltrating cells suggests that cell-mediated immunity
plays an important role in epithelial destruction. The initial
apoptotic event that occurs in the salivary gland epithelium prior
to lymphocytic infiltration is probably triggered by exogenous
agents, such as viral proteins. Subsequently, an increase in apoptotic protease activities may be involved in the progression of
self-protein proteolysis and tissue destruction. Recent data have
suggested that modified self protein generated during apoptosis
may play an important role in the pathogenesis of SS, together
with an abnormal surface exposure of some cytoplasmic or
nuclear autoantigens such as Ro52, Ro60 and La48 [51]. These
altered apoptotic mechanisms may be located at different levels
of the extrinsic and intrinsic apoptotic pathways.
Fas/FasL system. Several studies have analysed the role of
the Fas/FasL system in salivary gland lesions of patients with SS.
Bolstad et al. [115] demonstrated a substantial increase in
the salivary gland tissue expression of the negative regulator
molecules PD-1 and CTLA-4 and the apoptotic signal molecules
Fas and FasL in SS patients compared with controls, suggesting
the involvement of the Fas/FasL system in the apoptosis of
ductal and acinar epithelial cells. Abu-Helu et al. [116] showed
that salivary gland epithelial cell lines (SGEC) constitutively
expressed more membranous Fas and intracellular FasL than
controls, while Shibata et al. [117] detected Fas/FasL expression
in ductal and acinar cells of SS patients but not in controls.
However, Ohlsson et al. [118] found Fas-induced epithelial cell
TABLE 4. Expression of apoptotic-related molecules in lymphocytes and
epithelial cells from salivary glands of patients with SS
Analysis of infiltrating
lymphocytes
" Fas expression [125, 174]
" TNF/TNFR expression [122]
" Bcl-2 expression [78, 125, 126, 174]
" Bcl-x expression [131]
" Perforin [168]
" Granzyme B [168]
Analysis of
epithelial cells
" Fas/FasL expression [115, 117, 125, 174]
" TNF/TNFR expression in ductal cells [122]
" TRAIL-R1 and TRAIL-R2 in ductal
cells [123]
" PD-1 expression [115]
" p53 and p21 expression in ductal cells [124]
" Caspase-3 and cleaved PARP [128, 129]
" XIAP expression [131]
1359
apoptosis to be a rare event, with a frequency of less than 1% in
salivary glands from 18 SS patients. Other studies have suggested
that Fas may accelerate the apoptotic death of peripheral CD4
T cells in SS patients [119, 120], a process partially blocked by
the over-expression of Bcl-2 in CD3 T cells [121].
TNF/TNFR-1 system. TNF is another important
inducer of apoptosis. Some studies have analysed the intracellular role of TNF in the apoptosis of ductal and acinar
epithelial cells from patients with SS. McArthur et al. [55] found
that TNF causes a redistribution of several autoantigens
(such as the nuclear proteins Ro and La and the cytoplasmic
protein -fodrin) on the cell membrane of apoptotic cells.
Koski et al. [122] detected high expression of TNF/
TNFR in infiltrating lymphocytes, endothelial and ductal
epithelial cells of salivary glands of SS patients, but not in
acinar cells.
TRAIL/TRAIL-R system. A recently identified member
of the TNF ligand family is TNF-related apoptosis-inducing
ligand (TRAIL) or Apo-2L, which induces apoptosis in several
tumour cell lines but not in normal cells, since TRAIL is constitutively expressed in many human tissues. It is not known
why tumour cells are sensitive to TRAIL-mediated apoptosis
while normal tissues are resistant. A possible answer lies in
the existence of a family of four membrane-bound TRAIL
receptors (TRAIL-R1/R4), which although able to bind TRAIL,
differ in their ability to transduce the death signal. Only
one study has analysed TRAIL expression in primary SS.
Matsumura et al. [123] detected a higher expression of TRAILR1 and TRAIL-R2 in human salivary duct cells, but not of
TRAIL-R3 or TRAIL-R4, with IFN- up-regulating levels
of TRAIL-R1.
PD-1/PD-1L system. The programmed death-1 (PD-1)
receptor, an inhibitory co-stimulatory molecule found on
activated T cells, has been shows to play a role in the regulation
of immune responses and peripheral tolerance. Initial characterization of the PD-1/PD-1-ligand system has revealed that this
pathway can down-regulate TCR- and CD28-mediated signals.
In patients with primary SS, Bolstad et al. [115] demonstrated
a substantial increase in the salivary gland tissue expression of
PD-1 compared with controls.
p53/p21 system. p53 is a nuclear protein suppressor of
human cancer that serves as a critical regulator of cell survival
and proliferation. Loss of p53 activity allows the survival and
proliferation of cells that should otherwise be eliminated.
In primary SS, Mariette et al. [124] have evaluated p53 and
p21 expression in salivary glands from 10 patients and 10
controls. The p53 antigen was detected in the ductal cells of
nine SS patients and only one control, and the p21 antigen in
eight patients and two controls. Both antigens were located in
the ductal cells of SS patients, but not in acinar cells. The
expression of p53 and p21 in the ductal cells located around
lymphoid infiltrates may represent a defence mechanism allowing
DNA repair and thus preventing apoptosis, while the lack of
over-expression of p53 and p21 in acinar cells could be one of
the mechanisms responsible for acinar destruction by apoptosis
in SS salivary glands.
Bcl-2/Bax system. Apoptosis may also be activated from
inside the cell through specific sensors residing in the cell nucleus
and cytoplasm (intrinsic pathway of apoptosis regulation), with
mitochondrial function appearing to be critical in some cells for
executing a death programme. The Bcl-2 family of proteins,
located in the outer mitochondrial membrane, plays an important role in preventing or permitting apoptosis. Human Bcl-2
was the first identified proto-oncogene capable of protecting cells
from programmed cell death, and the pro-apoptotic Bcl-2
associated protein x (Bax) the first identified cell death promoter.
Kong et al. [125] demonstrated in SS that the expression of Bcl-2
in the majority of lymphocytes infiltrating the salivary glands
M. Ramos-Casals and J. Font
1360
makes them resistant to apoptotic cell death (blocked apoptosis).
Recently, Nakamura et al. [78] showed that Bcl-2 and Bcl-x were
preferentially expressed in infiltrating mononuclear cells rather
than in the acinar and ductal epithelial cells from salivary
glands of 17 SS patients, while Ohlsson et al. [126] detected Bcl-2
(but rarely Bax) in the infiltrating lymphocytes of salivary glands
from SS patients. However, Abu-Helu et al. [116] found that
SGEC cell lines constitutively expressed antiapoptotic proteins,
such as Bcl-2 and cFLIP, that might protect them from both
spontaneous and anti-Fas mAb-mediated apoptosis. Kamachi
et al. [127] found an inhibitory effect of IFN- in Bcl-2 expression,
which was enhanced by coadministration of TNF, leading to an
increase in the apoptosis of salivary gland cells. It seems that
apoptosis of the epithelial acinar and ductal cells may depend on
the imbalance between up-regulated death-promoters (Fas and
Bax) and down-regulated apoptosis-suppressor signals (Bcl-2).
Caspase system. Some studies have analysed the role of
the caspase cascade in the pathogenesis of SS. Jimenez et al.
[128] evaluated the presence of activated caspase-3 and -9 and
the cleavage product of PARP, a DNA repair enzyme that is
a substrate for caspase-3, in the salivary glands from 15 SS
patients and 5 normal controls by immunohistochemistry.
Compared with controls, a stronger expression of activated
caspase-3 and cleaved PARP in the acinar and ductal cells of
salivary glands was found in 13/15 (87%) SS patients, while
staining for activated caspase-9 was negative. The expression of
activated caspase-3, but not caspase-9, suggests that the
apoptotic death of epithelial cells in SS involves a type I, rather
than a type II, apoptotic pathway [128]. Masago et al. [129]
detected the expression of caspase-3 in both ductal and acinar
cells in salivary glands from SS patients but only in ductal
cells from normal controls. In addition, caspase-3 was also
expressed by lymphocytes infiltrating the salivary glands. All the
apoptotic cells stained positive for caspase-3 and Bax, suggesting
that the expression of these gene products precedes DNA
fragmentation [129].
Aiba-Masago et al. [130] found a role for caspase-1 in the
initiation of the caspase cascade induced via Fas/FasL in a rat
acinar cell line. Nakamura et al. [131] analysed the role of the
X chromosome-linked inhibitor of apoptosis (XIAP), a member
of the IAP family that inhibits caspase-7 and caspase-3
activation, and found a strong expression in the acinar and
+
Pro-apoptotic signals
Fas/FasL
TNFα /TNFα-R
TRAIL/ TRAIL-R
PD-1/PD-1L
Bax
Caspase-3
Granzyme B
IFNγ
Therapeutic
approaches
Blocking
ductal epithelial cells of SS patients but not in those of controls.
Because caspase-3 and caspase-7 are effector enzymes, XIAP
might protect salivary epithelial cells from apoptotic death in
SS [131]. Hayashi et al. [132] suggested that treatment with
caspase inhibitors might prevent the development of the inflammatory process in salivary glands, and Inoue et al. [57] found
that caspase-inhibiting agents could inhibit the cleavage of
-fodrin. Increased caspase cascade activity may be involved in
the progression of autoantigen proteolysis and tissue destruction
in primary SS. The presence of activated caspase-3 in salivary
glands indicates that excessive apoptosis may contribute to
epithelial destruction in primary SS.
Perforin/granzyme B system. Cytotoxic lymphocytes (CTL),
the key players in cell-mediated immunity, may induce apoptosis
by engaging death receptors or through exocytosis of cytolytic
granules. This mechanism depends on the synergy of a calciumdependent pore-forming protein (perforin) and a battery of
proteases (granzymes), and results in penetration of the target
cell by effector molecules. The role of this apoptotic pathway
has been little analysed in primary SS. In 1999, Kolkowski et al.
[104] found a higher expression of perforin in the majority of
salivary glands from 42 SS patients, while Nagaraju et al. [56]
recently described the cleavage of some autoantigens (-fodrin
and M3R) by granzyme B, but not by caspases, in a caspaseindependent apoptotic pathway induced by CTL, suggesting the
possible existence of both caspase-dependent and -independent
pathways as apoptotic effector mechanisms in the pathogenesis
of primary SS.
In summary, current studies focusing on the role of apoptotic
mechanisms in the aetiopathogenesis of primary SS suggest
that these mechanisms might contribute to the progression of
proteolysis of exocrine autoantigens, resulting in exocrine glandular damage. A possible apoptotic imbalance between promoter
(Fas, Bax, TNF, TRAIL and granzyme/caspases) and suppressor
(Bcl-2, cFLIP, PARP, XIAP, p53) apoptotic signals might be
central in the epithelial destruction of exocrine glands in primary
SS (Fig. 2).
Emerging aetiopathogenic concepts
In spite of the large number of studies suggesting a role for the
autoimmune aetiopathogenesis of the exocrine gland damage
-
+
Anti-apoptotic signals
Pro-repair signals
Bcl-2
cFLIP
PARP
XIAP
p53
p21
TFF-peptides
(Trefoil proteins):
Stimulating
Stimulating
TFF-1 (pS2)
TFF-2 (SP)
TFF-3 (ITF)
FIG. 2. The epithelial physiological balance: apoptosis versus repair of the epithelium. This figure is available in colour as
supplementary data at Rheumatology Online.
Aetiopathogenesis of primary Sjögren’s syndrome
in primary SS, recent studies have suggested the existence of
aetiopathogenic mechanisms other than lymphocytic-mediated
epithelial destruction through apoptosis, including the possible
role of new candidate antigens, hormonal factors, autonomic
dysfunction, altered epithelial repair and proteolytic mechanisms.
New candidate antigens
The aquaporins (AQP) are a family of small, integral membrane
proteins that function as plasma membrane transporters of
water [133]. Several studies have analysed the cellular distribution of AQP-5 in patients with SS, with controversial results.
In salivary glands, Tsubota et al. [134] found the expected apical
distribution of AQP-5 in lacrimal acinar cells from healthy
controls, while SS patients showed an abnormal cytoplasmic
distribution, and Steinfeld et al. [135] detected lower labelling
indices at the apical membrane of salivary glands. In contrast,
Beroukas et al. [136] found that the distribution and density of
AQP-5 in salivary glands did not differ between patients with
and without SS. These controversial results have recently been
analysed by Waterman et al. [137], who pointed out that the
techniques used in these studies differed in several ways.
Recently, other AQP subtypes (AQP-1 and AQP-3) have been
studied in primary SS. Beroukas et al. [138] described a reduced
expression of AQP-1 in myoepithelial cells surrounding acini,
while AQP-3 was expressed normally in the basolateral membrane of acinar epithelial cells. Further studies are necessary in
order to elucidate the role of AQP and their different isotypes
in the pathogenesis of SS.
Other molecules have been postulated as possible self antigens
in SS. ICA69, a self antigen expressed in brain, pancreas,
salivary and lacrimal glands, was studied by Winer et al. [139]
in congenic mice deficient in ICA69. Disruption of the ICA69
locus prevented lacrimal gland disease and greatly reduced
the spontaneous development of salivary gland disease in NOD
mice, although Gordon et al. [140] have recently described a
non-specific role for anti-ICA69 antibodies in a large series of
patients with primary SS. Billaut-Mulot et al. [141] identified
and cloned a novel gene encoding a 56 kDa protein named SS56
which is structurally related to the 52 kDa Ro/SSA antigen, and
detected anti-SS56 antibodies in 64% of patients with primary
SS and in 68% of SLE patients. Finally, L-type calcium channels, 1-adrenoreceptors and P2x purinoreceptors have also been
suggested as possible self antigens [142].
Hormonal factors
The epidemiological pattern of primary SS, with an overwhelming predominance of female patients [143], supports a
role for hormonal factors in the aetiopathogenesis of the autoimmune exocrinopathy. Furthermore, oestrogens are known
to modulate immunological responses and to regulate tissue
apoptosis. Recent experimental studies support a possible role
for sex hormones in the aetiopathogenesis of SS, a fact that
might influence the maintenance and remodelling of the
exocrine glands [144]. Ishimaru et al. [145] described the development of autoimmune exocrinopathy in oestrogen-deficient
mice, while Shim et al. [146] described the development of a
lymphoproliferative autoimmune disease resembling SS in an
aromatase-knockout mouse (ArKO). In addition, Kassi et al.
[147] have described the existence of oestrogen receptors (Er)
in cultured epithelial cells from salivary glands of SS patients,
suggesting a possible role for oestrogens in the growth, differentiation and function of salivary epithelium.
However, human studies analysing serum levels of oestrogen
and androgen hormones have shown results that contrast
with these experimental studies. Valtysdottir et al. [148] found
1361
a correlation of circulating values of dehydroepiandrosterone
(DHEA) with the quality of sexual life and mental well-being in
women with primary SS. Brennan et al. [149] found a significant
correlation between testosterone levels and values of erythrocyte
sedimentation rate (ESR), serum protein levels and focus score,
but no correlation was found between disease activity and
oestrogen levels. Sullivan et al. [150] described an androgen
deficiency (decreased levels of DHEA, 5-diol, dihydrotestosterone and androgen metabolites) with no significant alterations
in testosterone or oestrogen levels. This androgen deficiency is
in contrast to the correlation of androgenic hormones with
several clinical and analytical SS parameters described in the
two above-mentioned studies [148, 149]. In addition, a recent
pilot clinical trial using DHEA in patients with primary SS has
shown no evidence of clinical efficacy [151]. These contrasting
results on the circulating levels of oestrogen and androgen
hormones in primary SS are probably due to the small number
of patients studied together with the high variability of serum
levels of sex hormones, which did not allow definitive conclusions to be made on the specific role of sex hormones in the
aetiopathogenesis of SS.
Autonomic dysfunction
Autonomic dysfunction is now considered as another mechanism involved in the aetiopathogenesis of primary SS, in
addition to the autoimmune damage to the exocrine glands.
This is suggested by the fact that a considerable amount of
histologically normal salivary acinar tissue may be detected in
some cases [152] that is functional outside the patient [153].
Involvement of the autonomic (mainly parasympathetic) nervous
system, which controls exocrine secretion, may contribute to
glandular dysfunction and reduce salivation and tear production
[154–158]. Reports have suggested the up regulation of type-3
muscarinic cholinergic receptors (M3R), inhibition of parasympathetic neurotransmission by antibodies to M3R or increased
levels of cholinesterase as possible factors involved in this
autonomic dysfunction.
In patients with primary SS, an increased number of muscarinic cholinergic receptors are found in the salivary glands.
Potential mechanisms responsible for up-regulation of muscarinic
cholinergic receptors may be the impaired release of acetylcholine (ACh) following cytokine inhibition [159] or receptor
blockade by specific antibodies [155]. Beroukas et al. [160]
detected increased M3R expression in acini of patients with SS,
suggesting that this up-regulation of M3R might be induced by
antibodies antagonistic to M3R.
Recent studies have searched for circulating anti-M3R
antibodies in SS. Bacman et al. [161] found high levels of antiM3R antibodies in the sera of patients with primary and
associated SS, but not in healthy controls. The authors also
demonstrated the binding of antibodies to the second extracellular loop of protein G-coupled M3R in rat lachrimal and
salivary glands [161, 162], and Cavill et al. [163] reported that
these antibodies may mimic functional autoantibodies of patients
with primary SS. Waterman et al. [155] detected antibodies that
might act as M3R antagonists in smooth muscle in sera from
patients with both primary and associated SS, and Goldblatt
et al. [164] found that MR3-mediated contractions were inhibited
by Ig fractions in patients with primary SS, although these
antibodies were also detected in patients with other autoimmune
diseases. Other authors have detected anti-M3R antibodies
using a newly constructed cell line expressing human M3R [165].
The humoral immune response and the targeting of this
muscarinic M3 cell-surface signal transduction receptor might
negatively affect the secretory response through a translocation
of aquaporins [166].
1362
M. Ramos-Casals and J. Font
An additional mechanism that might contribute to autonomic
dysfunction is increased levels of cholinesterase (AChE) within
the salivary glands of patients with primary SS [167]. After its
release, ACh must diffuse from the terminal axon to the M3R
acinar cell, making ACh vulnerable to degradation by AChE
[168]. Dawson et al. [167] suggested that increased levels of
AChE within the salivary glands of patients with primary SS
might exacerbate the glandular dysfunction, and these authors
have recently shown that primary SS patients had significantly
higher levels of AChE in their saliva compared with control
subjects [168].
Further research may provide clues to the targeting of
immunomodulated cholinergic dysfunction as a possible therapeutic approach for SS. Recently, Cavill et al. [169] suggested
that intravenous immunoglobulin (IVIG) might neutralize autoantibodies that inhibit cholinergic neurotransmission, providing
a rationale for using IVIG to treat autonomic dysfunction in
primary SS.
Altered epithelial repair
Trefoil factor family (TFF) peptides are small (7–12 kDa)
protease-resistant secreted peptides designated TFF1 (pS2),
TFF2 (SP) and TFF3 (ITF). The TFF domain is an ancient
cysteine-rich shuffled module forming the basic unit for the
family of secretory TFF peptides. It is also an integral
component of mosaic proteins associated with mucous surfaces
[170, 171]. TFF peptides are secretory products typical of the
gastrointestinal tract, although their synthesis has recently been
demonstrated in a number of mucin-producing epithelial cells,
such as those of the respiratory tract, salivary glands, uterus and
conjunctiva. They play a pivotal role in maintaining the surface
integrity of these delicate epithelia as constituents of mucus gels,
and also modulate cell migratory processes due to their antiapoptotic properties and motogenic activity.
Recent studies have analysed the aetiopathogenic role of TFF
peptides in primary SS. Paulsen et al. [172] demonstrated that
the epithelium of the nasolacrimal ducts synthesizes TFF3 and,
in some cases, TFF1, but not TFF2. Devine et al. [173] found
that TFF1 mRNA was usually expressed at low levels by some
mucous cells, whereas TFF3 was produced abundantly. In
contrast, Polihronis et al. [174] found that TFF1 was expressed
by a significant percentage of acinar and ductal cells in SS
patients. Mucus-producing epithelial cells, especially in areas of
epithelial cell injury, generally express TFF1 and this could
account for the expression of TFF1 by epithelial cells in salivary
gland biopsies. It is possible that the TFF pathway constitutes a
mechanism of cell proliferation closely associated with the cell
cycle, possibly acting as a promoter of DNA synthesis in
opposition to the DNA-degrading messages of the different
apoptotic stimuli.
In contrast to apoptotic mechanisms that tend to destroy the
epithelium of salivary glands, the study of possible alterations
in these recently identified defensive mechanisms of epithelial
restoration may open new lines of research on the aetiopathogenesis of salivary gland tissue damage in primary SS (Fig. 2).
Proteolytic mechanisms
Several studies have analysed the effect of different factors
involved in maintaining the structural integrity of acini and ducts
in primary SS [175]. Goicovich et al. [176] described increased
levels of proteolytic activity against proteins of the basal lamina
(laminin and type IV collagen) and stroma (types I and III
collagen and fibronectin) of the salivary glands of SS patients,
suggesting a proteolytic action of matrix metalloproteinases
toward some macromolecules of the extracellular matrix that
form the basal lamina and stroma of glandular acini and ducts.
Enhanced degradation was most evident for fibronectin, laminin
and Type IV collagen of the structural organization observed
in the basal lamina and apical surface of acini, suggesting
additional mechanisms for glandular damage rather than
epithelial apoptosis in primary SS.
Conclusion
The increasing number of data published recently on the
aetiopathogenesis of SS has led to a change to the concept of
considering it as a ‘second line’ systemic autoimmune disease in
which no specific diagnostic and therapeutic guidelines exist.
Recent studies have demonstrated distinct aetiopathogenic
mechanisms in addition to lymphocytic infiltration, and have
focused not only on the epithelial damage mediated by apoptotic
signals but also on the possible role of hormonal factors and
autonomic dysfunction. While epithelitis and glandular damage
(secondary to an inadequate epithelial balance of pro-apoptotic
and defensive repair signals) are key aetiopathogenic mechanisms
that may account for the glandular manifestations of SS,
lymphocytic dysfunction seems to be most closely related to the
extraglandular, immunological and lymphoproliferative processes
that patients with SS may present. In addition, the role of
exogenous agents as triggering factors for the initial autoimmune
dysfunction deserves consideration.
Advances in our knowledge of aetiopathogenic mechanisms
are closely related to the development of future treatments for
SS. On the one hand, new agents should be directed at correcting
the epithelial imbalance between apoptosis and repair, including
either blocking agents of apoptotic mechanisms or agents
favouring epithelial restoration. On the other hand, new therapeutic approaches should be centred on correcting lymphocytic
dysfunction, with agents directed at modifying T-cell dysfunction
or diminishing B-cell hyperactivity (including agents antagonizing Blys/BAFF, B-cell attracting chemokines and CD20þ
cells). Other strategies may include the transplantation of
salivary and lachrimal glands or the use of gene therapy [177].
Acknowledgements
We are indebted to A. G. Tzioufas and H. M. Moutsopoulos for
providing critical feedback that helped shape the manuscript,
and to D. Buss for his editorial assistance.
The authors have declared no conflicts of interest.
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