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M. Ramos-Casals, J. Font, Primary Sjögren's syndrome: current and emergent aetiopathogenic concepts, Rheumatology, Volume 44, Issue 11, November 2005, Pages 1354–1367, https://doi.org/10.1093/rheumatology/keh714
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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 CD4+ cells rather than CD8+ 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).
1. Altered immune recognition | 1.1. Intrinsic factors | Molecular mimicry (self antigens) |
1.2. Extrinsic factors | Triggers of the autoimmune response (viruses) | |
2. Abnormal acquired immune responses | 2.1. T-cell dysfunction | Altered TCR repertoire of infiltrating T-cells |
2.2. B-cell dysfunction | Increased circulating plasma cells | |
Retention of CD27+ memory B cells in salivary glands | ||
Abnormal selection in editing Ig receptors | ||
Prominent Jkappa2 gene usage | ||
Lack of targeting of the hypermutation mechanism | ||
3. Altered regulation of the immune response | 3.1. Cytokines | Peripheral enhanced Th2 expression |
Predominant local Th1 response | ||
Increased frequency of IL-10 gene GCC haplotype | ||
3.2. Chemokines | 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 |
1. Altered immune recognition | 1.1. Intrinsic factors | Molecular mimicry (self antigens) |
1.2. Extrinsic factors | Triggers of the autoimmune response (viruses) | |
2. Abnormal acquired immune responses | 2.1. T-cell dysfunction | Altered TCR repertoire of infiltrating T-cells |
2.2. B-cell dysfunction | Increased circulating plasma cells | |
Retention of CD27+ memory B cells in salivary glands | ||
Abnormal selection in editing Ig receptors | ||
Prominent Jkappa2 gene usage | ||
Lack of targeting of the hypermutation mechanism | ||
3. Altered regulation of the immune response | 3.1. Cytokines | Peripheral enhanced Th2 expression |
Predominant local Th1 response | ||
Increased frequency of IL-10 gene GCC haplotype | ||
3.2. Chemokines | 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 |
1. Altered immune recognition | 1.1. Intrinsic factors | Molecular mimicry (self antigens) |
1.2. Extrinsic factors | Triggers of the autoimmune response (viruses) | |
2. Abnormal acquired immune responses | 2.1. T-cell dysfunction | Altered TCR repertoire of infiltrating T-cells |
2.2. B-cell dysfunction | Increased circulating plasma cells | |
Retention of CD27+ memory B cells in salivary glands | ||
Abnormal selection in editing Ig receptors | ||
Prominent Jkappa2 gene usage | ||
Lack of targeting of the hypermutation mechanism | ||
3. Altered regulation of the immune response | 3.1. Cytokines | Peripheral enhanced Th2 expression |
Predominant local Th1 response | ||
Increased frequency of IL-10 gene GCC haplotype | ||
3.2. Chemokines | 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 |
1. Altered immune recognition | 1.1. Intrinsic factors | Molecular mimicry (self antigens) |
1.2. Extrinsic factors | Triggers of the autoimmune response (viruses) | |
2. Abnormal acquired immune responses | 2.1. T-cell dysfunction | Altered TCR repertoire of infiltrating T-cells |
2.2. B-cell dysfunction | Increased circulating plasma cells | |
Retention of CD27+ memory B cells in salivary glands | ||
Abnormal selection in editing Ig receptors | ||
Prominent Jkappa2 gene usage | ||
Lack of targeting of the hypermutation mechanism | ||
3. Altered regulation of the immune response | 3.1. Cytokines | Peripheral enhanced Th2 expression |
Predominant local Th1 response | ||
Increased frequency of IL-10 gene GCC haplotype | ||
3.2. Chemokines | 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 |
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).
Polymorphic gene . | Altered polymorphic distribution . | Clinical associations . |
---|---|---|
Interleukin genes | ||
IL10 | ↑ GCC haplotype (13,16) | Earlier SS onset [15, 18]. ↑ vasculitis [17] |
IL4R | No differences [22, 23]. ↑ Q551 haplotype [24] | ↑ Parotidomegaly [23]. ↓ Raynaud's [25] |
TNFα | No differences [19, 20]. ↑ TNF2 allele [16, 21] | ↑ Renal involvement [21]. ↑ Anti-Ro/La antibodies [16, 21] |
IL6 | No differences [16, 27] | – |
IL1RA | No differences [28] | – |
TGFβ1 | No differences [16] | – |
Other genes | ||
MBL | ↑ Codon 54 (Japan [29, 30]). No differences (Caucasian [31, 32]) | – |
CTLA4 | No differences [20] | – |
CCR5 | ↓ Delta 32 genotype [28] | – |
Fas/FasL | No differences [34]. Altered Fas alleles [33] | – |
Polymorphic gene . | Altered polymorphic distribution . | Clinical associations . |
---|---|---|
Interleukin genes | ||
IL10 | ↑ GCC haplotype (13,16) | Earlier SS onset [15, 18]. ↑ vasculitis [17] |
IL4R | No differences [22, 23]. ↑ Q551 haplotype [24] | ↑ Parotidomegaly [23]. ↓ Raynaud's [25] |
TNFα | No differences [19, 20]. ↑ TNF2 allele [16, 21] | ↑ Renal involvement [21]. ↑ Anti-Ro/La antibodies [16, 21] |
IL6 | No differences [16, 27] | – |
IL1RA | No differences [28] | – |
TGFβ1 | No differences [16] | – |
Other genes | ||
MBL | ↑ Codon 54 (Japan [29, 30]). No differences (Caucasian [31, 32]) | – |
CTLA4 | No differences [20] | – |
CCR5 | ↓ Delta 32 genotype [28] | – |
Fas/FasL | No differences [34]. Altered Fas alleles [33] | – |
Polymorphic gene . | Altered polymorphic distribution . | Clinical associations . |
---|---|---|
Interleukin genes | ||
IL10 | ↑ GCC haplotype (13,16) | Earlier SS onset [15, 18]. ↑ vasculitis [17] |
IL4R | No differences [22, 23]. ↑ Q551 haplotype [24] | ↑ Parotidomegaly [23]. ↓ Raynaud's [25] |
TNFα | No differences [19, 20]. ↑ TNF2 allele [16, 21] | ↑ Renal involvement [21]. ↑ Anti-Ro/La antibodies [16, 21] |
IL6 | No differences [16, 27] | – |
IL1RA | No differences [28] | – |
TGFβ1 | No differences [16] | – |
Other genes | ||
MBL | ↑ Codon 54 (Japan [29, 30]). No differences (Caucasian [31, 32]) | – |
CTLA4 | No differences [20] | – |
CCR5 | ↓ Delta 32 genotype [28] | – |
Fas/FasL | No differences [34]. Altered Fas alleles [33] | – |
Polymorphic gene . | Altered polymorphic distribution . | Clinical associations . |
---|---|---|
Interleukin genes | ||
IL10 | ↑ GCC haplotype (13,16) | Earlier SS onset [15, 18]. ↑ vasculitis [17] |
IL4R | No differences [22, 23]. ↑ Q551 haplotype [24] | ↑ Parotidomegaly [23]. ↓ Raynaud's [25] |
TNFα | No differences [19, 20]. ↑ TNF2 allele [16, 21] | ↑ Renal involvement [21]. ↑ Anti-Ro/La antibodies [16, 21] |
IL6 | No differences [16, 27] | – |
IL1RA | No differences [28] | – |
TGFβ1 | No differences [16] | – |
Other genes | ||
MBL | ↑ Codon 54 (Japan [29, 30]). No differences (Caucasian [31, 32]) | – |
CTLA4 | No differences [20] | – |
CCR5 | ↓ Delta 32 genotype [28] | – |
Fas/FasL | No differences [34]. Altered Fas alleles [33] | – |
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 (TNFα) 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 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 R551 allele for Raynaud's phenomenon. With respect to the interleukin-1β (IL-1β) 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 (TGFβ1) in France [16]. The current data on polymorphic cytokine genes suggest that IL-10 and TNFα 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 α and β 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 α-fodrin on the surface of apoptotic-induced cells [55]. Nagaraju et al. [56] demonstrated the specific cleavage of α-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 α-fodrin proteolysis. Maruyama et al. [58] described a 150 kDa cleaved product of α-fodrin that is exposed as a neoepitope to the immune system. These studies suggest that an abnormal proteolysis of α-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-α-fodrin antibodies in SS (Table 3) [59–65]. Witte et al. [60] detected anti-α-fodrin antibodies in 55–64% of adult patients with primary SS and in 40–86% of those with secondary SS (depending on the Ig isotype). Other authors detected anti-α-fodrin antibodies in child/juvenile SS patients [61, 62], and de Seze et al. [65] have recently suggested a possible role for anti-α-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-α-fodrin antibodies for the diagnosis of primary SS of 32% and 21%, respectively. This suggests that anti-α-fodrin antibodies seem to reflect non-organ-specific autoimmunity, and probably have a limited discriminatory value for the diagnosis of primary SS.
Disease . | . | Prevalence . | References . |
---|---|---|---|
Primary SS | Adults | 25/63 (40%) | 59, 63 |
IgA | 80/165 (48%) | 60, 66 | |
IgG | 64/165 (39%) | 60, 66 | |
Childhood | 25/25 (100%) | 61, 62, 64 | |
Associated SS | Adults | 9/15 (60%) | 59 |
IgA | 13/22 (59%) | 60 | |
IgG | 9/22 (41%) | 60 | |
SLE | Adults | 28/97 (29%) | 59, 63 |
IgA | 17/100 (17%) | 60, 66 | |
IgG | 14/100 (14%) | 60, 66 | |
Childhood | 8/29 (28%) | 61, 62, 64 | |
RA | IgA | 16/42 (38%) | 60, 66 |
IgG | 9/42 (21%) | 60, 66 | |
Juvenile | 5/9 (56%) | 64 | |
Systemic sclerosis | IgA | 4/20 (20%) | 66 |
IgG | 3/20 (15%) | 66 | |
Inflammatory myopathies | IgA | 1/10 (10%) | 66 |
IgG | 3/10 (30%) | 66 |
Disease . | . | Prevalence . | References . |
---|---|---|---|
Primary SS | Adults | 25/63 (40%) | 59, 63 |
IgA | 80/165 (48%) | 60, 66 | |
IgG | 64/165 (39%) | 60, 66 | |
Childhood | 25/25 (100%) | 61, 62, 64 | |
Associated SS | Adults | 9/15 (60%) | 59 |
IgA | 13/22 (59%) | 60 | |
IgG | 9/22 (41%) | 60 | |
SLE | Adults | 28/97 (29%) | 59, 63 |
IgA | 17/100 (17%) | 60, 66 | |
IgG | 14/100 (14%) | 60, 66 | |
Childhood | 8/29 (28%) | 61, 62, 64 | |
RA | IgA | 16/42 (38%) | 60, 66 |
IgG | 9/42 (21%) | 60, 66 | |
Juvenile | 5/9 (56%) | 64 | |
Systemic sclerosis | IgA | 4/20 (20%) | 66 |
IgG | 3/20 (15%) | 66 | |
Inflammatory myopathies | IgA | 1/10 (10%) | 66 |
IgG | 3/10 (30%) | 66 |
Disease . | . | Prevalence . | References . |
---|---|---|---|
Primary SS | Adults | 25/63 (40%) | 59, 63 |
IgA | 80/165 (48%) | 60, 66 | |
IgG | 64/165 (39%) | 60, 66 | |
Childhood | 25/25 (100%) | 61, 62, 64 | |
Associated SS | Adults | 9/15 (60%) | 59 |
IgA | 13/22 (59%) | 60 | |
IgG | 9/22 (41%) | 60 | |
SLE | Adults | 28/97 (29%) | 59, 63 |
IgA | 17/100 (17%) | 60, 66 | |
IgG | 14/100 (14%) | 60, 66 | |
Childhood | 8/29 (28%) | 61, 62, 64 | |
RA | IgA | 16/42 (38%) | 60, 66 |
IgG | 9/42 (21%) | 60, 66 | |
Juvenile | 5/9 (56%) | 64 | |
Systemic sclerosis | IgA | 4/20 (20%) | 66 |
IgG | 3/20 (15%) | 66 | |
Inflammatory myopathies | IgA | 1/10 (10%) | 66 |
IgG | 3/10 (30%) | 66 |
Disease . | . | Prevalence . | References . |
---|---|---|---|
Primary SS | Adults | 25/63 (40%) | 59, 63 |
IgA | 80/165 (48%) | 60, 66 | |
IgG | 64/165 (39%) | 60, 66 | |
Childhood | 25/25 (100%) | 61, 62, 64 | |
Associated SS | Adults | 9/15 (60%) | 59 |
IgA | 13/22 (59%) | 60 | |
IgG | 9/22 (41%) | 60 | |
SLE | Adults | 28/97 (29%) | 59, 63 |
IgA | 17/100 (17%) | 60, 66 | |
IgG | 14/100 (14%) | 60, 66 | |
Childhood | 8/29 (28%) | 61, 62, 64 | |
RA | IgA | 16/42 (38%) | 60, 66 |
IgG | 9/42 (21%) | 60, 66 | |
Juvenile | 5/9 (56%) | 64 | |
Systemic sclerosis | IgA | 4/20 (20%) | 66 |
IgG | 3/20 (15%) | 66 | |
Inflammatory myopathies | IgA | 1/10 (10%) | 66 |
IgG | 3/10 (30%) | 66 |
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 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 CD8+ (and not T CD4+) 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 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 BV2+ of the infiltrating T cells recognize restricted epitopes and function as CD4+ 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 CD27+ 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 CD27+ 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 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.
Analysis of infiltrating | ↑ Fas expression [125, 174] |
lymphocytes | ↑ TNFα/TNFR expression [122] |
↑ Bcl-2 expression [78, 125, 126, 174] | |
↑ Bcl-x expression [131] | |
↑ Perforin [168] | |
↑ Granzyme B [168] | |
Analysis of | ↑ Fas/FasL expression [115, 117, 125, 174] |
epithelial cells | ↑ TNFα/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] |
Analysis of infiltrating | ↑ Fas expression [125, 174] |
lymphocytes | ↑ TNFα/TNFR expression [122] |
↑ Bcl-2 expression [78, 125, 126, 174] | |
↑ Bcl-x expression [131] | |
↑ Perforin [168] | |
↑ Granzyme B [168] | |
Analysis of | ↑ Fas/FasL expression [115, 117, 125, 174] |
epithelial cells | ↑ TNFα/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] |
Analysis of infiltrating | ↑ Fas expression [125, 174] |
lymphocytes | ↑ TNFα/TNFR expression [122] |
↑ Bcl-2 expression [78, 125, 126, 174] | |
↑ Bcl-x expression [131] | |
↑ Perforin [168] | |
↑ Granzyme B [168] | |
Analysis of | ↑ Fas/FasL expression [115, 117, 125, 174] |
epithelial cells | ↑ TNFα/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] |
Analysis of infiltrating | ↑ Fas expression [125, 174] |
lymphocytes | ↑ TNFα/TNFR expression [122] |
↑ Bcl-2 expression [78, 125, 126, 174] | |
↑ Bcl-x expression [131] | |
↑ Perforin [168] | |
↑ Granzyme B [168] | |
Analysis of | ↑ Fas/FasL expression [115, 117, 125, 174] |
epithelial cells | ↑ TNFα/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] |
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 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].
TNFα/TNFαR-1 system
TNFα is another important inducer of apoptosis. Some studies have analysed the intracellular role of TNFα in the apoptosis of ductal and acinar epithelial cells from patients with SS. McArthur et al. [55] found that TNFα causes a redistribution of several autoantigens (such as the nuclear proteins Ro and La and the cytoplasmic protein α-fodrin) on the cell membrane of apoptotic cells. Koski et al. [122] detected high expression of TNFα/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 TRAIL-R1 and TRAIL-R2 in human salivary duct cells, but not of TRAIL-R3 or TRAIL-R4, with IFN-γ 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 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-γ in Bcl-2 expression, which was enhanced by coadministration of TNFα, 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 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 α-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 calcium-dependent 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 (α-fodrin and M3R) by granzyme B, but not by caspases, in a caspase-independent 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 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, α1-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 (Erα) 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 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 anti-M3R 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].
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 CD20+ cells). Other strategies may include the transplantation of salivary and lachrimal glands or the use of gene therapy [177].
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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Rischmueller M, Limaye V, Lester S et al. Polymorphisms of the interleukin 10 gene promoter are not associated with anti-Ro autoantibodies in primary Sjögren's syndrome.
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Gottenberg JE, Busson M, Loiseau P et al. Association of transforming growth factor beta1 and tumor necrosis factor alpha polymorphisms with anti-SSB/La antibody secretion in patients with primary Sjögren's syndrome.
Anaya JM, Correa PA, Herrera M, Eskdale J, Gallagher G. Interleukin 10 (IL-10) influences autoimmune response in primary Sjögren's syndrome and is linked to IL-10 gene polymorphism.
Origuchi T, Kawasaki E, Ide A et al. Correlation between interleukin 10 gene promoter region polymorphisms and clinical manifestations in Japanese patients with Sjögren's syndrome.
Guggenbuhl P, Veillard E, Quelvenec E et al. Analysis of TNF-α microsatellites in 35 patients with primary Sjögren's syndrome.
Hadj Kacem H, Kaddour N, Adyel FZ, Bahloul Z, Ayadi H. HLA-DQB1 CAR1/CAR2, TNFa IR2/IR4 and CTLA-4 polymorphisms in Tunisian patients with rheumatoid arthritis and Sjögren's syndrome.
Pertovaara M, Hulkkonen J, Antonen J et al. Polymorphism of the tumour necrosis factor-alpha gene at position –308 and renal manifestations of primary Sjögren's syndrome.
Buschs N, Silvestri T, di Giovine FS et al. IL-4 VNTR gene polymorphism in chronic polyarthritis. The rare allele is associated with protection against destruction.
Ramos-Casals M, Font J, Brito-Zeron P et al. Interleukin-4 receptor a polymorphisms in primary Sjögren's syndrome.
Youn J, Hwang SH, Cho CS et al. Association of the interleukin-4 receptor alpha variant Q576R with Th1/Th2 imbalance in connective tissue diseases.
Lester S, Downie-Doyle SE, Gordon TP, Bardy PG, Rischmueller M, Pile KD. The IL-4R alpha Q576R polymorphism is not associated with primary Sjögren's syndrome.
Muraki Y, Tsutsumi A, Takahashi R et al. Polymorphisms of IL-1 beta gene in Japanese patients with Sjögren's syndrome and systemic lupus erythematosus.
Hulkkonen J, Pertovaara M, Antonen J, Pasternack A, Hurme M. Elevated interleukin-6 plasma levels are regulated by the promoter region polymorphism of the IL6 gene in primary Sjögren's syndrome and correlate with the clinical manifestations of the disease.
Petrek M, Cermakova Z, Hutyrova B et al. CC chemokine receptor 5 and interleukin-1 receptor antagonist gene polymorphisms in patients with primary Sjögren's syndrome.
Tsutsumi A, Sasaki K, Wakamiya N et al. Mannose-binding lectin gene: polymorphisms in Japanese patients with systemic lupus erythematosus, rheumatoid arthritis and Sjögren's syndrome.
Wang ZY, Morinobu A, Kanagawa S, Kumagai S. Polymorphisms of the mannose binding lectin gene in patients with Sjögren's syndrome.
Aittoniemi J, Pertovaara M, Hulkkonen J et al. The significance of mannan-binding lectin gene alleles in patients with primary Sjögren's syndrome.
Mullighan CG, Heatley S, Bardy PG, Lester S, Rischmueller M, Gordon TP. Lack of association between mannose-binding lectin gene polymorphisms and primary Sjögren's syndrome.
Bolstad AI, Wargelius A, Nakken B, Haga HJ, Jonsson R. Fas and Fas ligand gene polymorphisms in primary Sjögren's syndrome.
Mullighan CG, Heatley S, Lester S, Rischmueller M, Gordon TP, Bardy PG. Fas gene promoter polymorphisms in primary Sjögren's syndrome.
Kumagai S, Kanagawa S, Morinobu A et al. Association of a new allele of the TAP2 gene, TAP2*Bky2 (Val577), with susceptibility to Sjögren's syndrome.
Tapinos NI, Polihronis M, Thyphronitis G, Moutsopoulos HM. Characterization of the cysteine-rich secretory protein 3 gene as an early-transcribed gene with a putative role in the pathophysiology of Sjögren's syndrome.
Scofield RH, Farris AD, Horsfall AC, Harley JB. Fine specificity of the autoimmune response to the Ro/SSA and La/SSB ribonucleoproteins.
Garcia-Carrasco M, Ramos-Casals M, Rosas J et al. Primary Sjögren syndrome: clinical and immunologic disease patterns in a cohort of 400 patients.
Skopouli FN, Dafni U, Ioannidis JP, Moutsopoulos HM. Clinical evolution, and morbidity and mortality of primary Sjögren's syndrome.
Horsfall AC, Rose LM, Maini RN. Autoantibody synthesis in salivary glands of Sjögren's syndrome patients.
Tengner P, Halse AK, Haga HJ, Jonsson R, Wahren-Herlenius M. Detection of anti-Ro/SSA and anti-La/SSB autoantibody-producing cells in salivary glands from patients with Sjögren's syndrome.
Tzioufas AG, Hantoumi I, Polihronis M, Xanthou G, Moutsopoulos HM. Autoantibodies to La/SSB in patients with primary Sjögren's syndrome (pSS) are associated with upregulation of La/SSB mRNA in minor salivary gland biopsies (MSGs).
Topfer F, Gordon T, McCluskey J. Intra- and intermolecular spreading of autoimmunity involving the nuclear self-antigens La (SS-B) and Ro (SS-A).
Routsias JG, Tzioufas AG, Sakarellos-Daitsiotis M, Sakarellos C, Moutsopoulos HM. Epitope mapping of the Ro/SSA60KD autoantigen reveals disease-specific antibody-binding profiles.
Tzioufas AG, Yiannaki E, Sakarellos-Daitsiotis M, Routsias JG, Sakarellos C, Moutsopoulos HM. Fine specificity of autoantibodies to La/SSB: epitope mapping, and characterization.
Yiannaki EE, Tzioufas AG, Bachmann M et al. The value of synthetic linear epitope analogues of La/SSB for the detection of autoantibodies to La/SSB; specificity, sensitivity and comparison of methods.
Haaheim LR, Halse AK, Kvakestad R, Stern B, Normann O, Jonsson R. Serum antibodies from patients with primary Sjögren's syndrome and systemic lupus erythematosus recognize multiple epitopes on the La(SS-B) autoantigen resembling viral protein sequences.
Elagib KE, Tengner P, Levi M et al. Immunoglobulin variable genes and epitope recognition of human monoclonal anti-Ro 52-kd in primary Sjögren's syndrome.
Routsias JG, Kosmopoulou A, Makri A et al. Zinc ion dependent B-cell epitope, associated with primary Sjögren's syndrome, resides within the putative zinc finger domain of Ro60kD autoantigen: physical and immunologic properties.
Staikou EV, Routsias JG, Makri AA et al. Calreticulin binds preferentially with B cell linear epitopes of Ro60 kD autoantigen, enhancing recognition by anti-Ro60 kD autoantibodies.
Ohlsson M, Jonsson R, Brokstad KA. Subcellular redistribution and surface exposure of the Ro52, Ro60 and La48 autoantigens during apoptosis in human ductal epithelial cells: a possible mechanism in the pathogenesis of Sjögren's syndrome.
Casciola-Rosen LA, Anhalt G, Rosen A. Autoantigens targeted in systemic lupus erythematosus are clustered in two populations of surface structures on apoptotic keratinocytes.
Nakken B, Jonsson R, Bolstad AI. Polymorphisms of the Ro52 gene associated with anti-Ro 52-kd autoantibodies in patients with primary Sjögren's syndrome.
Chan EK, Di Donato F, Hamel JC, Tseng CE, Buyon JP. 52-kD SS-A/Ro: genomic structure and identification of an alternatively spliced transcript encoding a novel leucine zipper-minus autoantigen expressed in fetal and adult heart.
McArthur C, Wang Y, Veno P, Zhang J, Fiorella R. Intracellular trafficking and surface expression of SS-A (Ro), SS-B (La), poly(ADP-ribose) polymerase and alpha-fodrin autoantigens during apoptosis in human salivary gland cells induced by tumour necrosis factor-alpha.
Nagaraju K, Cox A, Casciola-Rosen L, Rosen A. Novel fragments of the Sjögren's syndrome autoantigens alpha-fodrin and type 3 muscarinic acetylcholine receptor generated during cytotoxic lymphocyte granule-induced cell death.
Inoue H, Tsubota K, Ono M et al. Possible involvement of EBV-mediated alpha-fodrin cleavage for organ-specific autoantigen in Sjögren's syndrome.
Maruyama T, Saito I, Hayashi Y et al. Molecular analysis of the human autoantibody response to alpha-fodrin in Sjögren's syndrome reveals novel apoptosis-induced specificity.
Watanabe T, Tsuchida T, Kanda N, Mori K, Hayashi Y, Tamaki K. Anti-alpha-fodrin antibodies in Sjögren syndrome and lupus erythematosus.
Witte T, Matthias T, Arnett FC et al. IgA and IgG autoantibodies against alpha-fodrin as markers for Sjögren's syndrome. Systemic lupus erythematosus.
Kobayashi I, Kawamura N, Okano M et al. Anti-alpha-fodrin autoantibody is an early diagnostic marker for childhood primary Sjögren's syndrome.
Maeno N, Takei S, Imanaka H et al. Anti-alpha-fodrin antibodies in Sjögren's syndrome in children.
Nordmark G, Rorsman F, Ronnblom L et al. Autoantibodies to alpha-fodrin in primary Sjögren's syndrome and SLE detected by an in vitro transcription and translation assay.
Takahashi K, Tatsuzawa O, Yanagi K, Hayashi Y, Takahashi H. Alpha-fodrin auto-antibody in Sjögren syndrome and other auto-immune diseases in childhood.
De Seze J, Dubucquoi S, Fauchais AL et al. Alpha-Fodrin autoantibodies in the differential diagnosis of MS and Sjögren syndrome.
Ruffatti A, Ostuni P, Grypiotis P et al. Sensitivity and specificity for primary Sjögren's syndrome of IgA and IgG anti-alpha-fodrin antibodies detected by ELISA.
Haddad J, Deny P, Munz-Gotheil C et al. Lymphocytic sialadenitis of Sjögren's syndrome associated with chronic hepatitis C virus liver disease.
Ramos-Casals M, García-Carrasco M, Zeron MP, Cervera R, Font J. Viral etiopathogenesis of Sjögren's syndrome: role of the hepatitis C virus.
Ramos-Casals M, Garcia-Carrasco M, Cervera R et al. Hepatitis C virus infection mimicking primary Sjögren syndrome. A clinical and immunologic description of 35 cases.
Vitali C, Bombardieri S, Jonsson R et al. Classification criteria for Sjögren's syndrome: a revised version of the European criteria proposed by the American–European Consensus Group.
Arrieta JJ, Rodriguez-Inigo E, Ortiz-Movilla N et al. In situ detection of hepatitis C virus RNA in salivary glands.
Koike K, Moriya K, Ishibashi K et al. Sialadenitis histologically resembling Sjögren syndrome in mice transgenic for hepatitis C virus envelope genes.
Toussirot E, Le Huede G, Mougin C, Balblanc JC, Bettinger D, Wendling D. Presence of hepatitis C virus RNA in the salivary glands of patients with Sjögren's syndrome and hepatitis C virus infection.
Ramos-Casals M, Loustaud-Ratti V, De Vita S et al. Sjögren syndrome associated with hepatitis C virus: a multicenter analysis of 137 cases.
Kordossis T, Paikos S, Aroni K et al. Prevalence of Sjögren's-like syndrome in a cohort of HIV-1-positive patients: descriptive pathology and immunopathology.
Williams FM, Cohen PR, Jumshyd J, Reveille JD. Prevalence of the diffuse infiltrative lymphocytosis syndrome among human immunodeficiency virus type 1-positive outpatients.
Hida A, Kawabe Y, Kawakami A et al. HTLV-I associated Sjögren's syndrome is aetiologically distinct from anti-centromere antibodies positive Sjögren's syndrome.
Nakamura H, Kawakami A, Tominaga M et al. Relationship between Sjögren's syndrome and human T-lymphotropic virus type I infection: follow-up study of 83 patients.
Mariette X, Agbalika F, Zucker-Franklin D et al. Detection of the tax gene of HTLV-I in labial salivary glands from patients with Sjögren's syndrome and other diseases of the oral cavity.
Perrot S, Calvez V, Escande JP, Dupin N, Marcelin AG. Prevalences of herpesviruses DNA sequences in salivary gland biopsies from primary and secondary Sjögren's syndrome using degenerated consensus PCR primers.
Dawson TM, Starkebaum G, Wood BL, Willkens RF, Gown AM. Epstein-Barr virus, methotrexate, and lymphoma in patients with rheumatoid arthritis and primary Sjögren's syndrome: case series.
Klussmann JP, Wagner M, Guntinas-Lichius O, Muller A. Detection of HHV-8 sequences and antigens in a MALT lymphoma associated with Sjögren's syndrome.
Ramos-Casals M, Cervera R, Garcia-Carrasco M et al. Cytopenia and past human parvovirus B19 infection in patients with primary Sjögren's syndrome.
De Re V, De Vita S, Battistella V et al. Absence of human parvovirus B19 DNA in myoepithelial sialadenitis of primary Sjögren's syndrome.
De Stefano R, Manganelli S, Frati E et al. No association between human parvovirus B19 infection and Sjögren's syndrome.
Triantafyllopoulou A, Tapinos N, Moutsopoulos HM. Evidence for coxsackievirus infection in primary Sjögren's syndrome.
Konttinen YT, Kasna-Ronkainen L. Sjögren's syndrome: viewpoint on pathogenesis. One of the reasons I was never asked to write a textbook chapter on it.
Sumida T, Kato T, Hasunuma T, Maeda T, Nishioka K, Matsumoto I. Regulatory T cell epitope recognized by T cells from labial salivary glands of patients with Sjögren's syndrome.
Pivetta B, De Vita S, Ferraccioli G et al. T cell receptor repertoire in B cell lymphoproliferative lesions in primary Sjögren's syndrome.
Matsumoto I, Okada S, Kuroda K et al. Single cell analysis of T cells infiltrating labial salivary glands from patients with Sjögren's syndrome.
Manavalan SJ, Valiando JR, Reeves WH et al. Genomic absence of the gene encoding T cell receptor Vbeta7.2 is linked to the presence of autoantibodies in Sjögren's syndrome.
Bohnhorst JO, Bjorgan MB, Thoen JE, Natvig JB, Thompson KM. Bm1–Bm5 classification of peripheral blood B cells reveals circulating germinal center founder cells in healthy individuals and disturbance in the B cell subpopulations in patients with primary Sjögren's syndrome.
Hansen A, Odendahl M, Reiter K et al. Diminished peripheral blood memory B cells and accumulation of memory B cells in the salivary glands of patients with Sjögren's syndrome.
Bohnhorst JO, Bjorgan MB, Thoen JE, Jonsson R, Natvig JB, Thompson KM. Abnormal B cell differentiation in primary Sjögren's syndrome results in a depressed percentage of circulating memory B cells and elevated levels of soluble CD27 that correlate with serum IgG concentration.
Hansen A, Gosemann M, Pruss A, Reiter K, Ruzickova S, Lipsky PE, Dorner T. Abnormalities in peripheral B cell memory of patients with primary Sjögren's syndrome.
Kaschner S, Hansen A, Jacobi A et al. Immunoglobulin Vlambda light chain gene usage in patients with Sjögren's syndrome.
Heimbacher C, Hansen A, Pruss A et al. Immunoglobulin Vkappa light chain gene analysis in patients with Sjögren's syndrome.
Garcia-Carrasco M, Font J, Filella X et al. Circulating levels of Th1/Th2 cytokines in patients with primary Sjögren's syndrome: correlation with clinical and immunological features.
Halse A, Tengner P, Wahren-Herlenius M, Haga H, Jonsson R. Increased frequency of cells secreting interleukin-6 and interleukin-10 in peripheral blood of patients with primary Sjögren's syndrome.
Perrier S, Serre AF, Dubost JJ et al. Increased serum levels of interleukin 10 in Sjögren's syndrome; correlation with increased IgG1.
Tishler M, Yaron I, Shirazi I, Yossipov Y, Yaron M. Increased salivary interleukin-6 levels in patients with primary Sjögren's syndrome.
Mitsias DI, Tzioufas AG, Veiopoulou C et al. The Th1/Th2 cytokine balance changes with the progress of the immunopathological lesion of Sjögren's syndrome.
Konttinen YT, Kemppinen P, Koski H et al. T(H)1 cytokines are produced in labial salivary glands in Sjögren's syndrome, but also in healthy individuals.
Kolkowski EC, Reth P, Pelusa F et al. Th1 predominance and perforin expression in minor salivary glands from patients with primary Sjögren's syndrome.
Ogawa N, Ping L, Zhenjun L, Takada Y, Sugai S. Involvement of the interferon-gamma-induced T cell-attracting chemokines, interferon-gamma-inducible 10-kd protein (CXCL10) and monokine induced by interferon-gamma (CXCL9), in the salivary gland lesions of patients with Sjögren's syndrome.
Amft N, Curnow SJ, Scheel-Toellner D et al. Ectopic expression of the B cell-attracting chemokine BCA-1 (CXCL13) on endothelial cells and within lymphoid follicles contributes to the establishment of germinal center-like structures in Sjögren's syndrome.
Salomonsson S, Larsson P, Tengner P, Mellquist E, Hjelmstrom P, Wahren-Herlenius M. Expression of the B cell-attracting chemokine CXCL13 in the target organ and autoantibody production in ectopic lymphoid tissue in the chronic inflammatory disease Sjögren's syndrome.
Salomonsson S, Jonsson MV, Skarstein K et al. Cellular basis of ectopic germinal center formation and autoantibody production in the target organ of patients with Sjögren's syndrome.
Groom J, Kalled SL, Cutler AH et al. Association of BAFF/BLyS overexpression and altered B cell differentiation with Sjögren's syndrome.
Szodoray P, Jellestad S, Teague MO, Jonsson R. Attenuated apoptosis of B cell activating factor-expressing cells in primary Sjögren's syndrome.
Mariette X, Roux S, Zhang J et al. The level of BLyS (BAFF) correlates with the titre of autoantibodies in human Sjögren's syndrome.
Patel YI, McHugh NJ. Apoptosis-new clues to the pathogenesis of Sjögren's syndrome?
Van Blokland SC, Van Helden-Meeuwsen CG, Wierenga-Wolf AF et al. Apoptosis and apoptosis-related molecules in the submandibular gland of the nonobese diabetic mouse model for Sjögren's syndrome: limited role for apoptosis in the development of sialoadenitis.
Bolstad AI, Eiken HG, Rosenlund B, Alarcon-Riquelme ME, Jonsson R. Increased salivary gland tissue expression of Fas, Fas ligand, cytotoxic T lymphocyte-associated antigen 4, and programmed cell death 1 in primary Sjögren's syndrome.
Abu-Helu RF, Dimitriou ID, Kapsogeorgou EK, Moutsopoulos HM, Manoussakis MN. Induction of salivary gland epithelial cell injury in Sjögren's syndrome: in vitro assessment of T cell-derived cytokines and Fas protein expression.
Shibata Y, Hishikawa Y, Izumi S, Fujita S, Yamaguchi A, Koji T. Involvement of Fas/Fas ligand in the induction of apoptosis in chronic sialadenitis of minor salivary glands including Sjögren's syndrome.
Ohlsson M, Skarstein K, Bolstad AI, Johannessen AC, Jonsson R. Fas-induced apoptosis is a rare event in Sjögren's syndrome.
Zeher M, Szodoray P, Gyimesi E, Szondy Z. Correlation of increased susceptibility to apoptosis of CD4– T cells with lymphocyte activation and activity of disease in patients with primary Sjögren's syndrome.
Ohashi H, Ogawa N, Goto Y, Karahashi T, Akamine N. Elevated Fas (CD95) and bcl-2 protein expression on T cells from patients with primary Sjögren's syndrome.
Tsunoda S, Kawano M, Koni I et al. Diminished expression of CD59 on activated CD8– T cells undergoing apoptosis in systemic lupus erythematosus and Sjögren's syndrome.
Koski H, Janin A, Humphreys-Beher MG, Sorsa T, Malmstrom M, Konttinen YT. Tumor necrosis factor-alpha and receptors for it in labial salivary glands in Sjögren's syndrome.
Matsumura R, Umemiya K, Kagami M et al. Expression of TNF-related apoptosis inducing ligand (TRAIL) on infiltrating cells and of TRAIL receptors on salivary glands in patients with Sjögren's syndrome.
Mariette X, Sibilia J, Roux S, Meignin V, Janin A. A new defensive mechanism to prevent apoptosis in salivary ductal cells from patients with Sjögren's syndrome: over-expression of p53 and p21.
Kong L, Ogawa N, Nakabayashi T et al. Fas and Fas ligand expression in the salivary glands of patients with primary Sjögren's syndrome.
Ohlsson M, Szodoray P, Loro LL, Johannessen AC, Jonsson R. CD40, CD154, Bax and Bcl-2 expression in Sjögren's syndrome salivary glands: a putative anti-apoptotic role during its effector phases.
Kamachi M, Kawakami A, Yamasaki S et al. Regulation of apoptotic cell death by cytokines in a human salivary gland cell line: distinct and synergistic mechanisms in apoptosis induced by tumor necrosis factor alpha and interferon gamma.
Jimenez F, Aiba-Masago S, Al Hashimi I et al. Activated caspase 3 and cleaved poly(ADP-ribose)polymerase in salivary epithelium suggest a pathogenetic mechanism for Sjögren's syndrome.
Masago R, Aiba-Masago S, Talal N et al. Elevated proapoptotic Bax and caspase 3 activation in the NOD.scid model of Sjögren's syndrome.
Aiba-Masago S, Masago R, Vela-Roch N, Talal N, Dang H. Fas-mediated apoptosis in a rat acinar cell line is dependent on caspase-1 activity.
Nakamura H, Kawakami A, Yamasaki S et al. Expression and function of X chromosome-linked inhibitor of apoptosis protein in Sjögren's syndrome.
Hayashi Y, Arakaki R, Ishimaru N. The role of caspase cascade on the development of primary Sjögren's syndrome.
Tsubota K, Hirai S, King LS, Agre P, Ishida N. Defective cellular trafficking of lacrimal gland aquaporin-5 in Sjögren's syndrome.
Steinfeld SD, Appelboom T, Delporte C. Treatment with infliximab restores normal aquaporin 5 distribution in minor salivary glands of patients with Sjögren's syndrome.
Beroukas D, Hiscock J, Jonsson R, Waterman SA, Gordon TP. Subcellular distribution of aquaporin 5 in salivary glands in primary Sjögren's syndrome.
Waterman SA, Beroukas D, Hiscock J, Jonsson R, Gordon TP. Aquaporins in primary Sjögren's syndrome: comment on the articles by Steinfeld et al.
Beroukas D, Hiscock J, Gannon BJ, Jonsson R, Gordon TP, Waterman SA. Selective down-regulation of aquaporin-1 in salivary glands in primary Sjögren's syndrome.
Winer S, Astsaturov I, Cheung R et al. Primary Sjögren's syndrome and deficiency of ICA69.
Gordon TP, Cavill D, Neufing P, Zhang YJ, Pietropaolo M. ICA69 autoantibodies in primary Sjögren's syndrome.
Billaut-Mulot O, Cocude C, Kolesnitchenko V et al. SS-56, a novel cellular target of autoantibody responses in Sjögren syndrome and systemic lupus erythematosus.
Ohlsson M, Gordon TP, Waterman SA. Role of anti-calcium channel and anti-receptor autoantibodies in autonomic dysfunction in Sjögren's syndrome.
Jonsson R, Gordon TP, Konttinen YT. Recent advances in understanding molecular mechanisms in the pathogenesis and antibody profile of Sjögren's syndrome.
Ishimaru N, Arakaki R, Watanabe M, Kobayashi M, Miyazaki K, Hayashi Y. Development of autoimmune exocrinopathy resembling Sjögren's syndrome in estrogen-deficient mice of healthy background.
Shim GJ, Warner M, Kim HJ et al. Aromatase-deficient mice spontaneously develop a lymphoproliferative autoimmune disease resembling Sjögren's syndrome.
Kassi E, Moutsatsou P, Sekeris CE, Moutsopoulos HM, Manoussakis MN. Oestrogen receptors in cultured epithelial cells from salivary glands of Sjögren's syndrome patients.
Valtysdottir ST, Wide L, Hallgren R. Mental wellbeing and quality of sexual life in women with primary Sjögren's syndrome are related to circulating dehydroepiandrosterone sulphate.
Brennan MT, Sankar V, Leakan RA et al. Sex steroid hormones in primary Sjögren's syndrome.
Sullivan DA, Belanger A, Cermak JM et al. Are women with Sjögren's syndrome androgen-deficient?
Pillemer SR, Brennan MT, Sankar V et al. Pilot clinical trial of dehydroepiandrosterone (DHEA) versus placebo for Sjögren's syndrome.
Fox RI, Maruyama T. Pathogenesis and treatment of Sjögren's syndrome.
Dawson LJ, Field EA, Harmer AR, Smith PM. Acetylcholine-evoked calcium mobilization and ion channel activation in human labial gland acinar cells from patients with primary Sjögren's syndrome.
Hakala M, Niemela RK. Does autonomic nervous impairment have a role in pathophysiology of Sjögren's syndrome.
Waterman SA, Gordon TP, Rischmueller M. Inhibitory effects of muscarinic receptor autoantibodies on parasympathetic neurotransmission in Sjögren's syndrome.
Humphreys-Beher MG, Brayer J, Yamachika S, Peck AB, Jonsson R. An alternative perspective to the immune response in autoimmune exocrinopathy: induction of functional quiescence rather than destructive autoaggression.
Nguyen KH, Brayer J, Cha S et al. Evidence for antimuscarinic acetylcholine receptor antibody-mediated secretory dysfunction in nod mice.
Wang F, Jackson MW, Maughan V et al. Passive transfer of Sjögren's syndrome IgG produces the pathophysiology of overactive bladder.
Zoukhri D, Kublin CL. Impaired neurotransmitter release from lacrimal and salivary gland nerves of a murine model of Sjögren's syndrome.
Beroukas D, Goodfellow R, Hiscock J, Jonsson R, Gordon TP, Waterman SA. Up-regulation of M3-muscarinic receptors in labial salivary gland acini in primary Sjögren's syndrome.
Bacman S, Berra A, Sterin-Borda L, Borda E. Muscarinic acetylcholine receptor antibodies as a new marker of dry eye Sjögren syndrome.
Bacman S, Perez Leiros C, Sterin-Borda L, Hubscher O, Arana R, Borda E. Autoantibodies against lacrimal gland M3 muscarinic acetylcholine receptors in patients with primary Sjögren's syndrome.
Cavill D, Waterman SA, Gordon TP. Antibodies raised against the second extracellular loop of the human muscarinic M3 receptor mimic functional autoantibodies in Sjögren's syndrome.
Goldblatt F, Gordon TP, Waterman SA. Antibody-mediated gastrointestinal dysmotility in scleroderma.
Gao J, Cha S, Jonsson R, Opalko J, Peck AB. Detection of anti-type 3 muscarinic acetylcholine receptor autoantibodies in the sera of Sjögren's syndrome patients by use of a transfected cell line assay.
Hocevar A, Tomsic M, Praprotnik S, Hojnik M, Kveder T, Rozman B. Parasympathetic nervous system dysfunction in primary Sjögren's syndrome.
Dawson LJ, Christmas SE, Smith PM. An investigation of interactions between the immune system and stimulus-secretion coupling in mouse submandibular acinar cells. A possible mechanism to account for reduced salivary flow rates associated with the onset of Sjögren's syndrome.
Dawson LJ, Caulfield VL, Stanbury JB, Field AE, Christmas SE, Smith PM. Hydroxychloroquine therapy in patients with primary Sjögren's syndrome may improve salivary gland hypofunction by inhibition of glandular cholinesterase.
Cavill D, Waterman SA, Gordon TP. Anti-idiotypic antibodies neutralize autoantibodies that inhibit cholinergic neurotransmission.
Hoffmann W, Jagla W. Cell type specific expression of secretory TFF peptides: colocalization with mucins and synthesis in the brain.
Hoffmann W, Jagla W, Wiede A. Molecular medicine of TFF-peptides: from gut to brain.
Paulsen FP, Hinz M, Schaudig U, Thale AB, Hoffmann W. TFF peptides in the human efferent tear ducts.
Devine DA, High AS, Owen PJ, Poulsom R, Bonass WA. Trefoil factor expression in normal and diseased human salivary glands.
Polihronis M, Tapinos NI, Theocharis SE, Economou A, Kittas C, Moutsopoulos HM. Modes of epithelial cell death and repair in Sjögren's syndrome (SS).
Fox RI, Stern M. Sjögren's syndrome: mechanisms of pathogenesis involve interaction of immune and neurosecretory systems.
Goicovich E, Molina C, Perez P et al. Enhanced degradation of proteins of the basal lamina and stroma by matrix metalloproteinases from the salivary glands of Sjögren's syndrome patients: correlation with reduced structural integrity of acini and ducts.
- apoptosis
- cytokine
- b-lymphocytes
- polymorphism
- immune response
- chemokines
- epithelium
- antigens
- autoantibodies
- autoantigens
- autoimmunity
- caspases
- exocrine glands
- genes
- bcl2 gene
- lymphocytes
- sjogren's syndrome
- t-lymphocytes
- antibodies
- salivary glands
- viruses
- epithelial cells
- autonomic dysfunction
- tumor necrosis factor ligand superfamily member 6
- proteolysis
- molecule
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