INTRODUCTION — Sjögren's syndrome (SS) is a chronic, multisystem inflammatory disorder characterized by diminished lacrimal and salivary gland function, which results in the unique combination of dry eyes and dry mouth. Additional disease manifestations may also be present, including dryness of the skin and other mucosal surfaces. Systemic extraglandular features include arthritis, nephritis, cytopenia, pneumonitis, and vasculitis. Neurologic manifestations include peripheral neuropathy, myelopathy, and cognitive disturbances. There is an increased risk of lymphoma in comparison with other autoimmune disorders. (See "Clinical manifestations of Sjögren's syndrome: Exocrine gland disease" and "Clinical manifestations of Sjögren's syndrome: Extraglandular disease".)
The pathogenesis of SS is thought to be a multistep process, triggered by an environmental factor, most likely viral, in a genetically predisposed individual. An immune response involving innate and adaptive immunity, leading to autoimmunity and chronic inflammation, are central components of the disease process.
The pathogenesis of SS is reviewed here. The clinical manifestations, diagnosis, treatment, and prognosis of this disorder are discussed separately. (See "Clinical manifestations of Sjögren's syndrome: Exocrine gland disease" and "Clinical manifestations of Sjögren's syndrome: Extraglandular disease" and "Diagnosis and classification of Sjögren's syndrome" and "Overview of the management and prognosis of Sjögren's syndrome" and "Treatment of dry eye in Sjögren's syndrome: General principles and initial therapy" and "Treatment of dry mouth and other non-ocular sicca symptoms in Sjögren's syndrome".)
OVERVIEW — The pathogenesis of SS is typically modeled as a multistep process, triggered by an environmental factor, most likely viral, in a genetically predisposed individual. The initial events engage the innate immune system, but propagation and perpetuation of the autoimmune process require a continual interplay between the innate and adaptive immune systems [1].
The result is autoreactive B-cell stimulation, autoantibody production, and chronic inflammation of the salivary and lacrimal glands and often other tissues. Extraglandular manifestations may arise from autoimmune exocrinopathy, akin to that in the salivary glands (eg, interstitial nephritis, biliary cholangitis), immune-complex deposition (eg, cryoglobulinemic vasculitis), and extranodal lymphoproliferation (eg, lymphocytic interstitial pneumonitis). Chronic stimulation of B cells in the target tissue may promote lymphomagenesis, again through a multistep process in a genetically susceptible individual.
RISK FACTORS AND ETIOPATHOGENESIS — Interactions between both genetic and nongenetic factors are involved in disease susceptibility and in the initiation as well as the progression of the disease process.
Genetic factors — Many different regions of the genome, both within and outside of the major histocompatibility complex (MHC), confer susceptibility to Sjögren's syndrome (SS) but differ between populations and studies [2,3]. (See 'HLA genes' below and 'Non-HLA genes' below.)
A familial tendency to develop SS has been well-documented, along with an increased risk of a variety of autoimmune disorders in relatives of patients with SS [4]. A concordance rate for SS in monozygotic twins has not been reported; however, it is estimated to be approximately 20 percent based upon studies of other autoimmune diseases that overlap with SS, including systemic lupus erythematosus (SLE) and rheumatoid arthritis [5,6]. Thus, a substantial role for epigenetic factors and the environment is likely in SS pathogenesis.
Multiple polymorphisms have been identified by genome-wide association studies (GWAS). These have involved cohorts of SS patients of European [2] and Han Chinese [3] descent, and another consisting of Sjögren's International Collaborative Clinical Alliance (SICCA) registrants, primarily of either European or Asian (including Chinese and Japanese) descent [7,8]. Many of the implicated genes are associated with innate or adaptive immune responses. Surprisingly, the majority of the identified single nucleotide polymorphism (SNPs) were located in the non-protein coding regions, which is suggestive of regulatory activity of these regions on gene expression.
HLA genes — SS shows the most robust genetic association within MHC genes, including those in the human leukocyte antigen (HLA)-DR region. While 20 to 25 percent of the general White European and American population shows the extended haplotype of HLA-DR3, B8, DQ2, and C4 null allele, this haplotype is present in approximately 50 percent of White Northern European patients with SS [4]. Considerable heterogeneity of this association is observed across different ethnic groups [7]. Examples include:
●A markedly increased frequency of HLA-DQB1*0201 and HLA-DQA1*0501 in White American patients with primary SS [9]
●DRB1*0803-DQA1*0103-DQB1*0601 in Han Chinese, with multiple different associations in one GWAS [3]
●HLA-DR5 in Greek patients [10]
●DRB1*0405-DRB4*0101-DQA1*0301-DQB1*0401 in Japanese patients [9]
●DRB1*1501-*0301 genotype in White French patients [11]
●DQA1*05:01-DQB1*02:01 in Colombian patients [12]
●HLA-B15 and DRB1*03 in Tunisian populations [13]
Non-HLA genes — Genes other than those within the HLA loci are also associated with an increased risk of disease [1]. The strongest associations on GWAS include IRF5 and TNIP1, which are both involved in innate immunity, and BLK, STAT4, IL12A, and CXCR5, which are involved in adaptive immunity (table 1). In patients with SS of Han Chinese descent, GTF1, a gene involved in regulating immunoglobulin heavy chain transcription is also a risk factor for SS [14]. Various other genes have been identified in such studies, but their degrees of association do not reach genome-wide significance; these include some involved in innate immunity, such as MBL2, FCGR2B, LTA [15], TNF, NCR3, and NFKBIA, and others that have a role in the adaptive immune response, including TAP2, EBF1, PTPN22, TNFRSF4, and IL10.
The information on different gene disease associations is curated by DisGeNET [16] and freely accessible at www.disgenet.org/home.
Epigenetic factors — Epigenetic factors, such as DNA methylation, histone acetylation, noncoding RNA transcripts, and gene recombination, may all play a role in the modulation of gene expression. DNA methylation has been analyzed in the peripheral blood and target tissue of patients with SS [17-20]. These studies have supported a role for methylation in the regulation of genes in SS. Interestingly, many of the epigenetically modified regions have been previously identified as genetic risk factors for SS [21-23]. Additional gene regulation in SS occurs through the modulation of gene expression by microRNAs (miRNAs). Differential expression of miRNAs has been reported in the lymphocytes and salivary glands of SS patients and controls, and these often target genes relevant to disease pathogenesis [23-25]. In summary, these studies demonstrate that complex interactions between genetic and epigenetic factors influence the development of SS.
Sex — The striking predominance of SS in women (15 to 20:1, female to male ratio) points to a role for sex hormones in the development of the disease, as it does for other systemic autoimmune diseases, such as SLE, rheumatoid arthritis, and systemic sclerosis. The clinical onset of SS in women is most often in the sixth decade of life, just after the onset of menopause. This is in sharp contrast to SLE, where the disease occurs most often in women during their reproductive-age years.
The characteristic autoantibodies of SS are detectable for up to 18 years before clinical disease onset [26], so the autoimmune process may be initiated in a woman during her reproductive-age years but not expressed clinically with sicca or other symptoms until estrogen levels drop sharply with the onset of menopause. In animal models, estrogen protects against lacrimal and salivary glandular inflammation while its withdrawal promotes apoptosis of salivary gland epithelial cells [27]. Women with SS have lower cumulative estrogen exposure, relative to non-SS women with sicca, when measured by an integration of age at menarche, age at menopause, parity, hysterectomy, and female hormone use [28]. Low serum concentrations of dehydroepiandrosterone and dihydrotestosterone have also been demonstrated [29], arguing for a protective role of androgens, similar to that of estrogen, in the pathogenesis of SS.
Alternatively, the sex bias of SS may be mediated independently of a sex hormone effect. Women with trisomy X (47, XXX) have normal sexual development and sex hormone levels, but have a risk of SLE and SS that is 2.5- and 2.9-fold higher, respectively, than in women with 46, XX, and 25- and 41-fold higher respectively than in men with 46, XY [30]. Thus, there is a sex chromosome dose effect in the predisposition of females to autoimmune rheumatic disease, which is independent of differences in sex hormone levels.
The X chromosome has the highest density of immunity-related genes, and transcriptional silencing of an entire X chromosome (X-chromosome inactivation) in each female cell, initiated during embryogenesis, serves to equalize the expression of X-linked genes between sexes. This inactivation process is mediated by allele-specific expression of the long noncoding RNA, termed XIST. Biallelic expression of X-linked immunity genes has been observed in the lymphocytes of female mammals, suggesting incomplete X-chromosome inactivation and providing an alternative mechanism for the sex bias in autoimmune diseases, including SS [31].
Although the frequency of SS development in males is significantly lower, some studies have suggested that male SS patients have increased risk of lymphoma development [32] and extraglandular manifestation [33].
The potential role of viral infection — The first signs of SS typically occur long before diagnosis, thereby impeding study of its etiology. Many observations suggest a role for viruses in the pathogenesis of SS, but no single virus has been implicated. Evidence of ongoing or past viral infection can be detected in many patients, but no virus has been found at high levels in target tissues [34]. Observations supporting a viral etiology include:
●Certain viruses, particularly Epstein-Barr virus (EBV), the ubiquitous herpes-type virus that causes infectious mononucleosis, frequently infect the salivary glands. EBV is spread to noninfected individuals via the saliva; primary EBV infections progress to lifelong latent infection with periodic reactivation, and the site of latency for EBV is in the salivary gland. EBV can induce strong immune responses by T cells and activate B-cell production of autoantibodies. (See "Virology of Epstein-Barr virus" and "Clinical manifestations and treatment of Epstein-Barr virus infection" and "Infectious mononucleosis".)
●EBV can be identified in the ectopic lymphoid structures present in the salivary glands of some SS patients (see 'The lymphocytic infiltrate and glandular pathology' below), but not in SS glandular tissue lacking such structures. EBV-infected plasma cells within these structures produced antibodies to anti-Ro52 and anti-La/SSB [35]. In addition, SS patients show a higher prevalence and titer of antibodies against EBV antigens [36]. These findings support a role for active EBV in supporting the local proliferation and differentiation of autoreactive B cells.
●At least three viruses (human T-lymphotropic virus [HTLV] type I, human immunodeficiency virus [HIV], and hepatitis C virus [HCV]) are associated with clinical syndromes that share many features of SS [37,38].
●Hepatitis delta virus (HDV) was detected in salivary glands of 50 percent of primary SS patients and induces a primary SS-like disease in mice [39].
●Retroelements are noncoding DNAs that constitute approximately half of the human genome and regulate gene expression. SS patients show increased levels of retroviral long interspersed nuclear element 1 [40]. These retroviral elements can activate innate immunity and induce excessive production of type I interferons (IFNs). Animal models have demonstrated a role for type I IFNs in SS pathogenesis [41].
MECHANISMS OF IMMUNE-MEDIATED INJURY — Glandular dysfunction in Sjögren's syndrome (SS) is generally presumed to result from autoimmune-induced inflammation and resultant damage and destruction of the tissue responsible for tear and saliva production. However, this assumption is not fully supported by two observations. First, there is a weak correlation between glandular dysfunction and the degree of glandular inflammation [42]. Second, glandular dysfunction can be induced in animal models of SS before the advent of inflammatory infiltrates [43]. In light of these observations, other mechanisms may contribute to the glandular dysfunction, including antibodies to the muscarinic receptor that may impair neural innervation of the gland (see 'Anti-muscarinic acetylcholine receptor antibodies' below) and direct effects of cytokines on neurotransmitter release or other secretory cell functions [44].
Glandular inflammation — Overexpression of interferon (IFN)-inducible genes in salivary glands and peripheral blood monocytes of SS patients (termed the IFN signature) highlights the importance of the innate immune system in pathogenesis [45,46]. Damage to the salivary gland epithelial cells (eg, by an exogenous or endogenous viral trigger) is thought to induce apoptosis and migration of the SSA (also termed SS-A or Ro60) antigen from the nucleus in a complex with human small noncoding Y RNA (hYRNA) to a bleb on the cell surface [47]. The SSA molecule thus escapes normal apoptotic degradation. The presence of antibody to the SSA-hYRNA complex promotes the uptake of this immune complex by local dendritic cells and B cells, access to intracytoplasmic toll-like receptors (TLRs), and stimulation of the IFN signatures characteristic of SS [48-50].
Plasmacytoid dendritic cells may also be activated directly by viral or other environmental factors. Activation of the type I IFN system by the innate immune system promotes adaptive immune responses through T- and B-cell activation and induction of cytokine production.
A cycle of mutual stimulation of the innate and acquired immune systems leads to the perpetuation of glandular injury and dysfunction. Tissue injury occurs through the activation of these immune pathways by lymphocytes within the glandular tissues or extraglandular sites, leading to the release of cytokines, including IFN-gamma, interleukin (IL) 17, B-cell activating factor (BAFF; also known as B lymphocyte stimulator [BLyS]), and others, and the production of characteristic autoantibodies. Apoptosis of glandular cells and dysfunction of residual epithelial cells and tissues occur due to cytokines and metalloproteinases that interfere with salivary gland organization and function. Furthermore, a premature senescence in salivary gland progenitor cells [51] and salivary gland stem cells [52] also contributes towards the chronicity of glandular dysfunction. (See 'Autoantibodies' below and 'The lymphocytic infiltrate and glandular pathology' below.)
Extraglandular manifestations — Extraglandular manifestations of SS can be classified based on their presumed pathogenesis, including autoimmune exocrinopathy, akin to that in the salivary glands (eg, interstitial nephritis, biliary cholangitis), immune-complex deposition (eg, cryoglobulinemic vasculitis), cell- or tissue-specific autoimmunity (eg, thrombocytopenia, ataxic sensory ganglionopathy, neuromyelitis optica), and lymphoproliferation (eg, lymphocytic interstitial pneumonitis) [53,54]. Fatigue and cognitive impairment most likely have multifactorial pathogeneses, but there is evidence for immune mechanisms, including antibodies directed against N-methyl-D-aspartate receptor subtype NR2 (anti-NR2) for the cognitive impairment and elevated heat shock protein 90a for the fatigue [55,56].
Autoantibodies — SS is characterized by the presence of autoantibodies, most notably anti-Ro/SSA and anti-La/SSB in 60 to 80 percent of those affected (see "The anti-Ro/SSA and anti-La/SSB antigen-antibody systems"). Antinuclear antibodies (ANA) are present in 90 percent of patients, and high-titer rheumatoid factor is also frequent. (See 'Ro/SSA and La/SSB' below and "Diagnosis and classification of Sjögren's syndrome" and "Clinical manifestations of Sjögren's syndrome: Extraglandular disease", section on 'Autoantibodies'.)
Autoantibodies can precede the clinical onset of SS by many years, as evidenced by the analysis of stored premorbid serum samples in SS patients [26]. Additionally, mothers of children with neonatal lupus have high-titer anti-Ro/SSA and anti-La/SSB antibodies and are often asymptomatic. However, these asymptomatic women are at an increased risk for SS. The fact that SS develops in only a minority of these individuals indicates that autoantibodies alone are insufficient for induction of disease [57].
Ro/SSA and La/SSB — Anti-Ro/SSA antibodies are predominantly of the immunoglobulin G1 (IgG1) subclass and recognize two distinct proteins, the 52kD, Ro52 protein and the 60kD, Ro60 protein, encoded by different genes [58]. Both antigens are located primarily in the nucleus but are also expressed in the cytoplasm and on the cell surface.
The SSA Ro52 autoantigen belongs to the large family of the tripartite motif (TRIM)-containing family of proteins [59]. Functionally, Ro52 is an E3 ubiquitin ligase, and it plays a critical role in the regulation of innate immunity, particularly the type I IFN response [60]. Ro52 also acts as an intracellular Fc receptor and has been shown to bind the Fc portion of IgG antibodies complexed with viruses [61]. Patients positive for anti-Ro52 often present with higher disease severity. However, in these patients, anti-Ro52 is also strongly associated with the presence of anti-Ro60 [62]. A pathogenic role of anti-Ro52 antibodies in the induction of salivary gland dysfunction has been demonstrated in experimental mouse model systems [63,64].
The 60kD Ro60 protein, also known as TROVE2, binds the small cytoplasmic RNA moieties termed hYRNA and is involved in the clearance of defective RNA transcripts [65]. The Ro60 protein, like Ro52, is also involved in the regulation of inflammatory gene expression by binding to endogenous Alu retroelements [66].
Anti-La/SSB antibodies are found in 50 percent of patients with SS. These antibodies recognize a 47 kD phosphoprotein associated with newly synthesized RNA polymerase III transcripts. The gene encoding SSB is unusual in that it has two promoter sites, encoding for two different size mRNAs, and raising the possibility of gene switching under disease conditions [67]. The pathogenic role of anti-La/SSB autoantibodies in SS is not clear.
Anti-muscarinic acetylcholine receptor antibodies — Antibodies to acetylcholine receptors of salivary glands might account for decreased secretion from histologically normal glands. It is uncertain whether such antibodies in SS are primary or secondary phenomena [68-70]. One report has shown a higher frequency of antibodies to the muscarinic (M) receptor for acetylcholine (M3R) in patients with SS compared with patients with systemic lupus erythematosus (SLE) (67 versus 2 percent) [71]. In another study of 15 patients with SS, antibodies were found in five of nine subjects with primary and six of six with secondary disease [72]. In animal models, these anti-M3 acetylcholine receptor antibodies decrease glandular secretion [69].
Some evidence suggests there may be binding of these autoantibodies to the extracellular domain of the human M3R, raising the possibility that SS may be among the autoimmune disorders such as Graves' disease or myasthenia gravis where antireceptor antibodies are pathogenic [73,74].
The lymphocytic infiltrate and glandular pathology — The primary pathologic lesion of SS is lymphocytic infiltration of the salivary and lacrimal glands. The infiltrates consist of focal aggregates of lymphocytes, beginning around the ducts and spreading to involve the entire lobule (image 1). The cellular composition of these infiltrates depends on their severity. T cells, primarily CD4+, predominate in milder infiltrates, which are smaller and respect the architecture of the gland. B cells become more predominant in larger and denser infiltrates associated with acinar destruction and loss of tissue architecture [75]. Migration of the lymphocytes to sites in the glands occurs due to a series of events, including a response to chemokines, adhesion to specific vascular adhesion molecules, and entry into the gland where they interact with dendritic cells and epithelial cells [76].
Salivary gland epithelial cells have the capacity to play an active role in the initiation and maintenance of glandular inflammation. Their potential pivotal role in SS immunopathogenesis has led to the concept of "autoimmune epithelitis" [77] as a unifying feature of the disease. Salivary gland epithelial cells, activated by type I IFN or a viral infection, can affect the following: (1) surface expression of major histocompatibility complex (MHC) class II molecules, including human leukocyte antigen (HLA)-DR, and costimulatory factors, including CD80, CD86, and CD40, empowering them to interact with T cells; (2) release of cytokines such as BAFF [78,79], interleukin (IL) 1, IL-6, tumor necrosis factor (TNF)-alpha, and IL-22 [80], which are crucial to both innate and adaptive immune responses; (3) promotion of lymphocytic and dendritic cell infiltration by production of CXCL13 and other chemokines [81]; and (4) mediation of the release of intracellular antigens (eg, Ro/SSA-La/SSB) through apoptosis [82] and the release of exosomes, thereby driving the generation of autoreactive B cells.
In approximately 30 to 40 percent of SS patients, the glandular periductal lymphoid aggregates develop a structure highly similar to typical secondary lymphoid organs, with B-cell follicles surrounded by T-cell rich areas, high endothelial venules, and networks of follicular dendritic cells [83,84]. These ectopic lymphoid structures promote antigen-driven selection of B-cell clones via affinity maturation and provide a conducive microenvironment for antibody production in the target tissue (picture 1) [85]. The development of these ectopic lymphoid structures is dependent on the expression of lymphotoxin-beta and lymphoid chemokines (eg, CXCL13, CCL19, and CCL21) by T, B, dendritic, and stromal cells within the infiltrate [83,86].
Pathogenetic roles have also been attributed to T helper 1 (Th1) cells, natural killer (NK)-like cells, and Th17 cells that produce IFN-gamma. Considerable attention has been given to the role of a subset of CD4+ T cells, termed the follicular helper cells (Tfh), in the pathogenesis of SS [87]. The Tfh cells are characterized by the expression of CXCR5, PD1, ICOS, and Bcl-6 [88]. These cells are the major producer of the cytokine IL-21, provide help to B cells, and are involved in the formation of germinal centers. SS patients have elevated levels of circulating Tfh, and these cells are readily detected in salivary gland biopsies [87].
Cytokines in the glandular tissue — Multiple cytokines have been identified in the salivary gland tissue and represent potential targets for therapy.
The cytokine milieu of salivary glands from SS patients is largely characterized by a Th1/Th17 profile, with production of proinflammatory IL-2, IL-10, and IFN-gamma by infiltrating CD4+ cells and IL-17 by infiltrating Th17 cells. In addition, the proinflammatory cytokines, IL-1, TNF-alpha, and IL-6, can be secreted by activated salivary gland epithelial cells [89,90].
BAFF is considered a key cytokine in SS; it is induced by type I and type II IFN and promotes the activation, proliferation, and survival of B cells. BAFF levels are elevated in the salivary glands and serum of SS patients, and the latter levels correlate with those of anti-SSA/Ro, -SSB/La, and rheumatoid factor [91]. BAFF is produced not only by monocytes, macrophages, and dendritic cells, but also by salivary gland epithelial cells and B and T cells. Thus, BAFF could be an important link between the activation of the innate immune system and the development of autoimmunity through the adaptive immune system.
Lymphomagenesis — Chronic B-cell stimulation and other factors may result, through a series of steps, in malignant B-cell transformation in some patients with SS. Patients with SS have an increased risk of lymphoma, with estimates ranging from 5- to 44-fold, compared with age-matched controls [92]. This increased risk is higher than that observed in other systemic autoimmune diseases, including rheumatoid arthritis, SLE and Crohn disease [93]. These lymphomas are most frequently extranodal marginal zone non-Hodgkin lymphomas (NHL) of "mucosal-associated lymphoid tissue" (MALT). Higher-grade diffuse B-cell lymphomas and T-cell lymphomas are much less frequent in SS [94,95]. The MALT lymphomas often develop in mucosal locations where SS is active, such as salivary glands or the gastrointestinal tract (MALT) [95]; or in the lung, where bronchial-associated lymphoid tissue (BALT) lymphomas can be seen [96,97]. (See "Clinical manifestations, pathologic features, and diagnosis of extranodal marginal zone lymphoma of mucosa associated lymphoid tissue (MALT)".)
The presence of ectopic lymphoid structures in minor salivary gland biopsies is associated with increased risk of lymphoma [98,99]. Such structures were much more common in biopsies from SS patients who later presented with an NHL compared with patients without NHL (86 versus 22 percent) [98]. Ectopic lymphoid structures are sites of antigen-driven B-cell stimulation and clonal expansion, Ig class switching, and somatic hypermutation, potentially engendering lymphoma development.
Chronic stimulation of autoimmune B cells may be associated with malignant transformation, through a series of steps involving the development of a clonal population and eventually uncontrolled clonal proliferation. Salivary gland MALT lymphomas frequently express B-cell antigen receptors with rheumatoid factor activity and bind IgG with high affinity [100,101]. Locally produced IgG autoantibodies directed against the ribonucleoproteins SSA/Ro52, SSA/Ro60, and SSB/La form immune complexes particularly suited for dual-ligand stimulation of B cells with rheumatoid factor B-cell and TLR-7 receptors [102]. The proliferation of these autoreactive B-cells is driven in part by BAFF, serum levels of which correlate with disease activity and the degree of B-cell activation.
Malignant transformation has been associated with specific genetic polymorphisms. A20 (encoded by gene TNFAIP3) is a regulator of NF-kappaB activation and is downregulated in SS [1]. Further, a polymorphism of this gene has been found in a high percentage of SS patients. Mutations and downregulation of A20 have been associated with increased germinal center (GC) formation and MALT lymphomas [103]. Polymorphisms of CXCR5, involved in the organization of GC structures, are associated with SS and NHL [104].
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●Beyond the Basics topics (see "Patient education: Sjögren's syndrome (Beyond the Basics)")
SUMMARY
●Both genetic and nongenetic factors are involved in disease susceptibility and the disease process. Molecular genetic analyses suggest important roles for human leukocyte antigen (HLA)-DR molecules, and genes encoding elements of both innate and acquired immunity. The strongest associations are with genes in the HLA-DR region, but there is considerable heterogeneity across different ethnic groups. Epigenetic factors may play a role through modulation of gene expression. (See 'Risk factors and etiopathogenesis' above and 'Genetic factors' above and 'HLA genes' above and 'Non-HLA genes' above.)
●Many observations suggest a role for viruses in the pathogenesis of Sjögren's syndrome (SS), but no single virus has been implicated. Evidence of ongoing or past viral infection can be detected in many patients, but no virus has been found at high levels in target tissues. An explanation might be that the viral trigger took place years before the development of SS. (See 'The potential role of viral infection' above.)
●A cycle of mutual stimulation of the innate and acquired immune systems leads to the perpetuation of glandular injury and dysfunction. Tissue injury occurs through the activation of these immune pathways by lymphocytes within the glandular tissues or extraglandular sites, leading to the release of cytokines, including interferon (IFN)-gamma, interleukin (IL) 17, IL-21, and B-cell activating factor. Salivary and lacrimal gland epithelial cells, as well as the local vascular adhesive molecules, play essential early roles. (See 'Mechanisms of immune-mediated injury' above.)
●SS is characterized by the presence of specific autoantibodies, which by some criteria are required for the diagnosis; these include anti-Ro/SSA and anti-La/SSB. Antinuclear antibodies (ANA) are present in 90 percent of patients, and high-titer rheumatoid factor is also frequent. Other antibodies, including antibodies to acetylcholine receptors of salivary glands, may also be seen. (See 'Autoantibodies' above and 'Ro/SSA and La/SSB' above.)
●The principal pathologic lesion of SS is a lymphocytic infiltration; the salivary and lacrimal glands are the most frequently affected tissues, but these infiltrates are common to all affected organs, including extraglandular sites, and can result in the glandular and systemic extraglandular features. The infiltrates consist of focal aggregates of lymphocytes, beginning around the ducts and spreading to involve the entire lobule. Migration of the lymphocytes occurs to the gland in response to chemokines, adhesion to specific vascular adhesion molecules, and entry into the glandular cells where they interact with dendritic cells and epithelial cells. (See 'The lymphocytic infiltrate and glandular pathology' above.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Paul Creamer, MD, who contributed to an earlier version of this topic review.
