Immunohistopathology of Sjögren's syndrome

Sj?gren's syndrome (SS) is characterized by keratoconjunctivitis sicca and xerostomia, which occur in an autoimmune lacrimal and salivary gland disease characterized by lymphocyte infiltrates of exocrine glands and/or Sj?gren's syndrome autoantibody production. It has been reported that aquaporin-5 distribution is abnormal in SS, perhaps as a result of paracrine effect of TNF-alpha. Also the neurogenic regulation of the salivary gland is impaired in SS. Apart from functional changes, the syndrome is also characterized by structural abnormalities of the secretory acinar apparatus. The acinar basement membrane is abnormal as it lacks laminin alpha1 chain, which may impair its capability to induce the progenitor cells to differentiate to acinar cells. CRISP-3 and TMPRSS-2 can be used as androgen markers and LIV-1 and Cyr61 as estrogen markers to study the sexual dimorphism of the salivary glands. Patients with SS seem to have low concentrations of dehydroepiandrosterone, which may predispose women and the exocrine glands to this syndrome.     

Immunopathogenesis of Sjögren's syndrome

Sjögren's syndrome (SS) is an autoimmune disease characterized by the sicca symptoms of dry eyes and dry mouth. Glandular dysfunction is thought to arise from destruction associated with lymphocytic infiltration. The degree of glandular destruction, however, does not correlate with the severity of sicca symptoms, suggesting that other mechanisms are involved, including abnormalities in parasympathetic neurotransmission. Autoantibodies against the muscarinic acetylcholine receptor have been implicated in this process, but multiple other autoantibodies have been found. Cytokines elaborated in the inflammatory lesions also appear to be involved and dysregulation of apoptosis are also involved in the pathogenesis of SS. A new two-stage model of SS has been proposed. First, there is a lymphocyte-independent phase during which inappropriate apoptosis results in the generation of apoptotic autoantigens which then attract lymphocytes. Subsequently, in the second lymphocyte-dependent phase, an immune attack causes further cell death and salivary dysfunction. Although the disease generally takes a rather stable and benign course, patients with SS have a significant risk of developing B cell lymphoma.     

Sjögren's syndrome

Sjogren's syndrome (SS) describes xeropthalmia and xerostomia due to lymphocytic infiltrates of lacrimal and salivary glands. SS may occur alone (primary SS) or in association with several other autoimmune diseases (secondary SS). The clinical features involve a wide variety of organs, including skin, eyes, oral cavity and salivary glands, and systems, including nervous, musculoskeletal, genitourinary and vascular. Sicca symptoms can be found in a number of other disorders including rheumatoid arthritis, systemic lupus erythematosus, scleroderma, primary biliary cirrhosis, and other rheumatic disorders.     

Pathogenesis of Sjögren's syndrome

The pathogenesis of Sj?gren's syndrome is poorly understood. Genetic and environmental factors appear to contribute to the development of this syndrome. Viral infection is one of the most likely environmental factors. The primary lesion of Sj?gren's syndrome is in the exocrine glands. A majority of the infiltrating cells in the lesion are CD(4+) CD45RO(+) memory T cells. Although antigen-presentation to T cells seems to occur in the exocrine tissues, these T cells are not fully activated. On the other hand, B cells comprise approximately 20% of the infiltrating cells, and several features of this syndrome are attributed to stimulated B cells. The presence of autoantibodies, such as anti-SS-A/Ro and SS-B/La antibodies, is one of the characteristic features and is associated with severe disorders. Some antibodies appear to play a direct pathogenic role, for example, in cases of congenital heart block and sicca symptoms. Chronic inflammation with possible T cell-dependent antigen stimulation appears to induce neoplastic transformation of lymphocytes.     

Role of dendritic cells in Sjögren's syndrome

Sjögren's syndrome (SS) is a chronic inflammatory and lymphoproliferative autoimmune disease of unknown aetiology. It is characterised by progressive mononuclear cell infiltration of the salivary and lacrimal glands and a decreased glandular secretion, resulting in dryness of the mouth and eyes (xerostomia and keratoconjunctivitis sicca, respectively). Dendritic cells (DC) are considered to be the most potent antigen‐presenting cells. Because of their central role in initiating an immune response while maintaining tolerance, impaired function of these cells might lead to the break of peripheral tolerance and initiation of immune responses to self‐antigens. This review will focus on the possible role of DC in SS.     

Sex steroids in Sjögren's syndrome

The purpose of the review is to consider pathomechanisms of Sj?gren's syndrome (SS), which could explain the female dominance (9:1), the most common age of onset (40-50 years) and targeting of the exocrine glands. Estrogens seem to specifically protect secretory glandular acinar cells against apoptosis whereas lack of estrogens during menopause and climacterium specifically leads to increased apoptosis of the exocrine secretory cells. Male gonads produce testosterone and convert it in exocrine glands to dihydrotesterosterone (DHT), which is anti-apoptotic and protects against acinar cell apoptosis. Estrogen-deficient women need to produce dehydroepiandrosterone (DHEA) in the adrenal glands and convert it to DHT in exocrine glands in a complex and branching reaction network in which individual enzymatic reactions are catalyzed in forward and backward directions by a myriad of different isoforms of steroidogenic enzymes. Tailoring DHT in peripheral tissues is much more complex and vulnerable in women than in men. In SS the intracrine steroidogenic enzyme machinery is deranged. These endo-/intracrine changes impair acinar remodeling due to impaired integrin α1β1 and integrin α2β1 expression so that the intercalated duct progenitor cells are unable to migrate to the acinar space, to differentiate to secretory acinar cells upon contact with laminin-111 and laminin-211 specifically found in the acinar basement membrane. The disarranged endo-/intracrine estrogen/androgen balance induces acinar cells to release microparticles and apoptotic bodies and to undergo apoptotis and/or anoikis. Membrane particles contain potential autoantigens recognized by T- (TCRs) and B-cell receptors (BCRs) and danger-associated molecular patterns (DAMPs) recognized by Toll-like receptors (TLRs). In membrane particles (or carrier-complexes) antigen/adjuvant complexes could stimulate professional antigen capturing, processing and presenting cells, which can initiate auto-inflammatory and autoimmune cascades, break the self-tolerance and finally lead to SS.     

Lymphoproliferative disorders in Sjögren's syndrome

Sj?gren's syndrome (SS) is a chronic organ-specific autoimmune disease characterized by lymphocytic infiltration into the salivary and lacrimal glands. About half of primary SS patients develop systemic disorders. Primary SS can be divided into three stages according to the extent of organ damage and the course of the disease. In stage I, (approx. 45% of cases), patients have only sicca syndrome and do not experience any systemic involvement, even after 10 years. In stage II (approx. 50% of cases), patients experience lymphocytic organ damage, which may involve the pulmonary, renal, hepatic, hematologic, and/or dermatologic systems, among others. Finally, in stage III (approx. 5% of cases), patients develop malignant lymphomas. Lymphomas in salivary glands are thought to arise from lymphoepithelial lesions in which there are close interactions among epithelial cells, T cells, and B cells. The B cells in the lesions become activated through the interaction between CD40L and CD40. The progression from polyclonal lymphoproliferation to monoclonal lymphoproliferation, to mucosa-associated lymphoid tissue (MALT) lymphoma, and finally to high-grade malignant lymphoma is regarded as a multi-step process. Antigenic activation of B cells, together with oncogenic events, including p53 inactivation and bcl-2 activation, may play important roles in B cell monoclonal proliferation and malignant transformation. The rheumatoid factor clone is regarded as a candidate B cell clone that undergoes transformation.     

Classification criteria of Sjögren's syndrome

Sjögren's syndrome (SS) is a chronic, systemic autoimmune disease that affects typically the exocrine glands causing mucosal dryness. Dry eyes and mouth are considered by far the most common and early symptoms of the disease but systemic complications may also occur. In 1993, the preliminary European criteria were proposed and widely accepted, consisting of both subjective and objective criteria. Almost ten years later, these classification criteria were revised by introducing more stringent rules and precise diagnostic procedures leading to the currently used American-European Consensus Group (AECG) criteria. The AECG criteria have been largely employed to conduct epidemiologic and clinical studies of patients with SS and proved to be more specific compared to the preliminary European criteria. The recent American College of Rheumatology/Sjögren's International Collaborative Clinical Alliance (ACR/SICCA) criteria that are based exclusively on objective tests, the stringency of the AECG criteria and the potential therapeutic use of biologic agents in SS clearly set the need for new classification criteria. Whether the new diagnostic approach will further encompass subclinical and early forms of the disease remains to be addressed by the scientific community.     

Antibodies against alpha-fodrin in Sjögren's syndrome

Alpha-fodrin is a part of the membrane skeleton and expressed in the majority of mammalian cells. It is cleaved in apoptosis by caspase 3. One of the cleavage products, a 120-kDa protein, represents a neoantigen. Antibodies against that cleavage product of alpha-fodrin have originally been described in a murine model of Sj?gren's syndrome. In addition, they are also present in up to 93% of patients with Sj?gren's syndrome, depending on the stringency of the classification used. Although antibodies against alpha-fodrin are observed in other diseases characterized by chronic apoptosis, they are a valuable laboratory marker in the evaluation of Sj?gren's syndrome.     

Polarization of B effector cells in Sjögren's syndrome

Analysis of salivary glands of patients with primary Sj?gren's syndrome has yielded conflicting results with respect to T helper (Th)1/Th2 polarization. This balance might parallel the progress of the local lesions. B-cells are now taking center stage in this disease. They can also be primed to differentiate into two cytokine-production pathways, dubbed B effector (Be) 1 and Be2 cells. This is discussed in the light of our recent finding that Be1 accompany Th1, while Be2 accompany in the tissue lesions.     

B-cell hyperactivity in primary Sjögren's syndrome

Primary Sjögren's syndrome (pSS) is characterized by mononuclear inflammatory infiltrates and IgG plasma cells in salivary and lacrimal glands which lead to irreversible destruction of the glandular tissue and is accompanied by sensation of dryness of mouth and eyes. B cells play a central role in the immunopathogenesis and exhibit signs of hyperactivity. Hyperactivity of B cells is the consequence of the coordinated and integrated action of stimulation of the B-cell receptor, CD40 and toll-like receptors in the presence of appropriate cytokines. As discussed, overexpression of type I IFN and BAFF on one hand and IL-6 and IL-21 on the other hand are critically involved in the enhanced plasma cell formation in pSS patients. Hyperactivity of B cells results in secretion of autoantibodies and production of various cytokines. These insights in the role of B cells in the pathogenetic process of pSS offer ample targets for successful therapeutical intervention in pSS.     

Type I interferons in Sjögren's syndrome

Sjögren's syndrome is a chronic autoimmune disease characterized by lymphocytic infiltration of the salivary and lachrymal glands resulting in dry eyes and mouth. Genetic predisposition, pathogenic infections and hormones have been implicated in the pathogenesis of the disease. Studies in the last several years have revealed marked over-expression of the type I interferon (IFN)-inducible genes in the peripheral blood and salivary glands of patients with Sjögren's syndrome. The expression of the type I IFN-inducible genes in Sjögren's syndrome also positively correlates to titers of anti-Ro and anti-La autoantibodies, which are typical for this disease. Plasmacytoid dendritic cells (pDC) are the major source of type I IFN production and activated pDC are detected in minor salivary gland biopsies from patients with primary Sjögren's syndrome. In addition, polymorphisms in genes important both for the production and response to type I IFN are associated to increased risk for Sjögren's syndrome. Because type I IFN bears a variety of biological functions, such as defense against viral infections and activation of the immune system, these results suggest that the type I IFN system has an important role in the pathogenesis of Sjögren's syndrome. A variety of mechanisms causing an activation of the type I IFN system are discussed in this review. Given the pivotal role of type I IFN in the disease process, therapeutic interventions targeting the type I IFN signaling pathway have the potential to benefit the patients with elevated type I IFN status and such hypothesis needs to be carefully evaluated in clinical development.     

Neurophysiological assessment of peripheral neuropathy in primary Sjögren's syndrome

Peripheral nervous system complications are rare in patients with primary Sjögren's syndrome. We investigated a group of six women aged 43–64 years who complained of pain and sensory symptoms. Conventional neurophysiological tests reflecting large nerve fiber function revealed normal motor conduction in all patients, whereas sensory nerve action potentials were absent in two. On the other hand, quantitative thermometry and autonomic nerve function tests indicating small nerve fiber function were more sensitive in the assessment of nerve dysfunction; these showed abnormalities in all cases. Vibrametry showed dysfunctions in four patients. The latter methods possess great sensitivity in discovering sensory disturbances. Neurophysiological assessment of the sensory and autonomic nervous system demonstrating sensory neuropathy contributes to early diagnosis of primary Sjögren's syndrome.Abbreviations HRV heart rate variation - PNS peripheral nervous system - pSS primary Sjögren's syndrome - SSEP short-latency somatosensory evoked potentials - SSR sympathetic skin response - SuCV sudomotor nerve conduction velocity     

Genetics of Sjögren's syndrome in the genome-wide association era

While Sj?gren's syndrome (SS) is more common than related autoimmune disorders, such as systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA), scientific and medical research in SS has lagged behind significantly. This is especially true in the field of SS genetics, where efforts to date have relied heavily on candidate gene approaches. Within the last decade, the advent of the genome-wide association (GWA) scan has altered our understanding of disease pathogenesis in hundreds of disorders through the successful identification of novel risk loci. With strong evidence for a genetic component in SS as evidenced by familial aggregation of SS as well as similarities between SS and SLE and RA, the application of GWA approaches would likely yield numerous novel risk loci in SS. Here we review the fundamental scientific principles employed in GWA scans as well as the limitations of this tool, and we discuss the application of GWA scans in determining genetic variants at play in complex disease. We also examine the successful application of GWA scans in SLE, which now has more than 40 confirmed risk loci, and consider the possibility for a similar trajectory of SS genetic discovery in the era of GWA scans. Ultimately, the GWA studies that will be performed in SS have the potential to identify a myriad of novel genetic loci that will allow scientists to begin filling in the gaps in our understanding of the SS pathogenesis.     

Viral etiopathogenesis of Sjögren's syndrome: role of the hepatitis C virus

Patients with hepatitis C virus (HCV) chronic infection present some extrahepatic manifestations that may mimic the clinical, immunologic and histological manifestations of primary Sj?gren's syndrome (SS). Thus, HCV patients with sicca symptomatology and positive autoantibodies could be misdiagnosed as a 'primary' SS. Nevertheless, there are several clinical and immunologic features that could help us differentiate both processes.     

Identification of candidate genes for Sjögren's syndrome using MRL/lpr mouse model of Sjögren's syndrome and cDNA microarray analysis

Sj?gren's syndrome is a chronic autoimmune disease characterized by focal lymphocytic infiltration of lacrimal and salivary glands, but the precise mechanism of this syndrome is poorly understood. To clarify the mechanism of onset and progression of Sj?gren's syndrome, it is necessary to identify Sj?gren's syndrome-related genes. For this purpose, we used MLR/MpJ-lpr/lpr (MRL/lpr) mouse as a model of human secondary Sj?gren's syndrome and analyzed specific mRNA expression pattern in MRL/lpr mouse salivary glands by in-house cDNA microarray. Among arrayed 2304 genes, 13 genes were isolated as highly expressed genes in MRL/lpr mouse salivary gland in comparison with MRL/MpJ-+/+ (MRL/+) mouse tissue. Subsequently, we performed RT-PCR analysis and confirmed the high expression level of nine genes; caspase3, Ly-6C.2, vimentin, Mel-14 antigen, cathepsin B, mpt1, Laptm5, Gnai2 and UCP2. Five of the nine genes have already been identified in patients with Sj?gren's syndrome or mice models of the syndrome, but the remaining four genes; mpt1, Laptm5, Gnai2, and UCP2 have not been reported previously as Sj?gren's syndrome-related genes. Although, further experiments are necessary to examine the relationship between these four genes and Sj?gren's syndrome, our system of mouse model of Sj?gren's syndrome combined with in-house cDNA microarray is suitable for the isolation of Sj?gren's syndrome-related genes.     

Sjögren's syndrome at the crossroad of polyautoimmunity

The coexistence of autoimmune diseases (i.e., polyautoimmunity) in Sj?gren's syndrome (SS) was investigated in a cross-sectional study involving 410 patients. Logistic regression analysis and the Rogers and Tanimoto index were used to evaluate risk factors and clustering, respectively. There were 134 (32.6%) patients with polyautoimmunity. The most frequent and closer coexistent diseases were autoimmune thyroid disease (21.5%), rheumatoid arthritis (8.3%), systemic lupus erythematosus (7.6%), and inflammatory bowel disease (0.7%) which together constituted a cluster group. There were 35 (8.5%) patients with multiple autoimmune syndrome. Besides disease duration, a history of habitual smoking and spontaneous abortion were found to be risk factors for the developing of polyautoimmunity. This study discloses a high prevalence of polyautoimmunity in SS, its associated risk factors and the grouping pattern of such a condition. These results may serve to define plausible approaches to study the common mechanisms of autoimmune diseases.