Primary Sjögren's syndrome (pSS) is an autoimmune disorder characterized by specific pathologic features and the production of typical autoantibodies. In addition, characteristic changes in the distribution of peripheral B cell subsets and differences in use of immunoglobulin variable-region genes are also features of pSS. Comparison of B cells from the blood and parotid gland of patients with pSS with those of normal donors suggests that there is a depletion of memory B cells from the peripheral blood and an accumulation or retention of these antigen-experienced B cells in the parotids. Because disordered selection leads to considerable differences in the B cell repertoire in these patients, the delineation of its nature should provide important further clues to the pathogenesis of this autoimmune inflammatory disorder.
autoimmunity; B cells; IgV gene usage; lymphocytes; Sjögren's syndrome
Lymphoma of the salivary gland accounts for 5% of cases of extranodal lymphoma and 10% of malignant salivary gland tumours. Most primary salivary gland lymphomas are B marginal zone lymphomas arising on a background of sialadenitis associated with autoimmune disorders such as Sjorgen's syndrome. Primary T cell lymphoma of the salivary gland is rare. This report describes a case of primary T cell lymphoma arising in the parotid gland of an elderly white man, which was notable for its striking resemblance to a B cell extranodal marginal zone lymphoma. Immunohistochemistry and gene rearrangement studies confirmed the clonal T cell nature of the tumour. There was no molecular evidence of Epstein-Barr virus (EBV) infection of neoplastic or surroundings cells. Only 14 cases of primary T cell lymphoma of the salivary glands have been recorded in the literature, most being from the Orient and having extremely variable prognosis. Those with a T/natural killer cell phenotype are associated with EBV infection. This case highlights the fact that T cell lymphoma in the salivary gland can mimic closely the morphological features of B cell extranodal marginal zone lymphoma.
salivary gland; T cell lymphoma; Epstein Barr virus
Minor salivary gland biopsy specimens from 11 patients with primary Sjögren's syndrome with circulating monoclonal IgM kappa cryoglobulins, seven without cryoglobulins, and four patients with rheumatoid arthritis and Sjögren's syndrome (one with monoclonal and three with polyclonal cryoglobulins) were examined by the peroxidase antiperoxidase bridge technique, using antihuman kappa and lambda antibodies. In 6/11 patients with primary Sjögren's syndrome and in one patient with Sjögren's syndrome and rheumatoid arthritis with monoclonal cryoglobulins a predominance of plasma cells containing intracytoplasmic kappa light chains was found (kappa:lambda greater than 3:1). Two of those seven patients had immunohistological features of immunocytomas. In the other five patients with circulating monoclonal cryoglobulins the kappa:lambda ratio of positive cells did not exceed 3:1, while six out of seven patients without cryoglobulins and the patients with rheumatoid arthritis and Sjögren's syndrome with polyclonal cryoglobulins had almost equal numbers of kappa and lambda stained cells. One of seven patients with primary Sjögren's syndrome without cryoglobulins had an increased number of lambda light chain positive cells, indicating a non-secretory lambda monoclonal population. These findings suggest that the main area of B cell monoclonal expansion in primary Sjögren's syndrome may be the affected exocrine glands.
The presence of multiple calculi in the major salivary glands is an uncommon finding. Sjögren’s syndrome is a chronic autoimmune disease characterized by lymphocyte-mediated destruction of the exocrine glands. The case is presented of a 49-year-old female with Sjögren’s syndrome found to have bilateral multiple sialolithiasis in the parenchyma of the parotid glands. The patient presented with a right sided painful inflamed swelling of the parotid region. Even though she had been diagnosed with primary Sjögren’s syndrome 3 years prior to admission, she did not report any previous episode of sialadenitis. Full blood count showed leukocytosis (white blood cells = 14,900/106L) with neutrophilia (75%). Radiological assessment included ultrasound and computed tomography scan of the parotids which demonstrated intra-parenchymal multiple calculi of both parotid glands and obstruction of the right Stensen’s duct. The patient was treated with intravenous antibiotics and anti-inflammatory drugs. On the second day of hospitalisation, she reported spontaneous extrusion of a calculus during massage of the gland, with immediate relief of symptoms. In patients with Sjögren’s syndrome and radiological findings of calculi in the major salivary glands, close observation is mandatory for better control of recurrent sialadenitis and early recognition of mucosa-associated lymphoid tissue lymphomas.
Parotid gland; Sialolithiasis; Sjögren’s syndrome
Primary Sjögren’s syndrome (SjS) is an autoimmune disorder characterized by lymphocytic infiltration of the salivary and lacrimal glands, B-cell clonal expansions and an increased risk of lymphoma. In order to understand the role of B cells in this disorder, the antibody repertoire and B-cell maturation were studied in a mouse model of SjS called B6.Aec1/2.
B6.Aec1/2 serum was analyzed for (auto)antibodies by ELISA and immunoprecipitation, B-cell development by flow cytometry, antibody gene rearrangements by CDR3 spectratyping and quantitative PCR. In order to test the functional consequences of the observed defects, B6.Aec1/2 mice were crossed with anti-dsDNA antibody heavy chain knock-in mice (B6.56R).
B6.Aec1/2 mice exhibit B-cell clonal expansions, have altered serum immunoglobulin levels and spontaneously produce multireactive autoantibodies. B6.Aec1/2 mice also have decreased numbers of bone marrow pre-B cells and decreased frequencies of kappa light chain gene deletion. These findings suggest that B6.Aec1/2 mice have a defective early B-cell tolerance checkpoint. B6.56R.Aec1/2 mice unexpectedly had lower anti-dsDNA antibody levels than B6.56R mice and less salivary gland infiltration than B6.Aec1/2 mice.
These data suggest that the early tolerance checkpoint defect in B6.Aec1/2 mice is not sufficient to promulgate disease in mice with pre-formed autoantibodies, such as B6.56R. Rather, B6.Aec1/2 mice may require a diverse B-cell repertoire for efficient T-B-cell collaboration and disease propagation. These findings imply that therapies aimed at reducing B-cell diversity or T-B interactions may be helpful in treating SjS.
Sjögren’s syndrome; B cell; autoantibody; receptor editing
A woman presented with painful enlargement of her parotid and submandibular glands. She was shown to have the previously unreported combination of idiopathic thrombocytopenic purpura, Sjögren's syndrome, Hashimoto's disease, and myasthenia gravis. Parotid gland biopsy and bone marrow examination showed the presence of a rare lymphoplasmacytoid lymphoma. There was amyloid deposition in the parotid glands, gums and on muscle biopsy. Immunohistochemical staining of the parotid lymphoma and amyloid was monotypic for lambda light chains, and there was also a lambda chain paraprotein. It is felt that the lymphoplasmacytic lymphoma was responsible for the light chain amyloidosis.
Randall disease is an unusual cause of extraocular motor nerve (VI) palsy. A 35-year-old woman was hospitalized for sicca syndrome. The physical examination showed general weakness, weight loss, diplopia related to a left VIth nerve palsy, hypertrophy of the submandibular salivary glands, and peripheral neuropathy. The biological screening revealed renal insufficiency, serum monoclonal kappa light chain immunoglobulin, urinary monoclonal kappa light chain immunoglobulin, albuminuria, and Bence-Jones proteinuria. Bone marrow biopsy revealed medullar plasma cell infiltration. Immunofixation associated with electron microscopy analysis of the salivary glands showed deposits of kappa light chains. Randall disease was diagnosed. The patient received high-dose melphalan followed by autostem cell transplantation which led to rapid remission. Indeed, at the 2-month followup assessment, the submandibular salivary gland hypertrophy and renal insufficiency had disappeared, and the peripheral neuropathy, proteinuria, and serum monoclonal light chain had decreased significantly. The persistent diplopia was treated with nerve decompression surgery of the left extraocular motor nerve. Cranial nerve complications of Randall disease deserve to be recognized.
AIMS: To investigate the possibility of an immune response to retroviral antigens or of detecting retrovirus in Sjögren's syndrome. METHODS: Retroviruses were sought in labial salivary glands and peripheral blood mononuclear cells from patients with Sjögren's syndrome by immunoblotting assay, immunohistochemical assay, polymerase chain reaction (PCR), reverse transcriptase (RT) activity assay, and transmission electron microscopy. RESULTS: Sera from five of 15 patients with Sjögren's syndrome (33%) reacted against p24 group specific antigen (gag) of human immunodeficiency virus (HIV). Labial salivary gland biopsy specimens from seven of the 15 patients with Sjögren's syndrome (47%) contained an epithelial cytoplasmic protein reactive with a monoclonal antibody to p24 of HIV. PCR was performed to detect HIV and human T lymphotropic virus type I (HTLV-I) genes from salivary gland tissues and peripheral blood mononuclear cells from patients with Sjögren's syndrome. Mn2+ dependent, Mg2+ independent RT activity was detected in the salivary gland tissues in three of 10 patients. A-type-like retroviral particles were observed in epithelial cells of salivary glands by transmission electron microscopy. Target genes for HIV and HTLV-I were not found in any of the salivary gland tissues or peripheral blood mononuclear cells from Sjögren's syndrome patients. CONCLUSIONS: The data suggest the presence of an unknown retrovirus similar to HIV in the salivary gland which might be involved in the pathogenesis of a subpopulation in Sjögren's syndrome.
Infection with HIV-1 occasionally results in a sicca syndrome, termed the diffuse infiltrative lymphocytosis syndrome, characterized by infiltration of the salivary glands with a predominance of CD8 T cells. This response is strongly associated with certain MHC class I and class II alleles. To define the salivary gland T cell receptor (TCR) repertoire, the primary structure of the TCR beta-chains was determined using in situ cDNA synthesis followed by the "anchored" polymerase chain reaction. The sequences of 59 beta-chains from five individuals with diffuse infiltrative lymphocytosis syndrome shared structural features suggesting antigenic clonal selection. Certain combinations of V beta J beta gene segments were selectively overrepresented in the repertoire sample, demonstrating a common restricted usage of certain V beta and J beta gene segments. The beta-chains derived from these overrepresented V beta J beta combinations revealed a preference for specific amino acids at position 97 in the third complementarity-determining region, a residue postulated to contact peptide antigen. Moreover, the nucleotides encoding this position were not germline in origin. TCR beta-chains in nonoverrepresented V beta J beta combinations did not exhibit preferential usage of selected somatically encoded residues. The pattern of TCR beta-chains expressed in the salivary gland of a control person with primary Sjögren's syndrome was considerably more heterogeneous and different from that found in diffuse infiltrative lymphocytosis syndrome.
AIMS: To determine the prevalence of plasma cell monotypia in labial salivary gland tissue of patients with and without Sjögren's syndrome, and to evaluate its relation to the development of systemic monoclonal lymphoproliferative disorders. METHODS: A quantitative immunohistological study was performed on labial salivary gland tissue of 45 patients with Sjögren's syndrome, 18 with rheumatoid arthritis without Sjögren's syndrome, and 80 healthy controls. In none of the patients with Sjögren's syndrome was there evidence of systemic monoclonal lymphoproliferative disease at the time of biopsy. RESULTS: Monotypic plasma cell populations, defined by a kappa:lambda ratio of > or = 3, were only observed in older patients (above 43 years) with Sjögren's syndrome. In almost all these patients monotypic plasma cell populations were present in multiple labial salivary gland tissues and the IgM/kappa monotypia was observed most frequently. The prevalence of monotypic plasma cell populations in the group with Sjögren's syndrome was 22% (10/45) and there was no significant predilection for primary Sjögren's syndrome. Of special clinical interest was the observation that progression to systemic monoclonal lymphoproliferative disease had occurred exclusively in this subgroup of patients with Sjögren's syndrome, with a prevalence of 30% (3/10). CONCLUSION: Quantitative immunohistological examination of labial salivary gland tissues provides pathologists with a simple method to select those patients with Sjögren's syndrome who have an increased relative risk at the time of biopsy to develop benign or malignant lymphoproliferative disorders.
Infiltrating T cells around salivary glands in the lips of Sjögren's syndrome (SjS) patients are crucial in the pathogenesis of this disease. To analyze the nature of infiltrating T cells, their T cell receptor repertoire was examined with quantitative polymerase chain reaction. The repertoire of V beta transcripts in lips of SjS was not restricted; however, the V beta 2 and V beta 13 genes were predominantly expressed on the T cells of lip specimens in six and four of seven lips, respectively. Predominance of these genes was specific in lips because no predominant V beta transcripts were found in lips from healthy subjects and PBLs from SjS patients. These results indicated that the V beta 2- and V beta 13-positive T cells expanded specifically and preferentially in SjS lips, thereby suggesting the possible role in triggering the autoimmunity of this disease.
Viral infections are often associated with salivary gland pathology. Here we review the pathogenesis of HIV-associated salivary gland disease (HIV-SGD), a hallmark of diffuse infiltrative lymphocytosis syndrome. We investigate the presence and contributions of viral diseases to the pathogenesis of salivary gland diseases, particularly HIV-SGD. We have detected BK viral shedding in the saliva of HIV-SGD patients consistent with viral infection and replication, suggesting a role for oral transmission. For further investigation of BKV pathogenesis in salivary glands, an in vitro model of BKV infection is described. Submandibular (HSG) and parotid (HSY) gland salivary cell lines were capable of permissive BKV infection, as determined by BKV gene expression and replication. Analysis of these data collectively suggests the potential for a BKV oral route of transmission and salivary gland pathogenesis within HIV-SGD.
Virus; salivary gland; HIV; DILS
OBJECTIVE—To determine the efficacy of corticosteroid irrigation of the parotid gland in relieving salivary flow deficiency in patients with Sjögren's syndrome.
METHODS—The parotid glands of 31 patients with primary (24) or secondary (seven) Sjögren's syndrome were irrigated either with saline solution followed by corticosteroid solution, or with saline solution alone. Salivary function was assessed by Saxon test.
RESULTS—Corticosteroid irrigation significantly increased the salivary flow rate in patients with Sjögren's syndrome (p< 0.0001), with clinical improvement detectable 3.7 (2.4) weeks (mean (SD)) after initial corticosteroid irrigation. The extent of improvement in salivary function was reciprocal to the clinical severity of the disease, with patients at the early stages obtaining 1.20 (0.57) g net increase in salivary flow rate, and patients at the most advanced stages obtaining 0.20 (0.47) g net increase. Repeated corticosteroid irrigations did not evoke corticosteroid refractoriness of the salivary gland; similar levels of net increase in salivary flow rate were observed after the second to fourth challenge of the corticosteroid in these patients. The sustained period was 8.4 (3.5) months (mean (SD)).
CONCLUSION—These findings suggest the clinical usefulness of corticosteroid irrigation therapy in relieving xerostomia in patients with Sjögren's syndrome.
Keywords: Sjögren's syndrome; xerostomia; corticosteroids
Chronic infiltration of lymphocytes into the salivary and lacrimal glands of Sjögren’s Syndrome patients leads to destruction of acinar cells and loss of exocrine function. Protein kinase C-delta (PKCδ) is known to play a critical role in B cell maintenance. Mice in which the PKCδ gene has been disrupted have a loss of B cell tolerance, multiple organ lymphocytic infiltration, and altered apoptosis. To determine if PKCδ contributes to the pathogenesis of Sjögren’s Syndrome, we quantified changes in indicators of Sjögren’s Syndrome in PKCδ−/− mice as a function of age. Salivary gland histology, function, the presence of autoantibodies, and cytokine expression were examined. Materials and Methods: Submandibular glands were examined for the presence of lymphocytic infiltrates, and the type of infiltrating lymphocyte and cytokine deposition was evaluated by immunohistochemistry. Serum samples were tested by autoantibody screening, which was graded by its staining pattern and intensity. Salivary gland function was determined by saliva collection at various ages. Results: PKCδ−/− mice have reduced salivary gland function, B220+ B cell infiltration, anti-nuclear antibody production, and elevated IFN-γ in the salivary glands as compared to PKCδ+/+ littermates. Conclusions: PKCδ−/− mice have exocrine gland tissue damage indicative of a Sjögren’s Syndrome-like phenotype.
PKCδ; autoimmunity; Sjögren’s syndrome
Sjögren's syndrome (SS) is an autoimmune disease characterized by keratoconjunctivitis sicca and xerostomia. There are actually no diagnostic criteria for SS, but classification criteria based on the revised American-European criteria have been elaborated. These include subjective criteria: ocular and oral symptoms, and objective criteria: ocular, histopathological, oral, and serological signs. SS is considered if 4 of the 6 criteria are present, when histopathology or serology is positive, or if 3 of any 4 objective criteria are present. A patient presented with both ocular and oral symptoms and signs but did not meet the SS classification criteria. Indeed, no anti-SSA or anti-SSB antibodies were detected, and minor salivary gland biopsy was normal. To further understand the origin of the sicca symptoms, a parotid gland biopsy was performed and showed important lymphocytic infiltrates. This could account for the sicca symptoms and signs since parotid glands are one the major contributors to salivary flow. Therefore, parotid gland biopsy could be a useful asset for the diagnosis of SS.
Fresh sera and concentrated urine from 17 patients with primary Sjögren's syndrome (SS) were fractionated by high-resolution agarose electrophoresis to investigate the presence of monoclonal immunoglobulins or their components. Homogeneous protein bands were found in the gamma-globulin region in 47% of serum samples and 76% of urine specimens of all patients tested. These monoclonal proteins were detected more often in patients with extraglandular SS (77% in serum, 100% in the urine) than in patients with glandular SS (14% in serum, 43% in the urine). Immunofixation electrophoresis showed that the majority of these monoclonal proteins were free kappa or lambda light chains. Fractionation of unconcentrated parotid salivas from five SS patients failed to reveal the presence of monoclonal light chains or immunoglobulins. The present findings further substantiate our previous observation that a monoclonal process coexists with the polyclonal activation in SS patients.
Salivary gland dysfunction is one of the key manifestations of Sjögren's syndrome.
(1) To assess prospectively loss of function of individual salivary glands in patients with primary and secondary Sjögren's syndrome in relation to disease duration and use of immunomodulatory drugs. (2) To study changes in sialochemical and laboratory values and subjective complaints over time.
60 patients with Sjögren's syndrome were included in this study. Whole and gland‐specific saliva (parotid and submandibular/sublingual (SM/SL)), samples were collected at baseline and after a mean of 3.6 (SD 2.3) years of follow‐up. Disease duration was recorded for all patients.
Patients with Sjögren's syndrome with short disease duration had significantly higher stimulated flow rates at baseline than those with longer disease duration (p<0.05). When compared with healthy controls, the decrease in SM/SL flow rates at baseline was more prominent than that in parotid flow rates (p<0.05). Over time, there was a significant further decrease of stimulated flow rates, especially of the parotid gland, accompanied by increasing problems with swallowing dry food (p<0.05). The decrease was independent of the use of corticosteroids or disease‐modifying antirheumatic drugs (DMARDs). Sialochemical variables remained stable.
Early Sjögren's syndrome is characterised by a decreased salivary gland function (parotis>SM/SL), which shows a further decrease over time, regardless of the use of DMARDs or steroids. Patients with Sjögren's syndrome with longer disease duration are characterised by severely reduced secretions of both the parotid and SM/SL glands. These observations are relevant for identifying patients who would most likely benefit from intervention treatment.
The clinical, light microscopic, ultrastructural, immunocytochemical and cytogenetic features of a case of monocytoid B cell lymphoma were investigated. The tumour initially affected the cervical and supraclavicular nodes, but 33 months later affected the left parotid salivary gland. The patient had subclinical Sjögren's syndrome. The neoplastic cells showed characteristic morphological features and had peri- and interfollicular distribution in the node. Immunocytochemically the tumour cells were L26, 4KB5, MB2, CD19, CD20, CD22 and IgM/kappa positive. Prominent plasmablastic plasmacytoid differentiation was present in the recurrent tumour, suggesting an origin from post-follicular B cells. The lymphoma cells showed unusual cytogenetic abnormalities.
Structures resembling germinal centers are seen in the salivary glands of patients with Sjögren's syndrome, but it is not known whether the microenvironment of these cell clusters is sufficient for the induction of a germinal center response. Therefore, we cloned and sequenced rearranged Ig V genes expressed by B cells isolated from sections of labial salivary gland biopsies from two Sjögren's syndrome patients. Rearranged V genes from B cells within one cell cluster were polyclonal and most had few somatic mutations. Two adjacent clusters from another patient each contained one dominant B cell clone expressing hypermutated V genes. None of the rearranged V genes was found in both clusters, suggesting that cells are unable to migrate out into the surrounding tissue and seed new clusters. The ratios of replacement to silent mutations in the framework and complementarity determining regions suggest antigen selection of high-affinity mutants. These results show that an antigen-driven, germinal center-type B cell response is taking place within the salivary glands of Sjögren's syndrome patients. In view of the recent demonstration of a germinal center response within the rheumatoid synovial membrane and the existence of similar structures in the target tissues of other autoimmune diseases, we propose that germinal center- type responses can be induced in the nonlymphoid target tissues of a variety of autoimmune diseases.
A patient presenting with bilateral enlargement of parotid and lacrimal glands, xerostomia, and keratoconjunctiva sicca, whose labial biopsy specimen showed changes consistent with Sjögren's syndrome, is described. The patient was initially misdiagnosed as having primary Sjögren's syndrome (SS). Subsequent investigations, however, performed to exclude an associated lymphoma or sarcoidosis, showed histological changes of the latter. The possibility that early infiltrates of the salivary glands in sarcoid may mimic those of SS is discussed.
Sjogren's syndrome (SS) is an autoimmune disease characterized by lymphocytic infiltration into lacrimal and salivary glands leading to symptomatic dry eyes and mouth. Immunohistological studies have clarified that the majority of infiltrating lymphocytes around the lacrimal glands and labial salivary glands are CD4 positive alphabeta T cells. To analyze the pathogenesis of T cells infiltrating into lacrimal and labial salivary glands, we examined T cell clonotype of these cells in both glands from four SS patients using PCR-single-strand conformation polymorphism (SSCP) and a sequencing method. SSCP analysis showed that some infiltrating T cells in both glands expand clonally, suggesting that the cells proliferate by antigen-driven stimulation. Intriguingly, six to sixteen identical T cell receptor (TCR) Vbeta genes were commonly found in lacrimal glands and labial salivary glands from individual patients. This indicates that some T cells infiltrating into both glands recognize the shared epitopes on autoantigens. Moreover, highly conserved amino acid sequence motifs were found in the TCR CDR3 region bearing the same TCR Vbeta family gene from four SS patients, supporting the notion that the shared epitopes on antigens are limited. In conclusion, these findings suggest that some autoreactive T cells infiltrating into the lips and eyes recognized restricted epitopes of a common autoantigen in patients with SS.
Sjögren’s syndrome(SS) represents a chronic autoimmune disease of unknown etiology that targets salivary and lacrimal glands and may be accompanied by multi-organ systemic manifestations. To further an understanding of immunopathology associated with SS and uncover therapeutic targets, we compared gene expression profiles of salivary glands with severe inflammation to those with mild or no disease.
Using microarray profiling of salivary gland tissues from SS patients and controls, we identified target genes that were further characterized in tissues, serum and in cultured cell populations by real time PCR and protein analyses.
Among the most highly expressed SS genes were genes associated with myeloid cells, including members of the mammalian chitinase family, not previously associated with exocrinopathies. Both chitinase-3-like-1(CHI3L1/YKL-40) and chitinase 1(CHIT1), highly conserved chitinase-like glycoproteins, one with and one lacking enzymatic activity, were evident at the transcriptome level, and detected within inflamed tissues. Chitinases are expressed during monocyte-to-macrophage differentiation, and augmented by cytokines, including IFNα.
Since elevated expression of these and other macrophage-derived molecules corresponded with more severe SS, these observations suggest potential immunopathologic macrophage involvement and furthermore, that the tissue macrophage transcriptional profile reflects multiple genes induced by IFNα.
Primary Sjögren's syndrome (pSS) is an autoimmune disorder characterized by specific pathological features. A hallmark of pSS is B-cell hyperactivity as manifested by the production of autoantibodies, hypergammaglobulinemia, formation of ectopic lymphoid structures within the inflamed tissues, and enhanced risk of B-cell lymphoma. Changes in the distribution of peripheral B-cell subsets and differences in post-recombination processes of immunoglobulin variable region (IgV) gene usage are also characteristic features of pSS. Comparison of B cells from the peripheral blood and salivary glands of patients with pSS with regard to their expression of the chemokine receptors CXCR4 and CXCR5, and their migratory capacity towards the corresponding ligands, CXCL12 and CXCL13, provide a mechanism for the prominent accumulation of CXCR4+CXCR5+ memory B cells in the inflamed glands. Glandular B cells expressing distinct features of IgV light and heavy chain rearrangements, (re)circulating B cells with increased mutations of cμ transcripts in both CD27- and CD27+ memory B-cell subsets, and enhanced frequencies of individual peripheral B cells containing IgV heavy chain transcripts of multiple isotypes indicate disordered selection and incomplete differentiation processes of B cells in the inflamed tissues in pSS. This may possibly be related to a lack of appropriate censoring mechanisms or different B-cell activation pathways within the ectopic lymphoid structures of the inflamed tissues. These findings add to our understanding of the pathogenesis of this autoimmune inflammatory disorder and may result in new therapeutic approaches.
The mouse model is the one of the most frequently used and well-established animal models, and is currently used in many research areas. To date, various mouse models have been utilized to elucidate underlying causes of multi-factorial autoimmune conditions, including pathological immune components and specific signaling pathways. This review summarizes the more recent mouse models for Sjögren’s syndrome, a systemic autoimmune disease characterized by lymphocytic infiltration in the exocrine glands, such as the salivary and lacrimal glands, and loss of secretory function, resulting in dry mouth and dry eyes in patients. Although, every Sjögren’s syndrome mouse model resembles the major symptoms or phenotypes of Sjögren’s syndrome conditions in humans, the characteristics of each model are variable. Moreover, to date there is no single mouse model that can completely replicate the human conditions. However, unique features of each mouse model provide insights into the roles of potential etiological and immunological factors in the development and progression of Sjögren’s syndrome. Here, we will overview the Sjögren’s syndrome mouse models. Lessons from these mouse models will aid us to understand underlying immune dysregulation in autoimmune diseases in general, and will guide us to direct future research towards appropriate diagnostic and therapeutic strategies to predict autoimmune disease including Sjögren’s syndrome.
Sjögren’s Syndrome; mouse models; T/B lymphocytes; autoantibodies; autoimmunity
Purpose of review
To summarize recent developments in our understanding of the pathogenesis of Sjögren's syndrome with a focus on the relationship between inflammation and exocrine dysfunction.
Animal models demonstrated the complex interactions between immunologic and nonimmunologic mechanisms in Sjögren's syndrome. Activation of the innate immune system can lead to exocrine dysfunction before or without significant inflammation, whereas in other models, salivary gland function is preserved despite intense inflammatory infiltrates. Primary or inflammation-related abnormalities in water channels contribute to the exocrinopathy. Activation of the innate immunity in patients is demonstrated by the upregulation of type-1 interferon-regulated genes (interferon signature) in peripheral blood and salivary glands and abnormal expression of B cell-activating factor and its receptors. Nonimmune mechanisms that may contribute to exocrine dysfunction include local and systemic androgen deficiency and autonomic nervous system dysfunction. Autoantibodies against the muscarinic acetylcholine receptors would provide a link between autoimmunity and exocrine dysfunction, but the data on the presence, frequency and physiologic affect of these antibodies remain controversial.
Recent discoveries from studies in patients with Sjögren's syndrome and animal models suggest a complex interplay between genetic factors, environmental and stochastic events that involve innate and adaptive immunity, hormonal mechanisms and the autonomic nervous system. Some of these findings suggest that exocrine gland dysfunction may precede autoimmunity or represent a process independent from inflammation in the pathogenesis of Sjögren's syndrome.
autonomic nervous system; exocrinopathy; innate immunity; sex steroids