Hyperglycemia and Salivary Gland Dysfunction in the Non-obese Diabetic Mouse: Caveats for Preclinical Studies in Sjögren's Syndrome.

The Non-obese Diabetic (NOD) mouse model for type I diabetes also develops some features of Sjögren's syndrome (SS). Since the source of the mice and the environment exert a strong influence on diabetes, this study investigated SS development in NOD mice obtained from two vendors. Female NOD mice from The Jackson Laboratory (JAX) and Taconic Biosciences were monitored for blood glucose and pilocarpine-induced salivation. The gut microbiome was analyzed by 16S rRNA sequencing of stool DNA. At euthanasia, serum cytokines and sialoadenitis severity were evaluated. The onset of diabetes was significantly accelerated in JAX mice compared to Taconic mice. Although the gut microbiome between the two groups was distinct, both groups developed sialoadenitis. There was no correlation between the severity of sialoadenitis and reduced saliva production. Instead, salivary gland dysfunction was associated with hyperglycemia and elevation of serum IL1ß, IL16, and CXCL13. Our data suggest that inflammatory pathways linked with hyperglycemia are confounding factors for salivary gland dysfunction in female NOD mice, and might not be representative of the mechanisms operative in SS patients. Considering that NOD mice have been used to test numerous experimental therapies for SS, caution needs to be exerted before advancing these therapeutics for human trials.

TNF-α Suppresses Autophagic Flux in Acinar Cells in IgG4-Related Sialadenitis.

IgG4-related sialadenitis (IgG4-RS) is a newly recognized immune-mediated systemic fibroinflammatory disease that affects salivary glands and leads to hyposalivation. Tumor necrosis factor-α (TNF-α) is a critical proinflammatory cytokine involved in several salivary gland disorders, but its role and mechanism regarding acinar cell injury in IgG4-RS are unknown. Here, we found that TNF-α level was significantly increased in serum and submandibular gland (SMG) of patients and that serum TNF-α level was negatively correlated with saliva flow rate. Ultrastructural observations of IgG4-RS SMGs revealed accumulation of large autophagic vacuoles, as well as dense fibrous bundles, decreased secretory granules, widened intercellular spaces, swollen mitochondria, and expanded endoplasmic reticulum. Expression levels of LC3 and p62 were both increased in patients' SMGs. TNF-α treatment led to elevated levels of LC3II and p62 in both SMG-C6 cells and cultured human SMG tissues but did not further increase their levels when combined with bafilomycin A1 treatment. Moreover, transfection of Ad-mCherry-GFP-LC3B in SMG-C6 cells confirmed the suppression of autophagic flux after TNF-α treatment. Immunofluorescence imaging revealed that costaining of LC3 and the lysosomal marker LAMP2 was significantly decreased in patients, TNF-α-treated SMG-C6 cells, and cultured human SMGs, indicating a reduction in autophagosome-lysosome fusion. Furthermore, the ratio of pro/mature cathepsin D was elevated in vivo, ex vivo, and in vitro. TNF-α also appeared to induce abnormal acidification of lysosomes in acinar cells, as assessed by lysosomal pH and LysoTracker DND-26 fluorescence intensity. In addition, TNF-α treatment induced transcription factor EB (TFEB) redistribution in SMG-C6 cells, which was consistent with the changes observed in IgG4-RS patients. TNF-α increased the phosphorylation of extracellular signal-regulated kinase (ERK) 1/2, and inhibition of ERK1/2 by U0126 reversed TNF-α-induced TFEB redistribution, lysosomal dysfunction, and autophagic flux suppression. These findings suggest that TNF-α is a key cytokine related to acinar cell injury in IgG4-RS through ERK1/2-mediated autophagic flux suppression.

Surgical Treatment of Chronic Parotitis

Abstract Introduction chronic parotitis (CP) is a hindering, recurring inflammatory ailment that eventually leads to the destruction of the parotid gland. When conservative measures and sialendoscopy fail, parotidectomy can be indicated. Objective to evaluate the efficacy and safety of parotidectomy as a treatment for CP unresponsive to conservative therapy, and to compare superficial and near-total parotidectomy (SP and NTP). Methods retrospective consecutive case series of patients who underwent parotidectomy for CP between January 1999 and May 2012. The primary outcome variables were recurrence, patient contentment, transient and permanent facial nerve palsy and Frey syndrome. The categorical variables were analyzed using the two-sided Fisher exact test. Alongside, an elaborate review of the current literature was conducted. Results a total of 46 parotidectomies were performed on 37 patients with CP. Neartotal parotidectomy was performed in 41 and SP in 5 cases. Eighty-four percent of patients was available for the telephone questionnaire (31 patients, 40 parotidectomies) with a mean follow-up period of 6,2 years. Treatment was successful in 40/46 parotidectomies (87%) and 95% of the patients were content with the result. The incidence of permanent and transient facial nerve palsy was 0 (0%) and 12 (26.1%), respectively. Frey syndrome manifested in 20 (43.5%) patients. Neither this study nor careful review of the current literature resulted in evident difference between SP and NTP regarding the primary outcome variables. Conclusion parotidectomy is a safe and effective treatment for CP in case conservative therapy fails. There is no evidence of a distinct difference between SP and NTP regarding efficiency, facial nerve palsy or Frey syndrome. (AU)

Minor salivary glands function is decreased in hyposalivation-related diseases.

OBJECTIVES: The aim of this cross-sectional study was to investigate the relationship between minor salivary gland (MSG) flow rates and oral dryness degrees in patients with xerostomia induced by primary Sjögren's syndrome (pSS), IgG4-related sialadenitis (IgG4-RS), radiation therapy-induced dry mouth (RTDM), or Steven-Johnson syndrome (SJS). DESIGN: 160 patients with pSS, IgG4-RS, RTDM, or SJS and their age- and sex-matched healthy control subjects were enrolled. The whole saliva flow rates and MSG flow rates were measured in four locations, including the upper labial, lower labial, buccal, and palatal mucosae. The degree of oral dryness was assessed in patient groups using the summated xerostomia inventory (SXI). RESULTS: The flow rates of whole saliva and most MSGs in patient groups were significantly lower than the flow rates in healthy control groups (P<0.05). The mean relative percentage of decrease in saliva flow rates was smaller in MSGs than in whole saliva in patient groups (P<0.05), indicating that these disorders have less impact on MSGs. Among the four MSG locations (the upper labial, lower labial, buccal, and palatal), buccal glands showed the highest flow rates in patient groups (P<0.05). SXI scores were significantly higher in pSS and RTDM patients than in IgG4-RS and SJS patients (P<0.05). The degree of xerostomia varied among different patient groups (P<0.05) and there was no clear correlation between MSG flow rates and SXI scores (P>0.05). CONCLUSIONS: MSG function is significantly reduced in pSS, RTDM, IgG4-RS, and SJS patients, but this reduction is more pronounced in the major salivary glands.

Association of Anticentromere Antibodies With More Severe Exocrine Glandular Dysfunction in Sjögren's Syndrome: Analysis of the Sjögren's International Collaborative Clinical Alliance Cohort.

OBJECTIVE: Anticentromere antibodies (ACAs) define a subset of primary Sjögren's syndrome (SS) with a unique phenotype, including features of limited cutaneous systemic sclerosis and a lower frequency of anti-SSA/SSB antibodies. We sought to determine whether ACAs are associated with more severe exocrine glandular dysfunction in a large cohort of primary SS subjects. METHODS: We performed a cross-sectional analysis of 1,361 subjects with primary SS from the Sjögren's International Collaborative Clinical Alliance Registry, stratified by the presence or absence of ACAs. ACAs were assayed by immunofluorescence staining on HEp-2 cells. RESULTS: ACAs were present in 82 of the 1,361 SS subjects (6%) and were associated with older age, female sex, and lower frequencies of anti-SSA/SSB, rheumatoid factor, and hyperglobulinemia. Among ACA-positive versus ACA-negative subjects, there was a higher frequency of a focus score ≥2 (71% versus 53%; P = 0.002), a higher median focus score (2.8 versus 2.5; P = 0.0440), and greater exocrine gland dysfunction: Schirmer's test value: median 4 versus 5 mm/5 minutes; P = 0.0003, and unstimulated whole saliva (UWS) flow rate: median 0.08 versus 0.37 ml/5 minutes; P < 0.0001. ACA-positive subjects had an increased risk of UWS <0.1 ml/minute (odds ratio [OR] 12.24 [95% confidence interval (95% CI) 4.91-41.02]) and Schirmer's test value <5 mm/5 minutes (OR 2.52 [95% CI 1.50-4.36]) after correcting for age, sex, anti-SSA/SSB, and focus score. Labial gland fibrosis was not different between the 2 groups. CONCLUSION: In a large international registry of SS, ACA had an independent association with more severe exocrine glandular dysfunction. This dysfunction was associated with more pronounced labial salivary glandular inflammation but not fibrosis.

[Postradial sialozoadenitis in patients with papillary carcinoma of the thyroid gland].

The authors present the results of investigation of 42 patients with salivary gland dysfunction after radioactive iodine-131 ablation therapy concerning papillary thyroid carcinoma. Clinical manifestations of postradial sialodenitis with secretory insufficiency of different degree were revealed. These side effects required an application of the special therapy.

Preferential M2 macrophages contribute to fibrosis in IgG4-related dacryoadenitis and sialoadenitis, so-called Mikulicz's disease.

IgG4-related dacryoadenitis and sialoadenitis (IgG4-DS) is characterized by bilateral swelling of glandular tissues with extensive fibrosis, and is immunologically considered a Th2-predominant disease. Recent studies reported that alternatively activated (M2) macrophages enhanced Th2 immune responses and fibrosis by production of pro-fibrotic factors (IL-10, IL-13 and CCL18). Therefore, we examined the association between M2 macrophages and fibrosis in submandibular glands from 7 patients with IgG4-DS, 10 patients with chronic sialoadenitis, 10 patients with Sjögren's syndrome, and 10 healthy subjects. The number of M2 macrophages in SMGs from patients with IgG4-DS was also significantly higher than in the other groups. Double immunofluorescence staining showed that IL-10 and CCL18 expression co-localized with M2 macrophage-marker (CD163). Furthermore, the SMG fibrosis score was positively correlated with the frequency of M2 macrophages in only IgG4-DS. These results indicate that IL-10 and CCL18 secreted by preferential M2 macrophages possibly play a key role in the development of severe fibrosis in IgG4-DS.

Obstructive sialadenitis of a transplanted submandibular gland: chronic inflammation secondary to ductal obstruction.

AIMS: To determine the pathological basis and clinical features of obstructive sialadenitis in transplanted submandibular glands (SMGs). METHODS: A total of 161 patients (174 eyes) with keratoconjunctivitis sicca underwent microvascular SMG transplantation. Patients were followed up at approximately 1 and 4 months and annually thereafter. Clinical data, including dry eye discomfort, symptoms of ductal obstruction, and Schirmer test, were recorded. Sialography was performed in six patients. In addition, SMG autotransplantation was performed in 22 rabbits. Salivary flow was recorded and the morphology of glands was examined at 6 months postoperatively by light microscopy. RESULTS: Among the patients, 16 out of 172 glands during the latent period (0-3 months) and 2 out of 154 glands with long-term follow-up (>1 year) showed obstructive sialadenitis. Typical manifestations were continuous small volumes of viscous secretions, recurrent gland swelling, decreased Schirmer test values, and irregular dilation of the main duct on sialography. The transplanted SMGs eventually showed no secretion in five cases. Of the 22 rabbit SMGs, 4 had obstructive sialadenitis. Morphological examination showed chronic inflammatory infiltration with salivary deposits. CONCLUSIONS: Obstructive sialadenitis of transplanted SMGs is a chronic inflammation secondary to ductal obstruction, which leads to insufficient ocular lubrication and potential treatment failure.

Anesthesia mumps resulting in temporary facial nerve paralysis after the auditory brainstem implantation in a 3-year-old child.

An acute transient sialadenitis of the major salivary glands in the early postoperative period is called 'anesthesia mumps'. It has been reported in different surgical procedures especially in neurosurgical procedures. Anesthesia mumps develops very fast after the extubation period but it usually regresses with no sequelae within a few hours. However, sometimes serious complication can occur such as respiratory distress. In this report, we present a 3-year-old girl with an anesthesia mumps and facial palsy occurring after successful auditory brainstem implantation and we discuss the cause and the management of this rare complication in this report.

Prediction of risk for symptomatic sialadenitis by post-therapeutic dual (131)I scintigraphy in patients with differentiated thyroid cancer.

OBJECTIVE: The aim of this study is to predict the risk of symptomatic sialadenitis after (131)I therapy using the early (third day post-therapy) and delayed (fifth or sixth day post-therapy) post-therapeutic (131)I scintigraphy images in patients with differentiated thyroid cancer (DTC). METHODS: Included in the study were 112 patients with DTC who underwent early and delayed (131)I scans after (131)I treatment. All patients had normal salivary gland function on salivary scintigraphy performed in the week before the (131)I treatment. Scintigraphy images were visually analyzed and the salivary gland-to-background uptake ratio (SUR) and percent change of the SUR between early and delayed scans were calculated. Calculation of effective half-life and absorbed dose in the salivary glands was performed based on the MIRD schema. RESULTS: Of 112 patients, symptomatic sialadenitis was diagnosed in 46 patients (41 %). Of these 46 patients, 83 % (38 patients) had persistent (131)I uptake in the salivary glands on both early and delayed scans. Among 55 patients with persistent (131)I uptake in the salivary glands, 69 % experienced symptomatic sialadenitis, while only 14 % of the other 57 patients experienced symptomatic sialadenitis (p < 0.0001). On the early (131)I scintigraphy, SURs of bilateral parotid glands on early scan in patients with symptomatic sialadenitis were significantly higher than in other patients (p = 0.001 for right and p = 0.004 for left). Further, patients with symptomatic sialadenitis had a higher decreasing rate of the SUR and shorter effective half-life of (131)I in bilateral parotid glands than other patients. Using visual analysis and SURs of right and left parotid glands on early (131)I scan as parameters, the sensitivities for predicting symptomatic sialadenitis were 83, 80, and 93 %, respectively. The mean values of effective half-life and absorbed dose in the parotid and submandibular glands were 20.8 ± 6.3 h and 2.7 ± 0.8 Gy, and 22.1 ± 7.9 h and 2.8 ± 1.1 Gy, respectively. CONCLUSIONS: Symptomatic sialadenitis can be predicted by post-therapeutic (131)I scintigraphy with high sensitivity. Post-therapeutic (131)I scintigraphy could provide effective information on the risk of symptomatic sialadenitis in DTC patients who underwent (131)I treatment.

[Importance of salivary gland focus score in the diagnosis of Sjögren's syndrome].

OBJECTIVE: To explore the correlation between labial salivary gland focus score (FS) and severity of Sjögren's syndrome patients. METHODS: From January 2009 to December 2010, a total of 77 patients with primary Sjögren's syndrome were recruited to undergo minor salivary gland biopsy, Schirmer's test, unstimulated whole salivary flow, organ function and serological test. Focus score was calculated for all biopsy samples. And the correlation between focus score and serological test and organ function damage was evaluated. RESULTS: Their pathological examinations revealed focal lymphocytic sialadenitis (n = 62), 10 cases with non-specific or sclerosing chronic sialadenitis (n = 10) and normal features (n = 5). Among 62 cases with focal lymphocytic sialadenitis, 46 cases had FS ≥ 1 and another 16 FS < 1. The median FS was 2.4 ± 2.5 . FS ≥ 1 was strongly associated with unstimulated whole salivary flow rates and ocular staining score (P < 0.05), but not significantly with dry mouth or eyes. FS was significantly correlated with serum immunoglobin G (IgG), immunoglobin M (IgM) and rheumatoid factor level (P < 0.05). Those with positive anti-SSA had higher FS level than those with negative anti-SSA antibody (P < 0.05). In addition, FS level was not significantly associated with organ function damage. CONCLUSION: Prior to determining FS, distinguishing focal lymphocytic sialadenitis from other types of sialadenitis is essential in assessing salivary gland biopsy. And the FS level might be associated with disease activity and positive anti-SSA. No correlation exists between FS and organ function damage.

Morphometric and functional changes of salivary gland dysfunction after radioactive iodine ablation in a murine model.

BACKGROUND: Ablation of the thyroid tissue using radioactive iodine (RAI) after the surgical removal of well-differentiated thyroid cancer can induce radiation-related salivary gland (SG) dysfunction. However, in vivo changes of SGs after RAI administration in appropriate animal models are not well described in the literature. This study was undertaken to document morphometric and functional changes during the 12 months after RAI administration in a murine model of RAI-induced SG dysfunction. METHODS: Four-week-old female C57BL/6 mice (n = 60) were divided into an RAI-treated group (n = 30) that received RAI orally (0.01 mCi/g body weight) and an unexposed control group (n = 30). Mice in both groups were divided into five subgroups (n = 6 per subgroup) and euthanized at 1, 2, 3, 6, and 12 months post-RAI administration. Salivary flow rates and salivary lag times were measured at 1, 2, 3, 6, and 12 months after RAI administration. Morphological and histological examinations and terminal deoxynucleotidyl transferase dUTP nick end labeling assays were performed. In addition, changes in salivary (99m)Tc pertechnetate uptake and excretion were observed by single-photon emission computed tomography. RESULTS: In RAI-treated mice, the SGs were significantly lighter than those of unexposed controls at all study time points. Lag times to salivation in the RAI-treated group were greater than in the unexposed controls, but mean salivary flow rates were lower. Histologic examinations of SGs in the RAI group showed pale cytoplasm, atypical ductal configuration, septal widening, cytoplasmic vacuolization with pleomorphism, lymphocyte infiltration, and increased fibrosis. Furthermore, more apoptotic cells were observed in acini and ducts in the RAI group. In addition, patterns of (99m)Tc pertechnetate uptake and excretion in the RAI group were quite different from those observed in controls at 1 and 12 months post-RAI. CONCLUSION: Various histological alterations were observed in mice exposed to RAI, that is, an increase in apoptotic acini and ductal cells and functional SG deterioration. The murine model of RAI-induced SG dysfunction used in the present study appears to be applicable to preclinical research on RAI-induced sialadenitis in patients with well-differentiated thyroid cancer.

Salivary gland function 5 years after radioactive iodine ablation in patients with differentiated thyroid cancer: direct comparison of pre- and postablation scintigraphies and their relation to xerostomia symptoms.

BACKGROUND: Chronic sialadenitis is one of the most frequent chronic complications after radioactive iodine (RAI) therapy for thyroid cancer. To evaluate the long-term effects of RAI ablation on salivary gland function, we investigated scintigraphic changes in salivary glands by direct comparison of two salivary gland scintigraphies (SGSs) taken before and at 5 years after an RAI ablation. METHODS: SGS was performed just before RAI ablation (pre-SGS) and ∼5 years after RAI ablation (F/U SGS) in 213 subjects who underwent thyroidectomy for thyroid cancer. The uptake score (U score) was graded, and the ejection fraction (EF) was quantified for the parotid and submandibular glands at pre-SGS and F/U SGS. Changes in salivary gland function were graded as mild, moderate, or severe according to the differences in U score and EF between the two SGSs. Xerostomia was assessed and compared with the SGS findings. RESULTS: Worsening of the U score was observed in 182 of 852 salivary glands (total: 21.3%; mild: 4.2%, moderate: 7.4%, severe: 9.7%), and 47.4% of the patients had a worsening U score for at least one of four salivary glands. A decrease in EF was observed in 173 of 852 salivary glands (total: 20.3%; mild: 5.4%, moderate: 6.8%, severe: 8.1%), and 43.7% of the patients experienced a decrease in the EF of at least one of the four salivary glands. Bilateral parotid gland dysfunction was the most commonly observed condition. Thirty-five (16.4%) patients complained of xerostomia at 5 years after RAI ablation. Scintigraphic changes in salivary gland function and xerostomia were more common in patients receiving 5.55 GBq, compared with 3.7 GBq. Xerostomia was more common in patients with submandibular gland dysfunction than those with parotid gland dysfunction (68.8% vs. 33.3%, p<0.05). The number of dysfunctional salivary glands was correlated with xerostomia (p<0.01). CONCLUSION: About 20% of the salivary glands were dysfunctional on SGS 5 years after a single RAI ablation, especially in patients who received higher doses of RAI. While parotid glands are more susceptible to (131)I-related damage, xerostomia was more associated with submandibular gland dysfunction and the prevalence of dysfunctional salivary glands.

[Progress in understanding the pathogenesis of Sjögren's syndrome in non-obese diabetic mice].

Sjögren's syndrome is a chronic autoimmune disease, the pathogenesis of which still remains to be explored. Non-obese diabetic (NOD) mouse, presenting impairment of secretory function as well as the development of sialoadenitis, which is in common with human Sjögren's syndrome, is considered as one of the appropriate animal models for the study of Sjögren's syndrome. With regard to genetic factors, apoptosis, autoantibodies and cytokines, this paper reviewed the progress in understanding the pathogenesis of Sjögren's syndrome in NOD mice.

Inducible tertiary lymphoid structures, autoimmunity, and exocrine dysfunction in a novel model of salivary gland inflammation in C57BL/6 mice.

Salivary glands in patients with Sjögren's syndrome (SS) develop ectopic lymphoid structures (ELS) characterized by B/T cell compartmentalization, the formation of high endothelial venules, follicular dendritic cell networks, functional B cell activation with expression of activation-induced cytidine deaminase, as well as local differentiation of autoreactive plasma cells. The mechanisms that trigger ELS formation, autoimmunity, and exocrine dysfunction in SS are largely unknown. In this article, we present a novel model of inducible ectopic lymphoid tissue formation, breach of humoral self-tolerance, and salivary hypofunction after delivery of a replication-deficient adenovirus-5 in submandibular glands of C57BL/6 mice through retrograde excretory duct cannulation. In this model, inflammation rapidly and consistently evolves from diffuse infiltration toward the development of SS-like periductal lymphoid aggregates within 2 wk from AdV delivery. These infiltrates progressively acquire ELS features and support functional GL7(+)/activation-induced cytidine deaminase(+) germinal centers. Formation of ELS is preceded by ectopic expression of lymphoid chemokines CXCL13, CCL19, and lymphotoxin-ß, and is associated with development of anti-nuclear Abs in up to 75% of mice. Finally, reduction in salivary flow was observed over 3 wk post-AdV infection, consistent with exocrine gland dysfunction as a consequence of the inflammatory response. This novel model has the potential to unravel the cellular and molecular mechanisms that regulate ELS formation and their role in exocrine dysfunction and autoimmunity in SS.

Temporal changes in salivary glands of non-obese diabetic mice as a model for Sjögren's syndrome.

OBJECTIVE: Non-obese diabetic (NOD) mice develop an autoimmune exocrinopathy that shows similarities with Sjögren's syndrome. They provide an experimental model to study the pathoetiogenesis of this disease. MATERIALS AND METHODS: Salivary gland (SG) function and salivary sodium content were measured in 8-, 12-, 16- and 20-week-old NOD and age-matched CB6 mice. In NOD mice, SG expression of phenotypic cell markers, B cell-stimulating and costimulatory molecules were evaluated. Cytokine levels were measured in serum and SG homogenates. RESULTS: Microscopically evident SG inflammation in NOD mice was preceded by expression of intercellular adhesion molecule 1 on epithelial cells in the presence of macrophages and relatively high levels of cytokines. Next, an influx consisting of mainly T, B, natural killer, plasma and dendritic cells was seen. Most cytokines, except for interleukin (IL)12/IL23p40 and B cell-activating factor, decreased or remained stable over time, while glandular function deteriorated from 16 weeks of age onward compared with CB6 mice. CONCLUSION: Sjögren's syndrome-like disease in NOD mice occurs in multiple stages; immunological and physiological abnormalities can be detected before focal inflammation appears and salivary output declines. Extrapolating this knowledge to human subjects could help in understanding the pathogenesis and aid the identification of potential therapeutic targets.

Acute sialadenitis secondary to submandibular calculi after botulinum neurotoxin injection for sialorrhea in a child with cerebral palsy.

Children with cerebral palsy and other neurologic diseases often present with sialorrhea. Intraglandular botulinum neurotoxin is being increasingly reported to be clinically effective for the treatment of sialorrhea. This treatment is becoming more popular in recent years because of being less invasive than surgical procedures. In addition, fewer adverse effects have been documented compared with oral or topical anticholinergic medication. We report the first case in a child with cerebral palsy who developed serious acute sialadenitis with submandibular sialolithiasis after intraglandular botulinum neurotoxin injection for sialorrhea.

Dysfunction of lacrimal and salivary glands in Sjögren's syndrome: nonimmunologic injury in preinflammatory phase and mouse model.

Sjögren's syndrome (SjS) is a chronic autoimmune disorder characterized by dry eyes and dry mouth due to dacryoadenitis and sialoadenitis with SS-A/Ro and/or SS-B/La autoantibodies in genetically predisposed individuals. Destruction of lacrimal and salivary glands by autoimmune reactions may lead to clinical manifestation. However, the mechanisms behind the decreased volume of secretions in tears and saliva are complex and are not fully understood. Exocrine gland dysfunction may precede autoimmunity (acquired immunity) or represent a process independent from inflammation in the pathogenesis of SjS. The preceded functional and morphologic changes of those tissues by nonimmunologic injury before the development of inflammation at the sites of target organs have been implicated. This paper focuses on the several factors and components relating to glandular dysfunction and morphologic changes by nonimmunologic injury during the preinflammatory phase in mouse model, including the factors which link between innate immunity and adaptive immunity.

Protein and mucin retention on oral mucosal surfaces in dry mouth patients.

Oral homeostasis depends largely on proteins and mucins present in saliva that coat all oral surfaces. The present study compared the protein composition of residual fluid on mucosal surfaces in subjects with normal salivary flow with that of patients with dry mouth caused by salivary hypofunction. Samples of residual mucosal fluid were collected using paper strips and then analysed by protein electrophoresis and immunoblotting. In both patients and controls, residual fluids on mucosal surfaces (except the anterior tongue in control subjects) had higher protein concentrations than unstimulated whole-mouth saliva. High-molecular-weight mucin (MUC5B) was present in greater amounts on the anterior tongue than on other surfaces in control subjects. In dry mouth patients who were unable to provide a measurable saliva sample, MUC5B was often still present on all mucosal surfaces but in reduced amounts on the anterior tongue. The membrane-bound mucin, MUC1, was prominent on buccal and labial surfaces in patients and controls. Statherin was still present on surfaces that were dried to remove salivary fluid, suggesting that it may be adsorbed as a protein pellicle. It is concluded that oral mucosal surfaces in dry mouth patients can retain MUC5B and other salivary proteins, although the functional integrity of these proteins is uncertain.