Increased Expression of the lncRNA NRON Along With NFATc1/PIM-1 in Labial Salivary Glands of Sjögren's Syndrome Patients.

The aim of our study was to analyze the expressions of nuclear factor of activated T cells (NFAT)-related substances including long noncoding RNA NRON which participates in pathophysiology of Sjögren's syndrome (SS), and to assess the histologic findings in individuals with SS. In this study, the expressions of NRON, NFATc1, CD3/CD4, and proviral integration site for Moloney murine leukemia virus (PIM)-1 were examined by in situ hybridization, immunohistochemical analysis, and immunofluorescence in labial salivary glands (LSGs) obtained from 16 patients with SS and five controls. The microcell count method has been applied to calculate the NFATc1-positive area/infiltrating cell area in LSGs, and we compared those results to the infiltrating cell area, focus score, serum immunoglobulin G, and the European League Against Rheumatism Sjögren's Syndrome Disease Activity Index. The NRON expression in the nuclei of cell-infiltration lesions of the SS patients were prominent. The NFATc1 expression was strong in the cytoplasm of infiltrating mononuclear cells and weak in ducts of both SS and controls. In SS, the NFATc1-positive area/infiltrating cell area was positively correlated with the infiltrating cell area and focus score. CD3/CD4 was expressed in infiltrating mononuclear cells, and PIM-1 colocalized with NFATc1 in the cytoplasm. These results suggest NRON along with NFATc1/PIM-1 in SS LSGs might participate in SS pathophysiology.

Comparison of the quantitative measurement of 18F-FDG PET/CT and histopathological findings in IgG4-related disease.

OBJECTIVES: To investigate the utility of 18F-FDG PET/CT in the diagnostic procedure of IgG4-related disease (IgG4-RD), we analysed the association between quantitative method of 18F-FDG PET/CT and histological findings. METHODS: Twenty-one patients with IgG4-RD in whom 18F-FDG PET/CT was performed at the time of diagnosis were enrolled. Tissue biopsy was performed at 24 sites in 21 patients. To perform quantitative analysis of 18F-FDG PET/CT imaging, the highest standardised uptake value (SUV) of the pixels (SUVmax) and the average SUV (SUVmean) within the biopsied lesion were measured. The SUVmean of the liver was also measured as a reference. RESULTS: The mean age at diagnosis was 64.6±11.9 years, and the median serum IgG4 level was 650 mg/dl. Histological findings were consistent with IgG4-RD (histopathology-positive) at 19 out of 24 sites. Although there was no significant difference in the values of SUVmax between histopathology-positive and histopathology-negative tissues, the values of SUVmean were significantly higher in the histopathology-positive tissue (4.98 and 3.54, respectively p<0.05). The values of SUVmean/liver were also higher in the histopathology-positive tissue (2.17 and 1.52, respectively p<0.05). To establish a cut-off value of SUVmean to determine which of multiple lesions should be biopsied, a ROC curve was constructed. ROC curve analysis indicated SUVmean=4.07 or SUVmean/liver=1.66 as a cut-off value. CONCLUSIONS: Our present study suggested that quantitative analysis of 18F-FDG-PET/CT imaging might be useful for selecting the biopsy site in IgG4-RD. The calculation of SUVmean, not of SUVmax, is important for evaluating IgG4-RD-related lesions in 18F-FDG PET/CT imaging.

Life prognosis and renal relapse after induction therapy in Japanese patients with proliferative and pure membranous lupus nephritis.

OBJECTIVE: We aimed to compare life prognosis and renal relapse after induction therapy in proliferative (PLN) and pure membranous LN (MLN). METHODS: We retrospectively analysed the cases of 140 of 172 patients with LN who underwent a renal biopsy at our hospital or community hospitals from 1993 to 2016. We determined the complete response (CR) rate at 12 months after the patients had started induction therapy, and we evaluated the predictive factors for CR, life prognosis and renal relapse in PLN and pure MLN. We defined PLN as International Society of Neurology and the Renal Pathology Society (ISN/RPS) Class III or IV and MLN as ISN/RPS Class V. RESULTS: The renal pathology of 99 (70.7%) patients was classified as PLN, and that of the other 41 (29.3%) patients as MLN. Fifty patients (50.5%) with PLN and 22 patients (53.7%) with MLN achieved a CR at 12 months. A multivariate analysis showed that a lower index of chronicity in PLN and a higher total haemolytic complement (CH50) level in MLN were predictive factors for achieving a CR at 12 months. A Kaplan-Meier analysis showed that the life prognosis (P = 0.93) and renal relapse (P = 0.52) were not significantly different between PLN and MLN. CONCLUSIONS: The predictive factors for a CR at 12 months post-induction therapy were index of chronicity in PLN and CH50 level in MLN. There were no significant differences in life prognosis or renal relapse between PLN and MLN in the achievement of a CR at 12 months post-induction therapy.

Comparison of complete renal response and mortality in early- and late-onset lupus nephritis: a multicenter retrospective study of a Japanese cohort.

BACKGROUND: Most patients with systemic lupus erythematosus (SLE) progress to lupus nephritis (LN) within 5 years of their SLE diagnosis, although it is not uncommon for LN to develop at later time points. Here we evaluated the clinical features of early- and late-onset LN. PATIENTS AND METHODS: We retrospectively analyzed the cases of 184 of the 201 patients who underwent a renal biopsy at Nagasaki University Hospital and associated community hospitals between 1990 and 2016 and were diagnosed as having LN. Early onset was defined as the development of LN within the first 5 years after the patient's SLE diagnosis, and late onset was defined as LN development > 5 years post-diagnosis. We analyzed the complete renal response (CR) at 6 and 12 months after induction therapy, the classification of renal pathology, and the mortality of the early- and late-onset LN groups. RESULTS: The mean follow-up duration after the renal biopsy was 123 ± 85 months. There were 113 (61.4%) early-onset patients and 71 (38.6%) late-onset patients. A multivariate analysis revealed that the following factors were predictive of CR: at 6 months: female sex (odds ratio [OR] 3.93, 95% confidence interval [CI] 1.31-11.77, p = 0.010), proteinuria (OR 0.83, 95% CI 0.71-0.97, p = 0.009), index of activity (0-24) (OR 0.83, 95% CI 0.70-0.99, p = 0.030), and early-onset LN (OR 2.39, 95% CI 1.15-4.98, p = 0.018); at 12 months: female sex (OR 3.60, 95% CI 1.32-9.83, p = 0.013), mixed LN (OR 0.18, 95% CI 0.04-0.80, p = 0.024), index of activity (0-24) (OR 0.80, 95% CI 0.68-0.94, p = 0.007), and early-onset LN (OR 2.10, 95% CI 1.05-4.23, p = 0.035). In a Cox proportional hazards and Fine-Gray regression model, the early-onset LN group had a significantly better mortality rate than the late-onset LN group (p = 0.038 and p = 0.043, respectively). CONCLUSIONS: In our cohort, early-onset LN was a better predictor of CR at 6 and 12 months than late-onset LN. Our results suggest that early-onset LN patients had lower mortality than late-onset LN patients.

IgA Vasculitis Triggered by Infective Endocarditis of Pulmonary Artery with Congenitally Corrected Transposition of the Great Arteries.

A man in his 40s with a history of congenitally corrected transposition of the great arteries (CCTGA) and closure of ventricular septal defect was referred to our hospital with purpura and hematuria. Presence of purpura, renal damage, and pathological findings on skin biopsy led to the diagnosis of IgA vasculitis (IgAV). Oral prednisolone (PSL) was initiated. However, Streptococcus pseudoporcinus was isolated from blood cultures, and transthoracic echocardiogram revealed vegetation on the pulmonary valve. From these findings, the diagnosis of infective endocarditis (IE) was made. Although the patient's condition improved after PSL interruption and antibiotic administration, his purpura relapsed. PSL readministration improved symptoms, with no further relapse even after gradual PSL dose reduction. The present case raises awareness of the importance of recognizing the occurrence of IE in IgAV patients, especially in those with congenital heart disease. CCTGA should be acknowledged as a risk factor for IE in the right-sided heart.

Development of hypocomplementemic urticarial vasculitis during certolizumab pegol treatment for rheumatoid arthritis: A case report.

WHAT IS KNOWN AND OBJECTIVE: Tumour necrosis factor-α-blocking agents potentially cause vasculitis. However, no study has reported on the association between hypocomplementemic urticarial vasculitis (HUV) and certolizumab pegol (CZP) usage. CASE DESCRIPTION: We present the first case of HUV development during CZP treatment for rheumatoid arthritis. Hypocomplementemic urticarial vasculitis improved after CZP was discontinued and the dose of oral prednisolone was increased. WHAT IS NEW AND CONCLUSION: Clinicians should be aware about the potential development of HUV during CZP treatment, which is presumed to be safe considering its unique structural characteristics that differ from those of other tumour necrosis factor-α-blocking agents.

Swollen joints and peripheral arthritis are signs of malignancy in polymyalgia rheumatica.

Aim: To analyze the clinical course and prognosis in patients diagnosed with polymyalgia rheumatica (PMR) complicated by the presence of malignancies.Methods: We retrospectively screened the case files of 216 patients hospitalized in our department between 2011 and December 2016 for the results of a thorough physical examination and data on treatment for rheumatic diseases. We identified 53 patients with PMR according to Bird's criteria and 43 patients with 2012 European League Against Rheumatism (EULAR)/American College of Rheumatology (ACR) classification criteria for PMR, then analyzed the clinical and serologic manifestations of PMR in patients with (n = 6) and without (n = 47 in Bird' criteria, n = 37 in 2012 EULAR/ACR criteria) malignancy.Result: No significant differences in age, gender, smoking, and serum markers were observed between PMR patients with and without malignancy, but there were statistically significant differences in tender joint counts and the presence of swollen joints and peripheral arthritis in both Bird's criteria and 2012 EULAR/ACR criteria.Conclusion: The presence of swollen joints and peripheral arthritis may be useful signs that indicate the coexistence of malignancies in patients with PMR.

Giant Cell Arteritis with Generalized Granuloma Annulare.

We report the case of an 80-year-old man with generalized granuloma annulare (GGA) who subsequently developed giant cell arteritis (GCA). Steroid treatment was effective for both diseases in this case. Although cases of concomitant GGA and GCA have rarely been reported, previous studies suggest that common histological characteristics underlie the two diseases. It is therefore necessary to recognize that GGA can be complicated by GCA, particularly when typical symptoms, such as headache and visual disturbance, are present.

Serum cytokine profiles and Mac-2 binding protein glycosylation isomer (M2BPGi) level in patients with autoimmune hepatitis.

Autoimmune hepatitis (AIH) is an autoimmune liver disease that is characterized by a progressive destruction of the liver parenchyma and the development of liver fibrosis. We aimed to examine the relationship between circulating cytokines/chemokines and the Mac-2 binding protein glycosylation isomer (M2BPGi) levels in Japanese patients with autoimmune hepatitis (AIH).We investigated the relationship between circulating cytokines/chemokines and M2BPGi levels in Japanese patients with AIH. Seventy-seven patients with well-documented AIH were enrolled in the National Hospital Organization (NHO)-AIH-liver-network database. We measured the serum levels of 20 cytokines in 31 selected AIH patients before and after steroid treatment using multisuspension cytokine array.Eleven cytokines and soluble adhesion molecules were increased in untreated AIH patients compared with treated AIH patients. Among these cytokines and soluble adhesion molecules, soluble intercellular adhesion molecule-1 (sICAM-1) and interferon-γ-inducible protein 10 (IP-10) were most downregulated by steroid therapy in AIH patients. We measured serum sICAM-1 and IP-10 by ELISA and found the levels were significantly higher in AIH patients (n = 77) compared with chronic viral hepatitis C patients (n = 32). Furthermore, there was a positive correlation between sICAM-1 or IP-10 and alanine aminotransferase, total bilirubin, and circulating M2BPGi levels. M2BPGi levels were increased in AIH patients with high stages of liver fibrosis. Additionally, M2BPGi levels were correlated with the histological grade of inflammation in AIH. Circulating M2BPGi levels were significantly reduced by steroid treatment in AIH patients.sICAM-1 and IP-10 are useful markers to assess immune-mediated hepatitis activity in AIH and they correlate with circulating M2BPGi. Serum M2BPGi levels increased in untreated AIH patients with active hepatitis and were decreased by steroid therapy. M2BPGi reflects autoimmune-mediated hepatic inflammation as well as liver fibrosis.

Podocyte foot process width is a prediction marker for complete renal response at 6 and 12 months after induction therapy in lupus nephritis.

Morphological change that includes diffuse effacement of podocyte foot processes is correlated with proteinuria in patients with lupus nephritis (LN). We collected the data of clinico-pathological parameters and assessed foot process width (FPW) as an index of podocyte effacement in 73 patients with LN who had undergone renal biopsy. The multivariate analysis revealed that female gender (OR: 5.288; 95%CI: 1.197-37.29; p = .0267) and FPW (OR = 0.999, 95%CI = 0.997-0.999, p = .0150) were significantly predictive of a complete renal response (CR) at 6 months, while lymphocyte counts (OR = 1.002; 95%CI = 1.001-1.003, p = .0028) and FPW (OR = 0.998, 95%CI = 0.996-0.999, p = .0027) were significantly predictive of CR at 12 months. The cut-off point determined by the Classification and Regression Trees algorithm showed that FPW <908.3 nm provides the best performance for predicting patients who achieve CR at 12 months. A smaller FPW appears to be a predictive factor for CR at 6 and 12 months after induction therapy.

Modulation of Apoptosis by Cytotoxic Mediators and Cell-Survival Molecules in Sjögren's Syndrome.

The pathogenesis of Sjögren's syndrome (SS) involves multiple factors including genetic background, cell death, and exocrine dysfunction. We here discuss apoptotic control in exocrine glands in SS by showing various pro- and anti-apoptotic pathways. Although the membrane-bound and soluble form of the Fas/Fas ligand system is a leading player with activation of the death domain and caspase 8/3 cleavage, the role of soluble Fas/FasL (including its polymorphism) in apoptosis is controversial. The tumor necrosis factor related apoptosis-inducing ligand (TRAIL)-mediated apoptosis of salivary gland epithelial cells (SGECs) involves a mitochondrial pathway that includes caspase 9 cleavage. The involvement of innate immunity cells such as toll-like receptors (TLRs) has been investigated; TLR2-4 and TLR7-9 are associated with the induction of inflammation in exocrine glands of SS patients. TLR3 has the potential to induce the apoptosis of SS patients' SGECs. Linkage of epidermal growth factor (EGF) was shown in exocrine glands in SS, and it inhibited the Fas/FasL system with the help of cell-survival factors. TLR3 has dual actions to cause inflammation as well as apoptosis, which are inhibited by EGF. In conclusion, apoptosis in exocrine glands of SS patients is tightly controlled by balance of pro-apoptotic signals and growth factor.

Combined classification system based on ACR/EULAR and ultrasonographic scores for improving the diagnosis of Sjögren's syndrome.

We retrospectively evaluated the effectiveness of combined use of salivary gland ultrasonography (US) and the 2016 American College of Rheumatology/European League Against Rheumatic Disease (ACR/EULAR) classification criteria for improving the diagnostic efficiency in patients with Sjögren's syndrome (SS). A US-based salivary gland disease grading system was developed using a cohort comprising 213 SS or non-SS patients who fulfilled the minimum requirements for classifying SS based on the American-European Consensus Group (AECG) and ACR criteria. Using 62 SS or non-SS patients from the 213 patients and who had also undergone all the 5 examinations needed for the ACR/EULAR classification, we compared the diagnostic accuracy of various combinations of the ACR/EULAR and US classifications for diagnosing SS, using the clinical diagnosis of SS by rheumatologists as the gold standard. The ACR/EULAR criteria discriminated clinical SS patients with 77% and 79% accuracy for those with primary or secondary SS and for those with primary SS, respectively. However, the integrated score system of the ACR/EULAR and US classifications yielded 92% and 93% accuracy for these 2 SS patient groups, respectively, provided that US score of 3 was assigned to patients with US grade ≥2, and then patients with integrated threshold score of ≥5 were diagnosed as SS. Cross-validation also indicated improved accuracy of the integrated ACR/EULAR and US score system (91.9 and 93.0% for primary/secondary and primary SS patients, respectively) over that by the ACR/EULAR criteria alone. (74.2 and 86.0%, respectively). The integrated ACR/EULAR and US scoring system can improve the diagnosis of patients with clinical SS.

Detection of human T lymphotropic virus type-I bZIP factor and tax in the salivary glands of Sjögren's syndrome patients.

OBJECTIVES: To detect HTLV-I bZIP factor (HBZ), tax and relevant molecules in labial salivary glands (LSGs) from patients with Sjögren's syndrome (SS). METHODS: The expressions of HBZ and tax in T cell lines and LSGs were analysed by in situ hybridization (ISH) or real time PCR. The expressions of forkhead box P3 (Foxp3) and p65 in immunohistochemistry were quantified. RESULTS: After specificity of ISH probes was determined in 5 T cell lines, in LSGs from an adult T-cell leukemia (ATL) patient and 3 HTLV-I-associated myelopathy (HAM)-SS patients, both HBZ and tax signals were detected in infiltrating mononuclear cells (MNCs) and ducts, and HBZ and tax were dominantly expressed in MNCs of ATL and HAM-SS, respectively. HBZ was dominantly observed in LSGs from 8 HTLV-I asymptomatic carrier (AC)-SS patients; faint expression of HBZ was observed in LSGs from 5 HTLV-I-seronegative SS patients. No cell adhesion molecule 1(CADM1) expressed in LSGs from the ATL patient. Although Foxp3 expression was observed in LSG MNCs of all of the SS patients, the ATL patient's expression was significantly greater than that of the AC-SS (p<0.01) and HTLV-I-seronegative SS (p<0.01) patients. The Foxp3 expression was similar in ATL and HAMSS, but significantly higher in HAM-SS than AC-SS (p<0.05). p65 was expressed in LSG MNC nuclei from all SS patients and co-expressed with Foxp3. The expressions of Foxp3 in ducts differed according to HTLV-I infection. CONCLUSIONS: These results suggest that HBZ-mediated Foxp3 expression is partly associated with the pathogenesis of HTLV-I-seropositive SS.

Efficacy of infliximab as a switched biologic in rheumatoid arthritis patients in daily clinical practice.

To assess the efficacy and safety of switching to infliximab (IFX) from other biological disease-modifying anti-rheumatic drugs (bDMARDs) among Japanese patients with rheumatoid arthritis (RA) in daily practice. We examined 24 consecutive RA patients who had not achieved low disease activity (LDA) as the disease activity score-28 for rheumatoid arthritis with erythrocyte sedimentation rate (DAS28-ESR) despite previous bDMARD therapy in this cohort study. We attempted to determine predictive variables that are associated with achieving DAS28-ESR LDA at 22 weeks post-IFX introduction, by performing univariate analysis. The median DAS28-ESR at baseline was 5.41. Sixteen patients (66.7%) had been treated with a tumor necrosis factor inhibitor (TNF-i), and the other eight patients (33.3%) received a non-TNF-i (abatacept or tocilizumab). Nine patients (37.5%) achieved LDA or remission at 22 weeks. Univariate analyses showed that the variable to predict LDA achievement at 22 weeks was tender joints (>8 counts) at baseline (adjusted odds ratio, 0.10; 95% confidence interval, 0.01-0.63; p = .02). Nine adverse events were observed during the study period, and infection requiring hospitalization was observed in one patient. Switching to IFX is effective to achieve LDA or remission for RA patients refractory to bDMARDs.

[Coexistence of Takayasu's arteritis and inflammatory colitis detected by fluorodeoxyglucose positron emission tomography].

  A woman in her thirties was diagnosed as Takayasu's arteritis (TAK) by dilatation, wall thickness of her abdominal aorta in contrast-enhanced computed tomography. Although she didn't have any subjective bowel symptoms, fluorodeoxyglucose (FDG)-positron emission tomography (PET) also revealed uptake of FDG in descending colon, and colonoscopy revealed aphthous colitis. After the start of steroid therapy, both arteritis and colitis were improved. FDG-PET can detect TAK and inflammatory bowel diseases at an early stage. FDG-PET is a less invasive module with a high sensitivity for detecting colitis, therefore should be considered for TAK even without physical colon symptoms.

Effectiveness of abatacept for patients with Sjögren's syndrome associated with rheumatoid arthritis. An open label, multicenter, one-year, prospective study: ROSE (Rheumatoid Arthritis with Orencia Trial toward Sjögren's syndrome Endocrinopathy) trial.

OBJECTIVE: To clarify the efficacy and safety of abatacept for secondary Sjögren's syndrome (SS) associated with rheumatoid arthritis (RA). METHODS: The primary endpoint of this open-labeled, prospective, observational multicenter study for secondary SS with RA was the remission rate of Simplified Disease Activity Index (SDAI) at 52 weeks after initiation of abatacept. The secondary endpoints included Saxon's test and Schirmer's test. Adverse events and adherence rate during the study period were also analyzed. RESULTS: Thirty-six patients (all females) were enrolled in this study. The mean SDAI decreased significantly from 20.6 ± 11.2 (±SD) at baseline to 10.0 ± 10.5 at 52 weeks (p < 0.05). Patients with SDAI remission increased from 0 (0 week) to 12 patients (33.3%) at 52 weeks. Saliva volume assessed by Saxon's test increased significantly from 2136 ± 1809 (0 week) to 2397 ± 1878 (24 weeks) mg/2 min (n = 34, p < 0.05). Saliva volume increased significantly from 2945 ± 2090 (0 week) to 3419 ± 2121 (24 weeks) mg/2 min in 11 patients with Greenspan grade 1 or 2 of labial salivary gland biopsy (p < 0.05), but no change was noted in 18 patients with Greenspan grade 3 or 4. Tear volume by Schirmer's test increased significantly from 4.2 ± 4.8 (0 week) to 6.4 ± 7.8 (24 weeks) mm/5 min (n = 30, p < 0.05). The adherence rate to abatacept was 80.6% (29/36) over the 52-week period. Twelve adverse events occurred in 10 of the 36 patients, and 7 of these events were infections. CONCLUSION: Abatacept seems to be effective for both RA and SS related manifestations.

Pulmonary Nocardiosis Caused by Nocardia concava with a Literature Review.

A 68-year-old man was admitted to our hospital with anorexia and leg pain. He was diagnosed with ANCA-associated vasculitis through a renal biopsy. Immunosuppression with two courses of steroid pulse therapies and intravenous cyclophosphamide followed by oral prednisolone at 40 mg/day were administered. About one month after starting the immunosuppression therapy, he complained of hemosputum. Chest computed tomography showed a cavitary lesion in the lung. Cultures from his sputum showed Nocardia species, and we were able to identify the species as N. concava using a 16S rRNA gene sequence analysis. Only three detailed reports of N. concava infection have so far been published worldwide.

Predictors of clinical outcomes in patients with neuropsychiatric systemic lupus erythematosus.

INTRODUCTION: Neuropsychiatric systemic lupus erythematosus (NPSLE), a serious organ disorder with a variety of symptoms, has diverse therapeutic outcomes because of the variability of NPSLE manifestations. A comprehensive association study of NPSLE among clinical and immunopathogenic aspects and outcomes has not been conducted. METHODS: We analyzed the laboratory data, NPSLE symptoms, and clinical outcomes at 1yr post-treatment and the profiles of 27 cytokines, chemokines and growth factors in cerebrospinal fluid (CSF) samples using the Bio-Plex Human 27-plex panel from 28 NPSLE patients. Univariate and multivariable competing risks regression analyses were used to determine the predictive factors of clinical response. We also tried to predict the outcome of NPSLE by the 27 cytokines/chemokines/growth factors using a weighted-voting (WV) algorithm. RESULTS: Of the two males and 26 females (92.9%), 16 were non-responders at 1yr post-treatment; in the final model, the independent predictors of non-responders were longer disease durations of SLE (odds ratio [OR]: 1.490, 95% confidence interval [CI]: 1.143-2.461, p=0.0003) and patients with more than one NPSLE symptom types (OR: 15.14, 95% CI: 1.227-452.1, p=0.0334). The pretreatment CSF interleukin (IL)-6, IL-10, interferon-gamma (IFN-γ) and tumor necrosis factor-alpha (TNF-α) levels were significantly higher in the non-responders (p=0.0207, p=0.0054, p=0.0242 and p=0.0077, respectively). We identified six "minimum predictive markers:" IL-10, TNF-α, IL-6, IFN-γ, IL-4 and IL-13 by a WV algorithm that showed the highest accuracy (70.83%) and highest Matthews correlation coefficient (54.23%). CONCLUSIONS: We have devised a numerical prediction scoring system that was able to separate the non-responders from responders. The patients with longer disease durations of SLE and those with more than one NPSLE symptom types had poorer outcomes. Our findings may indicate both the importance of making a diagnosis at an earlier phase for better therapeutic response and the usefulness of measuring multiple cytokines to predict NPSLE therapeutic outcomes.

Abnormal distribution of AQP5 in labial salivary glands is associated with poor saliva secretion in patients with Sjögren's syndrome including neuromyelitis optica complicated patients.

OBJECTIVE: To investigate whether aquaporins (AQPs) are involved in salivary gland dysfunction in patients with neuromyelitis optica (NMO) complicated with Sjögren's syndrome (SS). METHODS: Eight primary SS (pSS) patients, four NMO spectrum disorder (NMOsd) patients complicated with SS (NMOsd-SS), and three control subjects were enrolled. Immunohistochemistry of labial salivary glands (LSGs) was performed to determine the expressions of AQP4, AQP5, and tumor necrosis factor-alpha (TNF-α). In vitro expression of AQP5 was examined by Western blotting in cultured primary salivary gland epithelial cells (SGECs). RESULTS: No expression of AQP4 was shown in all LSGs. AQP5 was clearly expressed in the all acini, but the predominant localization of AQP5 in the apical side was diminished in the patients with pSS or NMOsd-SS compared with the controls and tended to be even lower in NMOsd-SS than pSS. The abnormal localization of AQP5 was associated with poor saliva secretion. No difference was found in TNF-α expression in the LSGs between patients with pSS and NMOsd-SS. AQP5 expression of SGECs in vitro was not changed by TNF-α or interleukin-10. CONCLUSIONS: Our results suggest that AQP5 but not AQP4 contributes to salivary secretion in patients with SS including those with NMO complicated with SS.

Analysis of the downstream mediators of toll-like receptor 3-induced apoptosis in labial salivary glands in patients with Sjögren's syndrome.

OBJECTIVES: The aim of this study was to clarify the molecular mechanisms elicited by toll-like receptor (TLR)3 in salivary gland cell death in patients with SS. METHODS: Expression of TLR3 and its downstream molecules was examined by immunohistochemical analysis, immunofluorescence, Western blot (WB), and antibody dot-blot array in labial salivary glands (LSGs), and cultured primary salivary gland epithelial cells (SGECs) obtained from patients with SS. We also investigated the difference of expression between ducts/alveoli of LSGs and cultured SGECs. RESULTS: Phosphorylated Fas-associated protein with death domain (p-FADD) or caspase-8 was not found in ducts or alveoli of LSGs from SS patients and controls. Weak expression of receptor-interacting serine/threonine-protein kinase 3 (RIPK3) was found in SS patients, whereas no staining was observed in LSGs of controls. In contrast to LSGs, stimulation of SGECs with polyinosinic:cytidylic acid (poly I:C) significantly induced the expression of RIPK3, p-FADD, and cleaved caspase-8 by immunofluorescence and RIPK3, p-FADD, and cleaved caspase-3 by WB. However, it was counteracted by epidermal growth factor (EGF). Co-localization of anti-apoptotic molecules hemeoxygenase-2, heat shock protein 27, and p-protein kinase B or p-Akt was induced in EGF-stimulated SGECs. CONCLUSIONS: We observed that poly I:C induced apoptosis of SGECs in vitro compared with a relatively low prevalence of apoptosis found in the ducts and alveoli of LSGs in vivo. Thus, we speculate that other counter-regulatory mechanisms, including those induced by EGF, might exist to protect against TLR3-mediated apoptosis of ductal and acinar epithelial cells in vivo.