Immune complexome analysis reveals the presence of immune complexes and identifies disease-specific immune complex antigens in saliva samples from patients with Sjögren's syndrome.

Sjögren's syndrome (SS) is a chronic autoimmune disease that mainly damages the salivary and lacrimal glands. Immune complex (IC) formation triggers local inflammation through IC deposition and decreased antigen function. Some ICs can leak from the lesion and into the saliva, but no salivary ICs have been reported to date. We used immune complexome analysis to comprehensively identify antigens incorporated into IC (IC-antigens) in saliva samples from patients with SS (n = 9) or with xerostomia (n = 7). Neutrophil defensin 1 (67%), small proline-rich protein 2D (67%), myeloperoxidase (44%), neutrophil elastase (44%), cathepsin G (33%), nuclear mitotic apparatus 1 (33%) and phosphatidylinositol 4-phosphate 3-kinase C2 domain-containing subunit gamma (33%) were identified as new IC-antigens specifically and frequently detected in the saliva of SS patients. Of these, neutrophil defensin 1, myeloperoxidase, neutrophil elastase and cathepsin G are neutrophil intracellular proteins, which suggests that repeated destruction of neutrophils due to abnormal autoimmunity may be involved in the pathogenesis of SS. We also analyzed serum samples from three SS patients. There was little overlap of IC-antigens between two of the samples (fewer than 30% of the IC-antigens in the saliva samples), suggesting that many ICs are formed locally and independently of the circulation. In addition, we found that four SS-specific salivary antigens show sequence homology with several proteins of oral microbiomes but no antigen has homology with Epstein-Barr virus proteins. The homology between some IC-antigens and oral microbiome proteins may indicate the impact of oral infection on local autoimmunity through molecular mimicry theory.

Effects of cigarette smoking and human T-cell leukaemia virus type 1 infection on anti-citrullinated peptide antibody production in Japanese community-dwelling adults: the Nagasaki Islands Study.

Objectives: We investigated whether the positivity of anti-citrullinated peptide antibody (ACPA) is associated with cigarette-smoking status and human T-cell leukaemia virus type 1 (HTLV-1) infection in a general population in Nagasaki, Japan, which is an ageing and HTLV-1-endemic area.Method: Baseline data from community-dwelling people in the Nagasaki Islands Study (NaIS) were included in this cross-sectional analysis. ACPA and HTLV-1 were measured in 3887 subjects without a history of treatment for rheumatoid arthritis. A logistic regression analysis was performed to assess the relationship between ACPA positivity and candidates of correlation with ACPA, i.e. the cigarette-smoking status quantified by Brinkman's index (BI) and HTLV-1 positivity.Results: Fifty-one subjects (1.3%) showed ACPA positivity, and 650 subjects (16.6%) were HTLV-1 carriers. In an age- and gender-adjusted logistic regression analysis, the BI [odds ratio (OR) 1.09, 95% confidence interval (CI)1.02-1.14, p = 0.0031] and a BI value > 500 (OR 3.92, 95% CI 1.72-9.22, p = 0.0014) were each significantly associated with ACPA positivity. HTLV-1 positivity did not show any association with ACPA positivity.Conclusion: A significant effect of cigarette-smoking status on ACPA production was revealed, whereas HTLV-1 positivity was not associated with ACPA production in this general population.

Complement profile in microscopic polyangiitis and granulomatosis with polyangiitis: analysis using sera from a nationwide prospective cohort study.

OBJECTIVE: The complement cascade, especially the alternative pathway of complement, has been shown in basic research to be associated with anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis (AAV). We aimed to elucidate relationships between serum complement components and clinical characteristics in AAV. METHOD: In a nationwide prospective cohort study (RemIT-JAV-RPGN), we measured the serum levels of C1q, C2, C3, C3b/iC3b, C4, C4b, C5, C5a, C9, factor B, factor D, factor H, factor I, mannose-binding lectin, and properdin in 52 patients with microscopic polyangiitis (MPA) and 39 patients with granulomatosis with polyangiitis (GPA). RESULTS: The properdin level of MPA and GPA was significantly lower than that of healthy donors. The properdin level was negatively correlated with the Birmingham Vasculitis Activity Score (BVAS) (ρ = -0.2148, p = 0.0409). The factor D level at 6 months was significantly positively correlated with the Vasculitis Damage Index (VDI) at 6, 12, and 24 months (ρ = 0.4207, 0.4132, and 0.3115, respectively). Patients with a higher ratio of C5a to C5 had higher neutrophil percentage and serum immunoglobulin G levels, and significantly lower creatinine levels. Cluster analysis divided the MPA and GPA patients into three subgroups. A principal component (PC) analysis aggregated 15 types of complements into alternative pathway-related PC 1 and complement classical pathway and common pathway-related PC 2. CONCLUSIONS: The serum levels of properdin and factor D were correlated with the BVAS and the VDI in MPA and GPA, respectively. Our analyses suggested the pathological heterogeneity of MPA and GPA from the aspect of complement components.

Anti-citrullinated protein antibody titre as a predictor of abatacept treatment persistence in patients with rheumatoid arthritis: a prospective cohort study in Japan.

Objective: Successful rheumatoid arthritis (RA) outcome depends on treatment efficacy in the early stages of the disease and its sustainability. It is thus critical to identify factors predicting treatment persistence with biological agents, such as abatacept. We compared clinical profiles, including early changes in autoantibody titres at 3 months, between patients with RA demonstrating sustained persistence and those discontinuing abatacept treatment.Method: We prospectively enrolled 71 and 78 active RA patients treated with abatacept and tumour necrosis factor inhibitors (TNF-Is), respectively, who had previous disease-modifying anti-rheumatic drug) failure. Clinical characteristics were compared between non-continuation and continuation groups stratified according to abatacept or TNF-I persistence for at least 12 months from treatment initiation.Results: Significantly larger decreases in rheumatoid factor titre and anti-citrullinated protein autoantibody (ACPA) titre were observed in the continuation group of abatacept therapy at 3 months, and early reduction in ACPA titre remained a significant and independent predictor of sustained persistence with abatacept in multivariate analysis. In addition, we obtained the area under the receiver operator characteristics curve of 0.904 from a model including baseline ACPA titre and reduction of ACPA titre at 3 months. Sustained reduction of RA disease activity score at 12 months was significantly and independently associated with reduced ACPA titre at 3 months.Conclusions: Persistence with abatacept and sustained therapeutic response are associated with an early reduction in ACPA titre. Prediction of abatacept continuation and efficacy will facilitate the optimal design of therapy in the early stages of RA.

Complete renal response at 12 months after induction therapy is associated with renal relapse-free rate in lupus nephritis: a single-center, retrospective cohort study.

BACKGROUND: Lupus nephritis (LN) is a major risk factor for overall morbidity and mortality in systemic lupus erythematosus (SLE). METHODS: We retrospectively analyzed cases of proliferative and membranous LN patients who underwent a renal biopsy at our hospital in 1993-2016. We analyzed the association between complete renal response (CR) rates at 12 months after induction therapy and predictive factors for CR and their association with renal flares. RESULTS: Of the 95 cases analyzed, we were able to track the therapeutic responses of 81 patients at 12 months after their induction therapy. The median follow-up duration after renal biopsy was 51 months (interquartile range: 16.5-154.5 months). The Cox proportional hazards model showed that, compared to not attaining CR at 12 months, the attainment of CR at 12 months was correlated with being free from renal flares. The multivariate logistic analysis revealed that the predictive factors for CR at 12 months were the anti-La/SSB antibodies (U/ml) (odds ratio (OR) 1.22, 95% confidence interval (CI) 1.01-1.63, p = 0.0220), blood urea nitrogen (BUN) (OR 0.68, 95% CI 0.44-0.90, p = 0.00048) and serum ß2 microglobulin (MG) (OR 0.26, 95% CI 0.06-0.74, p = 0.00098) levels. CONCLUSIONS: Among LN patients, being free from renal flares was associated with attaining CR at 12 months after induction therapy. Anti-La/SSB antibodies were a positive predictive factor, and BUN and serum ß2MG levels were negative predictive factors of CR at 12 months.

Factors predictive of long-term mortality in lupus nephritis: a multicenter retrospective study of a Japanese cohort.

BACKGROUND: Lupus nephritis (LN) is a major determinant of mortality in systemic lupus erythematosus (SLE). Here we evaluated the association between complete renal response (CR) and mortality in LN. METHODS: We retrospectively analyzed the cases of 172 of 201 patients with LN for whom data on the therapeutic response at 6 and 12 months after induction therapy were available. The patients underwent a renal biopsy at Nagasaki University Hospital and community hospitals in Nagasaki between the years 1990 and 2016. We determined the CR rates at 6 and 12 months after induction therapy initiation and evaluated the predictive factors for CR and their relationship with mortality. We performed univariate and multivariable competing risks regression analyses to determine the factors predictive of CR. The patients' survival data were analyzed by the Kaplan-Meier method with a log-rank test. RESULTS: The median follow-up duration after renal biopsy was 120 months (interquartile range: 60.3-191.8 months). The 5-, 10-, 15- and 20-year survival rates of our cohort were 99.3, 94.6, 92.0 and 85.4%, respectively. During follow-up, nine patients (5.2%) died from cardiovascular events, infection, malignancy and other causes. The multivariate analysis revealed that the following factors were predictive of CR. At 6 months: male gender (odds ratio (OR) 0.23, 95% confidence interval (CI) 0.08-0.65, p = 0.0028), proteinuria (g/gCr) (OR 0.83, 95% CI 0.71-0.97, p = 0.0098) and index of activity (0-24) (OR 0.84, 95% CI 0.71-0.99, p = 0.0382). At 12 months: male gender (OR 0.25, 95% CI 0.09-0.67, p = 0.0043) and index of activity (0-24) (OR 0.82, 95% CI 0.69-0.98, p = 0.0236). The Kaplan-Meier analysis showed that compared to not achieving CR at 12 months, achieving CR at 12 months was significantly correlated with the survival rate (OR 0.18, 95% CI 0.04-0.92, p = 0.0339). CONCLUSIONS: Our results suggest that the survival rate of patients with LN is associated with the achievement of CR at 12 months after induction therapy, and that male gender and a higher index of activity (0-24) are the common predictive factors for failure to achieve CR at 6 and 12 months.

Activation of Toll-like receptor 7 signaling in labial salivary glands of primary Sjögren's syndrome patients.

The aim of this study was to determine the expressions of Toll-like receptors (TLRs) 7-9 and type I interferon (IFN) signal in labial salivary glands (LSGs) and cultured salivary gland epithelial cells (SGECs) from primary Sjögren's syndrome (pSS) patients. We performed an immunohistochemistry analysis of LSGs from 11 patients with pSS as defined by American-European Consensus Group classification criteria and five healthy subjects. The pSS patients' SGECs were analyzed by immunofluorescence and western blotting. IFN-α expression was examined by immunosorbent assay and flow cytometry. Mononuclear cells (MNCs) from pSS patients' LSGs showed TLR-7-dominant expression. B cells, plasma cells and plasmacytoid dendritic cells (pDCs) co-expressed with TLR-7. Myeloid differentiation primary response gene 88 (MyD88), tumor necrosis factor receptor-associated factor 6 (TRAF6) and interferon regulatory factor 7 (IRF7) co-expressed with the pDC marker CD303 in LSGs. Ducts from pSS patients dominantly expressed TLR-7, and TLR-7 in the ducts co-expressed with MyD88, TRAF6 and IRF7. Type I IFNs including IFN-α and IFN-ß were detected in MNCs and ducts in pSS patients' LSGs. Increased TRAF6 expression and the nuclear translocation of IRF7 in SGECs were detected by immunofluorescence following loxoribine (a TLR-7 ligand) stimulation despite IFN-ß pretreatment. Western blotting showed increased TRAF6 expression in SGECs following IFN-ß and loxoribine stimulation. Although no increase in IFN-α was detected in supernatant from stimulated SGECs, the IFN-α in supernatant from stimulated peripheral blood pDCs from pSS patients was significantly increased. Our findings suggest that TLR-7 is dominantly expressed in both MNCs and ducts with downstream signals for type I IFNs, indicating that TLR7-dominant innate immunity is related to the development of sialadenitis in pSS.

Administration of teriparatide improves the symptoms of advanced bisphosphonate-related osteonecrosis of the jaw: preliminary findings.

Teriparatide is a synthetic polypeptide hormone that contains the 1-34 amino acid fragment of the recombinant human parathyroid hormone that stimulates bone formation. Currently, it is approved only for the treatment of osteoporosis. The outcomes of daily teriparatide injections for the treatment of bisphosphonate-related osteonecrosis of the jaw in 10 patients are reported here. Two of the 10 cases dropped out due to adverse events. Of the remaining eight cases, seven exhibited clinical improvement of the jaw-related symptoms of osteonecrosis and progression of the sequestration, while one case did not show improvement of the symptoms. Administration of teriparatide in patients with osteonecrosis of the jaw promotes bone formation and subsequent sequestration over a short period of time. These results suggest that adjunctive teriparatide therapy is a viable and effective option for treating osteonecrosis of the jaw.

Multiple drug combination of anti-diabetic agents as a predictor for poor clinical response to liraglutide.

AIM: Aim of the study was to retrospectively analyze the clinical parameters that contribute to the therapeutic outcome of GLP-1 analogues. METHODS: We enrolled 106 patients with type 2 diabetes mellitus (T2DM), treated with liraglutide (N.=69) or exenatide (N.=37) for longer than three months. The patients were divided into two groups: good responders and poor responders to GLP-1 analogues, based on pretreatment and post-treatment HbA1c levels. Good responders were those whose HbA1c level had decreased by 1% or more, or maintained at less than 7%. All other patients were categorized as poor responders. We used univariate and multivariate analyses to assess pretreatment parameters between the two groups. RESULTS: Approximately 35% of the patients were poor responders. Our analysis of the pretreatment clinical parameters revealed that number of anti-diabetic agents and use of sulfonylurea were significantly associated with poor response to liraglutide (P=0.02 and P=0.03, respectively) in a multivariate analysis. We were not able to find any candidate related to clinical response to exenatide. CONCLUSION: Our study showed that the therapeutic effects of GLP-1 analogues on T2DM patients were heterogeneous. T2DM patients who require multiple anti-diabetic agents, especially sulfonylurea, do not benefit from liraglutide treatment.

MEFV gene polymorphisms and TNFRSF1A mutation in patients with inflammatory myopathy with abundant macrophages.

Inflammatory myopathy with abundant macrophages (IMAM) has recently been proposed as a new clinical condition. Although IMAM shares certain similarities with other inflammatory myopathies, the mechanisms responsible for this condition remain unknown. Patients with familial Mediterranean fever (FMF) and tumour necrosis factor receptor-associated periodic syndrome (TRAPS) also often develop myalgia. We therefore investigated the polymorphisms or mutations of MEFV and TNFRSF1A genes in patients with IMAM to identify their potential role in this condition. We analysed the clinical features of nine patients with IMAM and sequenced exons of the MEFV and TNFRSF1A genes. The patients with IMAM had clinical symptoms such as myalgia, muscle weakness, erythema, fever and arthralgia. Although none of the patients were diagnosed with FMF or TRAPS, seven demonstrated MEFV polymorphisms (G304R, R202R, E148Q, E148Q-L110P and P369S-R408Q), and one demonstrated a TNFRSF1A mutation (C43R). These results suggest that MEFV gene polymorphisms and TNFRSF1A mutation are susceptibility and modifier genes in IMAM.

Effects of Janus kinase inhibitor tofacitinib on circulating serum amyloid A and interleukin-6 during treatment for rheumatoid arthritis.

The Janus kinase inhibitor tofacitinib is currently being investigated as a disease-modifying agent in rheumatoid arthritis (RA). We investigated the in-vivo effects of tofacitinib treatment for 4 weeks on elevated circulating acute-phase serum amyloid (SAA) levels in 14 Japanese patients with RA. SAA levels fell from 110·5 ± 118·5 µg/ml (mean ± standard deviation) at treatment initiation to 15·3 ± 13·3 µg/ml after 4 weeks treatment with tofacitinib. The reduction in SAA levels was greater in patients receiving tofacitinib plus methotrexate compared with those receiving tofacitinib monotherapy. Tofacitinib was also associated with reduced serum interleukin (IL)-6, but had no effect on serum levels of soluble IL-6 receptor. Patients were divided into groups with adequate (normalization) and inadequate SAA responses (without normalization). Serum IL-6 levels were reduced more in the group with adequate SAA response compared with those with inadequate SAA response. These results suggest that tofacitinib down-regulates the proinflammatory cytokine, IL-6, accompanied by reduced serum SAA levels in patients with active RA. The ability to regulate elevated serum IL-6 and SAA levels may explain the anti-inflammatory activity of tofacitinib.

Aggressive pulmonary calcification developed after living donor kidney transplantation in a patient with primary hyperparathyroidism.

Metastatic pulmonary calcification, defined as calcium deposition in the intact lung, is commonly seen in patients with chronic renal failure, and it is known to be a benign clinical condition when detected by chance in an asymptomatic patient. Here we report the case of a 33-year-old woman who developed rapid and aggressive metastatic pulmonary calcification shortly after a living donor kidney transplantation, which induced acute antibody-mediated rejection. The patient's metastatic pulmonary calcification was successfully improved by extensive treatment for graft rejection, the correction of her accompanying primary hyperparathyroidism, and medical treatment with a bisphosphonate and sodium thiosulfate. Aggressive pulmonary calcification is reported as a rare complication seen in patients who have undergone a failed renal transplantation. A failed renal graft and accompanying secondary hyperparathyroidism seem to accelerate metastatic calcification. Most of the patients who develop aggressive pulmonary calcification suffer from the rapid progression of dyspnea and occasionally fever, and they die of respiratory failure. Pulmonary calcification should be considered in a patient developing dyspnea and unexplained pulmonary infiltrate, especially in the context of renal graft rejection; otherwise the prognosis of the patient will be very poor.

Genetic deletion of granzyme B does not confer resistance to the development of spontaneous diabetes in non-obese diabetic mice.

Granzyme B (GzmB) and perforin are proteins, secreted mainly by natural killer cells and cytotoxic T lymphocytes that are largely responsible for the induction of apoptosis in target cells. Because type 1 diabetes results from the selective destruction of ß cells and perforin deficiency effectively reduces diabetes in non-obese diabetic (NOD) mice, it can be deduced that ß cell apoptosis involves the GzmB/perforin pathway. However, the relevance of GzmB remains totally unknown in non-obese diabetic (NOD) mice. In this study we have focused on GzmB and examined the consequence of GzmB deficiency in NOD mice. We found that NOD.GzmB(-/-) mice developed diabetes spontaneously with kinetics similar to those of wild-type NOD (wt-NOD) mice. Adoptive transfer study with regulatory T cell (Treg )-depleted splenocytes (SPCs) into NOD-SCID mice or in-vivo Treg depletion by anti-CD25 antibody at 4 weeks of age comparably induced the rapid progression of diabetes in the NOD.GzmB(-/-) mice and wt-NOD mice. Expression of GzmA and Fas was enhanced in the islets from pre-diabetic NOD.GzmB(-/-) mice. In contrast to spontaneous diabetes, GzmB deficiency suppressed the development of cyclophosphamide-promoted diabetes in male NOD mice. Cyclophosphamide treatment led to a significantly lower percentage of apoptotic CD4(+) , CD8(+) and CD4(+) CD25(+) T cells in SPCs from NOD.GzmB(-/-) mice than those from wt-NOD mice. In conclusion, GzmB, in contrast to perforin, is not essentially involved in the effector mechanisms for ß cell destruction in NOD mice.

Thymus histology and concomitant autoimmune diseases in Japanese patients with muscle-specific receptor tyrosine kinase-antibody-positive myasthenia gravis.

BACKGROUND AND PURPOSE: The differences in the characteristics of thymus histology, coexisting autoimmune diseases and related autoantibodies between anti-muscle-specific receptor tyrosine kinase (MuSK)-antibody (Ab)-positive myasthenia gravis (MG) patients, and anti-acetylcholine receptor (AChR)-Ab-positive MG patients are not clearly defined. METHODS: The types of thymus histology, coexisting autoimmune diseases and associated Abs in 83 MuSK-Ab-positive patients nationwide were investigated and were compared with those in AChR-Ab-positive patients followed at our institute (n = 83). As for the autoantibodies associated with thymoma, titin Abs were measured. RESULTS: Thymoma was not present in any of the MuSK-Ab-positive patients but presented in 21 patients (25.3%) amongst the AChR-Ab-positive patients. Titin Abs were absent in MuSK-Ab-positive patients but positive in 25 (30.1%) of the AChR-Ab-positive patients. Concomitant autoimmune diseases were present in eight MuSK-Ab-positive patients (9.6%) amongst whom Hashimoto's thyroiditis and rheumatoid arthritis predominated, whereas 22 AChR-Ab-positive patients (26.5%) had one or more concomitant autoimmune diseases of which Graves' disease predominated. CONCLUSIONS: Differences in frequency of thymoma and thymic hyperplasia, coexisting autoimmune diseases and autoantibody positivity between MuSK-Ab-positive and AChR-Ab-positive MG were indicated, suggesting that, in contrast with AChR-Ab-positive MG, thymus does not seem to be involved in the pathogenic mechanisms of MuSK-Ab-positive MG.

Adipogenesis of the mesenchymal stromal cells and bone oedema in rheumatoid arthritis.

OBJECTIVES: Bone oedema is a pathological change in rheumatoid arthritis (RA) that is detectable by magnetic resonance imaging (MRI). Recent histological analyses revealed that a prominent feature of bone oedema is the replacement of adipose tissue with inflammatory cells. Here, we demonstrate the possible roles of mesenchymal stromal cells (MSCs) in bone oedema formation and the pathogenic potential of the cells in RA. METHODS: Adipogenesis of bone marrow-derived human MSCs was induced by a standard adipogenic induction medium in the presence or absence of cytokines. The cytokine productions from MSCs were screened by an antibody array system and confirmed by ELISA. The migration assay was performed to determine the locomotive abilities of undifferentiated MSCs or MSCs after adipogenesis. The expression of α smooth muscle actin (SMA) and F-actin was examined by immunostaining and phalloidin staining, respectively. RESULTS: TNF-α, interleukin (IL)-1ß, IL-6, and TGF-ß clearly inhibited the adipogenesis of MSCs. Production of IL-6 was markedly reduced, and IL-8 secretion was augmented in MSCs after adipogenesis. The mobility of MSCs after adipogenesis was clearly reduced in migration assays compared to that of undifferentiated MSCs. Consistent with these findings, SMA and F-actin expressions were clearly suppressed in MSCs committed to adipogenesis. CONCLUSIONS: Our data suggest that the inflammatory milieu promotes bone oedema by blocking adipogenesis of MSCs. In bone oedema, the enhanced IL-6 production and the increased mobility of MSCs may contribute to the progression of RA. Therefore, bone oedema may be an important target lesion in the treatment of RA.

Macrophage-dominant sialadenitis in human T-cell leukemia virus type I-associated myelopathy after living-donor liver transplantation.

A 64-year-old man who suffered from human T-cell leukemia virus type I (HTLV-I)-associated myelopathy (HAM) after living-donor liver transplantation (LDLT) for liver cirrhosis due to hepatitis C virus infection complained of xerostomia. Although exocrine function test results were positive, autoantibodies including anti-SS-A/SS-B antibodies and sialography showed negative findings. Labial salivary gland biopsy revealing infiltration of 60 counts of mononuclear cells (MNCs) in minor salivary glands led to a diagnosis of Sjögren's syndrome-like sialadenitis. Immunohistochemistry demonstrated dominant CD68 staining and major histocompatibility complex class II on the surface of infiltrating MNCs. Herein we have reported a rare condition of macrophage-dominant sialadenitis in a patient with HAM after LDLT.

Association of distinct clinical subsets with myositis-specific autoantibodies towards anti-155/140-kDa polypeptides, anti-140-kDa polypeptides, and anti-aminoacyl tRNA synthetases in Japanese patients with dermatomyositis: a single-centre, cross-sectional study.

OBJECTIVE: To determine the association of distinct clinical subsets with myositis-specific autoantibodies (MSAs) towards anti-155/140-kDa polypeptides [anti-155/140 antibodies (Abs)], anti-140-kDa polypeptides (anti-140 Abs), and anti-aminoacyl tRNA synthetases (ARS Abs) in Japanese patients with dermatomyositis (DM). METHODS: We compared the clinical features and short-term prognoses of 30 DM patients whose serological status included these MSAs. The MSAs were determined by immunoprecipitation. RESULTS: Anti-155/140 Abs (n = 5), anti-140 Abs (n = 8), and anti-ARS Abs (n = 7) did not overlap each other. All of the anti-155/140 Ab-positive patients (n = 5) were complicated by malignancies, as were all of the anti-140 Ab-positive patients (n = 8), who showed rapidly progressive interstitial lung disease (ILD). The survival rate at 6 months from the diagnosis of DM was significantly lower in the anti-140 Ab-positive patients than in the other patients. CONCLUSION: This is the first study to report, in a single cohort of DM patients, that distinct clinical subsets are distributed in an anti-155/140 Ab-positive group, an anti-140 Ab-positive group, or an anti-ARS Ab-positive group. Our data also confirm previous evidence that anti-155/140 Abs are involved in malignancies and that anti-140 Abs are involved in rapidly progressive ILD.

Calcium/calmodulin-dependent protein kinase II (CaMKII) regulates tumour necrosis factor-related apoptosis inducing ligand (TRAIL)-mediated apoptosis of fibroblast-like synovial cells (FLS) by phosphorylation of Akt.

OBJECTIVE: We tried to determine whether calcium/calmodulin-dependent protein kinase II (CaMKII) regulates tumour necrosis factor-related apoptosis inducing ligand (TRAIL)-mediated apoptosis of fibroblast-like synovial cells (FLS). METHODS: CaMKII expression in FLS was studied by both western blotting and real time reverse transcription polymerase chain reaction (RT-PCR). TRAIL-mediated apoptosis of FLS was quantified by disruption of mitochondrial transmembrane potential (DeltaPsim), Leu-Glu-His-Asp (IETD) ase activity and DNA degradation. Involvement of CaMKII and other kinases, including extracellular signal-regulated kinase (ERK), p38, c-Jun N-terminal kinase (JNK) and Akt during TRAIL-mediated apoptosis of FLS was estimated by the use of specific each kinase chemical inhibitor. RESULTS: Predominant expression of delta and gamma isoform of CaMKII, especially delta isoform, was determined in cultured FLS. TRAIL rapidly induced apoptosis of FLS as well as the phosphorylation of extracellular signal-regulated kinase (ERK), p38, c-Jun N-terminal kinase (JNK) and Akt. Chemical kinase inhibitor toward CaMKII and Akt significantly augmented TRAIL-mediated apoptosis of FLS whereas those toward ERK, p38 and JNK did not. Notably, CaMKII chemical inhibitor abrogated TRAIL-induced phosphorylation of Akt. Elevation of Leu-Glu-His-Asp (IETD) ase activity was associated with the apoptotic phenomena, which was almost suppressed by IETD competitive peptides. CONCLUSION: Our results suggest a first observation that CaMKII regulates TRAIL-mediated apoptosis of FLS through Akt, standing an upstream of caspase-8-dependent cascades. Furthermore, CaMKII is suggested to be a new therapeutic target molecule of rheumatoid arthritis (RA).

HTLV-I infection results in resistance toward salivary gland destruction of Sjögren's syndrome.

OBJECTIVE: The role of HTLV-I infection in Sjögren's syndrome (SS) remains unclear. In this study, we clinically compared radiographic imaging with histological cellular infiltration between HTLV-I-seropositive and HTLV-I-sero-negative SS. METHODS: Sixty primary SS patients were divided into two age-matched groups based on the seropositivity of the anti-HTLV-I antibody. We evaluated the two groups through labial salivary gland biopsy-proven cellular infiltration and sialography-proven radiographic gland destruction. RESULTS: In these 60 pSS patients, the incidence of abnormalities as determined by salivary gland biopsy and sialography was 51.7% (31/60) and 76.7% (46/60), respectively. Although there was no difference in the prevalence of abnormal findings between salivary gland biopsy and sialography in the whole 60 patients, there were significantly fewer abnormalities determined by sialography in HTLV-I-seropositive SS patients in comparison with HTLV-I-seronegative SS patients. Also, these findings were strengthened by the results that none of HTLV-I-seropositive SS patients with focus score 0 had abnormal sialography findings. CONCLUSION: Our results suggest that HTLV-I infection results in resistance toward salivary gland destruction of Sjögren's syndrome.