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Sjögren’s syndrome (SS) is an autoimmune disease characterized by inflammation with lymphoid infiltration and destruction of the salivary glands. Although many genome-wide association studies have revealed disease-associated risk alleles, the functions of the majority of these alleles are unclear. Here, we show previously unrecognized roles of GTF2I molecules by using two SS-associated single nucleotide polymorphisms (SNPs), rs73366469 and rs117026326 (GTF2I SNPs). We found that the risk alleles of GTF2I SNPs increased GTF2I expression and enhanced nuclear factor-kappa B (NF-κB) activation in human salivary gland cells via the NF-κB p65 subunit. Indeed, the knockdown of GTF2I suppressed inflammatory responses in mouse endothelial cells and in vivo. Conversely, the over-expression of GTF2I enhanced NF-κB reporter activity depending on its p65-binding N-terminal leucine zipper domain. GTF2I is highly expressed in the human salivary gland cells of SS patients expressing the risk alleles. Consistently, the risk alleles of GTF2I SNPs were strongly associated with activation of the IL-6 amplifier, which is hyperactivation machinery of the NF-κB pathway, and lymphoid infiltration in the salivary glands of SS patients. These results demonstrated that GTF2I expression in salivary glands is increased in the presence of the risk alleles of GTF2I SNPs, resulting in activation of the NF-κB pathway in salivary gland cells. They also suggest that GTF2I could be a new therapeutic target for SS.

The purpose of this study was to illustrate the clinical and imaging properties of giant intraosseous cyst-like lesions (GICLs) of the metacarpal bones extending beyond the central diaphysis in rheumatoid arthritis (RA) patients on magnetic resonance (MR) images. A keyword search was conducted to extract GICLs of the metacarpal bones out of MR reports in RA patients. There were nine GICLs extending from the subchondral bone region beyond the central diaphysis of the metacarpal bones on MR images in eight subjects with RA (seven females, one male). The age range was from 60 to 87 years with a median age of 65.5 years. The average disease duration was 13.1 years. As for the disease activity, one was low, six were moderate and one was high. None of the nine lesions were visible on radiography. The Steinbrocker stage distribution was as follows: I (n = 3), II (n = 2), and III (n = 3). Intraosseous cyst-like lesion of the metacarpal bones on MR images is a relatively rare manifestation in patients with long-standing RA. Although the lesion seems to be derived from subcortical bone break, it is not necessarily erosive in nature.

We recently reported that NF-κB–mediated inflammation caused by breakpoint cluster region (BCR) is dependent on the α subunit of casein kinase II (CK2α) complex. In the current study, we demonstrate that presenilin 1 (Psen1), which is a catalytic component of the γ-secretase complex and the mutations of which are known to cause familial Alzheimer disease, acts as a scaffold of the BCR–CK2α–p65 complex to induce NF-κB activation. Indeed, Psen1 deficiency in mouse endothelial cells showed a significant reduction of NF-κB p65 recruitment to target gene promoters. Conversely, Psen1 overexpression enhanced reporter activation under NF-κB responsive elements and IL-6 promoter. Furthermore, the transcription of NF-κB target genes was not inhibited by a γ-secretase inhibitor, suggesting that Psen1 regulates NF-κB activation in a manner independent of γ-secretase activity. Mechanistically, Psen1 associated with the BCR–CK2α complex, which is required for phosphorylation of p65 at serine 529. Consistently, TNF-α–induced phosphorylation of p65 at serine 529 was significantly decreased in Psen1-deficient cells. The association of the BCR–CK2α–p65 complex was perturbed in the absence of Psen1. These results suggest that Psen1 functions as a scaffold of the BCR–CK2α–p65 complex and that this signaling cascade could be a novel therapeutic target for various chronic inflammation conditions, including those in Alzheimer disease.

The objective of this study is to identify the effects of statins and risk factors for thrombosis in patients with new onset of systemic lupus erythematosus (SLE) with or without antiphospholipid antibodies (aPL). Consecutive patients with SLE without history of thrombotic events were retrospectively enrolled from April 1997 to February 2014. The development of first thrombosis and death caused by thrombosis were defined as the study endpoint. Risk and protective factors for developing thrombosis were analyzed. A total of 152 patients, 80 positive and 72 negative for aPL, were included. In aPL-positive patients, 15 developed arterial ( n = 6) and venous ( n = 9) thrombosis (median follow-up period 69 months). Cox's proportional hazards model showed that older age at SLE onset and IgG-anticardiolipin antibodies (aCL) were statistically significant risks for thrombosis. Statin therapy was identified as a statistically significant protective factor against thrombosis (hazard ratio 0.12, 95% confidence interval 0.01-0.98). In aPL-negative patients (median follow-up period 46 months), seven patients developed thrombosis (five arterial and two venous). No risk factors for thrombosis were found in this group. In aPL-positive patients with SLE, the late disease onset and the presence of IgG-aCL represented additional risk factors for thrombosis. Statin treatment appeared as a protective factor for thrombosis.

OBJECTIVE We have previously reported that the coactivation of NF-κB and STAT3 in nonimmune cells, including synovial fibroblasts, enhances the expression of NF-κB target genes and plays a role in chronic inflammation and rheumatoid arthritis (RA). This study was undertaken to examine the role of NF-κB activation in chondrocytes and better understand the pathogenesis of RA. Furthermore, transmembrane protein 147 (TMEM147) was investigated as a representative NF-κB activator in chondrocytes. METHODS Clinical samples from RA patients were analyzed by immunohistochemistry. Specimens obtained from patients with polydactyly were used as control samples. The functional contribution of chondrocytes and TMEM147 to arthritis was examined in several murine models of RA. In vitro experiments (quantitative polymerase chain reaction, RNA interference, immunoprecipitation, and confocal microscopy) were performed to investigate the mechanism of action of TMEM147 in chondrocytes. RESULTS Samples obtained from RA patients and mouse models of RA showed coactivation of NF-κB and STAT3 in chondrocytes (P < 0.001). This coactivation induced a synergistic expression of NF-κB targets in vitro (P < 0.01). Chondrocyte-specific deletion of STAT3 significantly suppressed the development of cytokine-induced RA (P < 0.01). TMEM147 was highly expressed in chondrocytes from RA patient samples and the mouse models of RA. Gene silencing of TMEM147 or anti-TMEM147 antibody treatment inhibited the cytokine-mediated activation of NF-κB in vitro (P < 0.01) and suppressed cytokine-induced RA in vivo (P < 0.01). Mechanistically, TMEM147 molecules acted as scaffold proteins for the NF-κB complex, which included breakpoint cluster region and casein kinase 2, and enhanced NF-κB activity. CONCLUSION These results suggest that chondrocytes play a role in the development of RA via TMEM147-mediated NF-κB activation and indicate a novel therapeutic strategy for RA.

The joint space difference index (JSDI) is a newly developed radiographic index which can quantitatively assess joint space narrowing progression of rheumatoid arthritis (RA) patients by using an image subtraction method on a computer. The aim of this study was to investigate the reliability of this method by non-experts utilizing RA image evaluation. Four non-experts assessed JSDI for radiographic images of 510 metacarpophalangeal joints from 51 RA patients twice with an interval of more than 2 weeks. Two rheumatologists and one radiologist as well as the four non-experts examined the joints by using the Sharp-van der Heijde Scoring (SHS) method. The radiologist and four non-experts repeated the scoring with an interval of more than 2 weeks. We calculated intra-/inter-observer reliability using the intra-class correlation coefficients (ICC) for JSDI and SHS scoring, respectively. The intra-/inter-observer reliabilities for the computer-based method were almost perfect (inter-observer ICC, 0.966-0.983; intra-observer ICC, 0.954-0.996). Contrary to this, intra-/inter-observer reliability for SHS by experts was moderate to almost perfect (inter-observer ICC, 0.556-0.849; intra-observer ICC, 0.589-0.839). The results suggest that our computer-based method has high reliability to detect finger joint space narrowing progression in RA patients.

The breakpoint cluster region (BCR) is known as a kinase and cause of leukemia upon fusing to Abl kinase. In this study, we demonstrate that BCR associated with the α subunit of casein kinase II (CK2α), rather than BCR itself, is required for inflammation development. We found that BCR knockdown inhibited NF-κB activation in vitro and in vivo. Computer simulation, however, suggested that the putative BCR kinase domain has an unstable structure with minimal enzymatic activity. Liquid chromatography–tandem mass spectrometry analysis showed that CK2α associated with BCR. We found the BCR functions are mediated by CK2α. Indeed, CK2α associated with adaptor molecules of TNF-αR and phosphorylated BCR at Y177 to establish a p65 binding site after TNF-α stimulation. Notably, p65 S529 phosphorylation by CK2α creates a p300 binding site and increased p65-mediated transcription followed by inflammation development in vivo. These results suggest that BCR-mediated inflammation is dependent on CK2α, and the BCR–CK2α complex could be a novel therapeutic target for various inflammatory diseases.

Central nervous system (CNS), which is made up of brain and spinal cord, is protected from the invasion of harmful agents, such as various pathogens, chemical products or immune cells by a special structure "Blood Brain Barrier (BBB)". BBB highly preserves the homeostasis of CNS environment. On the other hand, there are many diseases in CNS regions which is associated with infection or autoimmunity, that means there may exist the "gateway" for pathogens or immune cells to attack CNS. Until recently, the molecular mechanism of the gateway formation has not been elucidated. Through studies in the multiple sclerosis model experimental autoimmune encephalomyelitis, we have clarified the mechanism of the gateway formation, and also the locations of gateways which depend on the regional neural activation. Further more, we have also discovered a massive chemokine-inducing mechanism "inflammation amplifier" via co-activation of NF-κB pathway and STAT3 pathway. It is essential for the development of inflammation in various diseases and is a molecular basis of BBB breakdown.

Objective To investigate the prevalence and significance of the autoantibodies against complement component 1 q subcomponent (C1q) in patients with APS. Methods In all, 40 consecutive primary APS patients, 42 patients with non-SLE CTDs and 20 SLE patients negative for aPL were enrolled in this retrospective analysis. Refractory APS was defined as a clinical status of recurring thrombosis or pregnancy morbidity during adequate secondary prophylaxis. An ELISA was used to measure serum levels of anti-C1q antibodies and anaphylatoxins (C3a, C4a). Results Anti-C1q antibodies were found in 36% (15/42) and 2.5% (1/40) of primary APS patients and controls, respectively. Among primary APS patients, anti-C1q antibody titres were significantly correlated with serum C4a levels (P = 0.013). Neither the prevalence nor the titre of anti-C1q antibodies was associated with any specific clinical manifestations of APS, nor titres of aPL. Refractory APS patients (n = 10) had a higher prevalence of anti-C1q antibodies (9/10 vs 6/32, P = 0.01) than APS patients without recurrence (n = 32). Conclusion Anti-C1q antibodies are associated with complement activation in APS and may contribute to the pathogenesis, particularly in refractory cases.