In rheumatoid arthritis (RA), ACPA (anti-citrullinated protein/peptide antibody) is elevated with high specificity, and clinically, anti-CCP (cyclic citrullinated peptide) antibody is widely used for diagnosis of RA. It is thought ACPAs are produced with genetic background such as HLA-DR, environmental factors such as periodontal disease and smoking, however, the pathogenic role of ACPA in RA has not been elucidated. These were showed immune complexes including ACPA or ACPA itself promoted inflammatory cytokine production such as TNF. PADs (peptidylarginine deiminases) were expressed and citrullinated proteins existed in RA synovium. ACPAs were deposited on the site of citrulline in CD68 positive cells of RA synovium. The damage of bone and cartilage is observed in RA. It was also suggested that deposition of ACPAs caused osteoclastogenesis and bone loss. We introduce several findings about the pathogenic role of ACPA in RA.

  Systemic lupus erythematosus (SLE) is an autoimmune disease involving multiple lesions that cause inflammation and the production of autoantibodies. Lupus nephritis (LN) and neuropsychiatric SLE (NPSLE) are common organ-threatening manifestations of SLE and result in significant morbidity and mortality. In the last 30 years, steroids and immunosuppressive drugs have improved the prognosis of patients with SLE, and today the 5-year survival rate exceeds 90%. However, the treatment of SLE still largely depends on these medications and sometimes results in death due to complications. In recent years, biologic agents and low-molecular-weight compounds have emerged that are expected to be effective against refractory LN and NPSLE. For the diagnosis of SLE, the classification revised in 1997 proposed by the American College of Rheumatology and the classification standards of the Systemic Lupus International Collaborating Clinics 2012 classification criteria have been used, but they are not necessarily useful for early diagnosis. New biomarkers are needed for the early diagnosis of SLE. In this article, we summarize the unmet needs of diagnosis and treatment with SLE, especially those with LN and NPSLE, with data from our own experiences.

  Human Intestine has a diverse population of bacteria which induces pathogens to disrupt not only the intestinal homeostasis but whole body immune systems. Dysbiosis, the abnormal proliferation and reduction of the microbiota, breaks down the homeostasis of the immunity and metabolisms in the host. The evolution of the microbiota analysis technology contributed to reveal the molecular biological complex interaction between the microbiota and its host systemically as well as locally. Because several diseases are caused by the dysbiosis, fecal transplantation would be the new therapeutic target for them. It has been investigated in some intestinal diseases such as CD infection, or inflammatory bowel disease. Here, we review these symbiotic interactions and the current state for the clinical application.

  Since the discovery of loss-of-function mutations in filaggrin (FLG) gene in atopic dermatitis (AD) individuals, significant attention has been paid against the skin barrier as an initial starting point of atopic march. Although FLG is a significant cornification-associated gene, skin barrier formation is a complex process mediated by an array of genes with specific functions. In this article, the mechanism of physical skin barrier formation is reviewed in detail, focusing on specific gene functions and inherited disorders caused by genetic aberrations. Additionally, the mechanism of percutaneous sensitization with environmental allergens in association with FLG-deficiency is reviewed in order to clarify the link between defective skin barrier and atopic march. Finally, updated knowledge of psoriasis pathophysiology in connection with genetic defect in skin barrier is reviewed. This article would provide a novel opportunity to understand the allergic/autoimmune disorders from the viewpoint of non-classical immune cells.

  Antiphospholipid syndrome (APS) is a clinical disorder characterized by thrombosis and/or pregnancy morbidity in the persistence of the pathogenic autoantibodies, the antiphospholipid antibodies (aPL). Recurernt thrombosis is often observed in patients with APS which requires persistent prophylaxis. However, an uniform prophylactic treatment for APS patients is inadequate and stratification of the thrombotic risks is important as aPL are prevalently observed in other various diseases or elderly population. It is previously known that the multiple positivity or high titre of aPL correlate to the thrombotic events. To progress the stratification of the thrombotic risks and to quantitatively analyze them, antiphospholipid score (aPL-S) and the Global Anti-Phospholipid Syndrome Score (GAPSS) were defined as the scoring-systems. Both of these scoring-systems were raised from the large patient cohort data and either aPL profile classified in detail (aPL-S) or simplified aPL profile with classical thrombotic risk factors (GAPSS) were put into scoring system. They have shown a degree of accuracy in identifying high-risk APS patients, especially those at a high risk of thrombosis. However, there are several areas requiring improvement, or at least that clinicians should be aware of, before these instruments are applied in clinical practice. One such issue is standardisation of the aPL tests, including general testing of phosphatidylserine dependent antiprothrombin antibodies (aPS/PT).

  Cytokines play important roles in the pathogenesis of autoimmune diseases. Anti-TNFα antibody therapy for rheumatoid arthritis, Crohn's disease, and psoriasis has made enough progress to change its treatment goal. This review focuses on the recent advances that have been made in understanding TNFR signaling through ubiquitin system. Genome-wide association studies (GWAS) identified numerous susceptibility loci associated with autoimmune diseases. Ubiquitin related genes TNFAIP3 and TNIP1 have been linked to multiple autoimmune diseases. Here, we review the importance of TNFAIP3 and TNIP1-mediated regulation of ubiquitin-dependent signaling. To monitor the dynamics of ubiquitin chain formation in vivo, we have developed a polyubiquitin-mediated fluorescence complementation (PolyUb-FC) assay. The PolyUb-FC assay has the advantage that monoubiquitination is non-fluorescent and chain-specific poly-ubiquitination can be directly visualized in living cells without using antibodies. The PolyUb-FC will be a useful tool for analyzing the dynamics of polyubiquitin chain generation.

  A 65-year-old woman with a 17-year history of polymyositis and 8-year history of rheumatoid arthritis who was treated with a low dose of prednisolone and tacrolimus (Tac) was admitted to our hospital because of general malaise and hypertension. Blood tests showed thrombocytopenia, hemolytic anemia with fragmented erythrocytes, and hypercreatinemia. Based on these clinical features, she was diagnosed with thrombotic micro-angiopathy (TMA). Thrombocytopenia and hemolytic anemia with fragmented erythrocytes improved with the discontinuation of Tac and plasma exchange; however, hypertension and renal dysfunction persisted. TMA due to calcineurin inhibitor (CNI) nephropathy was suspected based on the histopathological findings of renal biopsy. However, the condition was atypical of a CNI nephropathy because the trough level of Tac was lower than that reported previously and renal dysfunction persisted after drug discontinuation. She had mild sclerodactylia and Raynaud's symptoms, although the diagnostic criteria for systemic sclerosis (SSc) were not satisfied. Moreover, the patient tested positive for anti PL-7 antibody. The relationship between anti PL-7 antibody and pathogenesis of SSc has been reported. In this case, it was suspected that CNI nephropathy worsened because of the potential basic factors of SSc. These findings indicate that TMA may occur in patients testing positive for anti PL-7 antibody who are treated with Tac.

  In Kawasaki disease (KD), endothelial damage and an elevation in coagulant factors provoke thrombosis. Lupus anticoagulant (LA) is strongly associated with the risk of thrombosis in patients with antiphospholipid syndrome; however, there has been no report of positive LA in KD patients. A previously healthy, 2-year-old boy was admitted due to fever, bilateral conjunctivitis, redness of the lips, and unilateral cervical lymphadenopathy. Typical Kawasaki disease was diagnosed on day 5 of illness. Adenovirus antigens were detected in his stool. After the KD symptoms were successfully treated with intravenous immunoglobulin, his activated partial thromboplastin time (APTT) increased to 88 seconds at eight days of illness. The cross-mixing test showed an inhibition pattern, and the presence of LA was proved using diluted Russell's viper venom time. APPT elongation improved due to continued low dose aspirin therapy without thromboembolisms. The possibility of contamination by LA was low because six other patients treated with the same immunoglobulin lot showed no APTT elongation. We speculated that KD-related infections led to the presence of LA, which may have triggered the thrombosis. Further accumulation of data is warranted to elucidate the role of LA in KD patients.

  A 49-year-old female with a chief complaints of arthralgia, and a medical history is Hashimoto's disease presented to us. She had been previously treated for Sjögren's syndrome at our hospital. She had anterior chest and polyarticular pain. On admission, her blood test results were as follows: white blood cells, 12700/μl; C reactive protein, 24.8 mg/dl; erythrocyte sedimentation rate 122 mm/h, Anti-streptolysin O, 1179 IU/ml;an, ASK, 10240. She had tenderness in both her hand and finger joints, recurrent episodes of tonsillitis and pustular eruption. Her imaging studies were remarkable for inflammation of the sacroiliac joint and bone erosion of the hand joint, among other findings. We considered a diagnosis of either axial spondyloarthritis or synovitis acne, pustulosis, hyperostosis and osteitis (SAPHO) syndrome due to an opportunistic tonsillar infection. The differential diagnosis between axial spondyloarthritis or SAPHO syndrome is difficult to make. We discuss this case in the context of previous literature.

  A female in her sixties with slowly progressive type 1 diabetes mellitus (SPT1DM) and chronic thyroiditis was referred to our rheumatology department with swelling in her fingers. A prominent atherosclerotic lesion was revealed upon brain magnetic resonance imaging, and she was found to have mixed connective tissue disease (MCTD) positive for proteinase 3 (PR3)-antineutrophil cytoplasmic antibody (ANCA). This rare case of MCTD accompanying SPT1DM and PR3-ANCA suggested that a synergy between MCTD and PR3-ANCA triggers atherosclerosis.