Systemic autoimmune diseases are characterized by multiple organ damages, whose pathogenesis caused by the activation of autoreactive T cells reacting against antigens of the body's own tissues and B cells producing autoantibodies. Following the animal studies, Tfh cells have been identified as a critical subset for the formation and function of B cell responses in humoral immunity, but also play an important role in autoimmunity. In fact, circulating Tfh cells are reported to increase and correlate with disease activity and autoantibody production in human autoimmune diseases. However, the evidence from human studies highlighted apparent differences between mouse and human Tfh cell differentiation. Furthermore, there is increased recognition of functional plasticity and diversity of Tfh cells. This may be advantageous in terms of host defense but needs to be borne in mind in thinking about effective therapies for autoimmune diseases. Thus, better understanding of the extrinsic and intrinsic signals that control plasticity and diversity of Tfh cells will have important therapeutic applications to control autoimmunity.

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  Treatment of organ involvements accompanied by systemic autoimmune diseases is still challenging for clinicians, reminding the existence of unmet needs. Among them, lupus nephritis (LN), neuropsychiatric lupus, interstitial lung diseases (ILD) complicated with polymyositis/dermatomyositis (PM/DM) or systemic sclerosis (SSc) are the most severe conditions with poor prognosis. Because of the rarity and severity of the disease status, and of variety in evaluation methods, randomized clinical trials tend to be difficult in recruiting patients, in designing protocols, and in meeting primary endpoints. In such tough conditions, superiority of IVCY over corticosteroids alone for LN has been established, which is now going to be replaced by mycophenolate mofetil (MMF). Moreover, non-inferiority of tacrolimus to MMF is reported and efficacy of biologics such as Rituximab and Abatacept for LN is under investigation. In contrast, PM/DM-ILD is not suitable for randomized controlled trial because of the severity/acute progression in some patients. Intensive immunosuppressive regimen is recommended for those with poor prognostic factor(s). Cyclophosphamide has limited efficacy in SSc-ILD. Hematopoietic stem cell transplantation elongated patient survival and improved ILD, but with high treatment-related mortality rate. Efficacy of rituximab and MMF has been reported in small-sized trials. In this review, previously established treatment as well as emerging immunotherapies for organ involvements will be discussed. Our experiences in autoimmune settings also will be introduced.

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  Human immunological memory is the key distinguishing hallmark of the adaptive immune system and plays an important role in the prevention of morbidity and the severity of infection. The differentiation system of T cell memory has been clarified using mouse models. However, the human T cell memory system has great diversity induced by natural antigens derived from many pathogens and tumor cells throughout life, and profoundly differs from the mouse memory system constructed using artificial antigens and transgenic T cells. We believe that only human studies can elucidate the human immune system. The importance of immunological memory in cancer immunotherapy has been pointed out, and the trafficking properties and long-lasting anti-tumor capacity of memory T cells play a crucial role in the control of malignant tumors. Adoptive cell transfer of less differentiated T cells has consistently demonstrated superior anti-tumor capacity relative to more differentiated T cells. Therefore, a human T cell population with the characteristics of stem cell memory is thought to be attractive for peptide vaccination and adoptive cell transfer. A novel human memory T cell population that we have identified is closer to the naive state than previous memory T cells in the T cell differentiation lineage, and has the characteristics of stem-like chemoresistance. Here we introduce this novel population and describe the fundamentals of immunological memory in cancer immunotherapy.

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  Epigenetic modifications play a central role in the cellular programming of gene expression. Two of the most characterized epigenetic modifications are DNA methylation and histone modification. Recent observation that a number of GWAS SNP for immunological diseases localize to immune enhancers suggests the importance of epigenetic modifications that control enhancer activity. Epigenome-wide analysis of DNA-methylation in systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) revealed differential DNA methylation in a number of disease-related gene pathways. With regard to histone mark, the requirement of millions of cells for established protocol prevents application to clinical samples. However, recent technical advances enable us to capture open chromatin in small amount of patient samples. As epigenetic modifications function as an integrator of environmental stimulation and the underlying genetic variant, detailed epigenetic analysis combined with genetic and environmental factors may facilitate the understanding of the progression of human immunological diseases.

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  There has been no effective therapy in the unresectable melanoma for more than 40 years. Anti-PD-1 antibody and anti-CTLA-4 antibody have totally changed the situation. They have clearly shown the survival benefits of the patients with metastatic melanoma. However, immune checkpoint inhibitors sometimes induce various kinds of immune-related adverse events (irAEs). It is very important for the clinicians to know the reported cases of irAEs and to keep in mind the symptoms of irAEs for the early detection. This review describes the previously reported irAEs and adequate managements for irAEs induced by immune checkpoint inhibitors.

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  For assessing clinical disease activity in rheumatoid arthritis (RA), several composite measures of physical findings, patents'/evaluators' visual analog scales, and acute phase reactants has been used, contributing to advance in therapies through many clinical trials. However, more objective indices have been desired due to subjectivity in conventional indices. The Multi-Biomarker Disease Activity (MBDA) score is a novel blood-test based disease activity score of single integer ranging 1-100, derived from pre-specified algorithms in combination with 12 serum biomarkers (VCAM-1, EGF, VEGF-A, IL-6, TNF-RI, YKL-40, MMP-1, MMP-3, leptin, resistin, SAA, CRP). The MBDA score not only reflects disease activity in RA, but also is predictive for radiographic progression and risk of flare after drug reduction. Herein we review clinical usefulness of the MBDA score in RA.

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  Sjögren's syndrome (SS) is a chronic inflammatory autoimmune disease characterized by lymphocytic infiltration of the exocrine glands, especially the salivary and lacrimal glands. As a result of salivary gland dysfunction, most patients with SS have xerostomia, related to a reduced salivary flow rate. In addition to the discomfort due to xerostomia, dry mouth can cause various intraoral manifestations such as refractory stomatitis, ulcer and atrophic changes in the oral mucosa and tongue, and patients' quality of life (QOL) is impaired severely. These manifestations are believed to be caused mainly by a decrease in the clearance in the oral cavity owing to hyposalivation. However, since saliva has several beneficial physiological effects on the intraoral environment, qualitative changes in sialochemistry should also be considered a cause of the refractory intraoral manifestations in SS. Salivary epidermal growth factor (EGF) is considered an important cytoprotective factor against injuries, and it contributes to wound healing in the oral cavity. We evaluated changes in salivary EGF levels and assessed the association between salivary EGF levels and the severity of intraoral manifestations in SS patients. The results showed that the salivary EGF levels decreased with the progression of SS, and this deterioration in saliva quality as well as hyposalivation could play a role in the pathogenesis of refractory intraoral manifestations in SS patients. Our findings provide new target for therapeutic intervention in SS.

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  Transforming growth factor (TGF)-β family is a cytokine family with various biological processes and forms a highly homologous group of three mammalian isoforms, TGF-β1, TGF-β2, and TGF-β3. Most of the attention on TGF-β family in immunology has been mainly focused on TGF-β1 in that TGF-β1 induces anti-inflammatory regulatory T cells (Treg), and inflammatory T helper 17 (Th17) cells in combination with interleukin-6. Although little attention has been focused on the immunological roles of TGF-β2 and TGF-β3, the function of TGF-β3 for maintaining immunological homeostasis has recently been identified such as the induction of Th17 cells and direct regulatory effects on humoral immunity. TGF-β1 and TGF-β3 shares similar anti-inflammatory or pro-inflammatory functions, but exhibits significantly different effects on fibrosis and chondrogenesis. For the clinical application of TGF-βs, the mechanisms by which each TGF-β isoform regulates immunity has to be elucidated. In this review, we provide an overview of the effects, cellular targets, and therapeutic potential of TGF-βs on immune responses and autoimmune diseases.

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  Manifestation of rheumatoid arthritis (RA) can be attributed to both genetic and environmental factors. Some researchers have been focusing on intestinal microbiota which is thought to be one of the environmental factors that may enhance the development of RA. The advancement of culture-independent, high throughput microbial DNA sequencing had enabled us to understand the interplay between intestinal microbiota and host immune systems. In this study, we have reviewed the previous findings in animal and human studies with respect to the role of intestinal microbiota in RA. Mouse models of arthritis have demonstrated that gut microbiota plays a critical role in the disease development. K/BxN and IL-1 receptor-antagonist knock-out mice did not develop disease in germ free condition, however, colonization of particular intestinal bacteria was sufficient to induce arthritis. Moreover, the dysbiosis was observed in the human RA patients from United States, China and Finland. Thus, we believe that endeavors to improve the dysbiosis would serve as a novel therapeutic or preventive strategy in RA patients.

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  TAFRO syndrome is a newly defined disease entity which is characterized by thrombocytopenia, anasarca, myelofibrosis, renal dysfunction, and organomegaly. A histological pattern of multiple lymphadenopathy of atypical Castleman's disease (CD) is also an important characteristic. A 48-year-old man was referred to our hospital with fever, asthenia, bilateral pleural effusion, ascites, generalized edema, dyspnea, hypoalbuminemia, severe thrombocytopenia, anemia, renal failure and proteinuria, whereas bacterial culture and serological and PCR tests for various viruses were all negative. A CT scan showed multiple lymphadenopathy and tissue sampling of inguinal lymph nodes showed a compatible histology with plasma cell type CD. A diagnosis of TAFRO syndrome was made. Ten days after hospitalization, sudden cardiac insufficiency and anuria developed. Despite glucocorticoid pulse therapy, tocilizumab and plasmapheresis, clinical and laboratory features did not improve. On the 34^th hospital day, we started rituximab. His general condition started to improve in several days, and by one month later anasarca had improved drastically. Thrombocytopenia and renal function gradually improved and finally normalized. Cardiac motion also improved. This is the first report of a TAFRO syndrome patient with cardiomyopathy, who was successfully treated with rituximab.

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  Familial Mediterranean fever (FMF) is a hereditary autoinflammatory disease caused by Mediterranean FeVergene (MEFV) mutations on Chromosome 16, and characterized by periodic fever of and serositis. FMF is the result of gain-of-function mutations in pyrin that lead to interleukin-1β activation. FMF can be classified as “typical” and “atypical” types based on clinical finding and genetic screening. Although MEFV genotyping has enabled FMF to be confirmed in some cases, the diagnosis remains predominantly clinical since genotyping has shown that the disease is characterized by variable manifestations in Japanese. In 1976, the first report performed on the case of Japanese FMF with periodic fever of and serositis. Since 2002, genetic analyses are performed on Japanese FMF patients by K. Shiozaki et al. and N. Tomiyama et al. In our case, she was a 25-year-old Japanese woman with at periodic fever and abdominal pain. MEFV gene analysis demonstrated a heterozygous mutation of variant M694I, leading to a diagnosis of FMF. After the increase dose (up to 3 mg/day) of colchicine, periodic fever and abdominal pain disappeared. It is the important candidate of FMF for differential diagnosis with unexplained periodic fever and serositis, such as our case.

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  Major histocompatibility complex (MHC) molecule is important for immune system through its function of presentation of peptide antigens. MHC is the gene most strongly associated with susceptibility to many autoimmune diseases. We recently found a novel function of MHC class II molecules to transport cellular misfolded proteins to the cell surface without processing to peptides. Interestingly, misfolded proteins transported to the cell surface by MHC class II molecules were found to be a specific targets for autoantibodies produced in patients with autoimmune diseases such as rheumatoid arthritis and antiphospholipid syndrome. Furthermore, autoantibody binding to misfolded proteins complexed with MHC class II molecules is strongly associated with the susceptibility to autoimmune diseases conferred by each MHC class II allele. Therefore, misfolded proteins associated with MHC class II molecules might be involved in the pathogenesis of autoimmune diseases.

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  A 77-year-old woman with a 15-year history of rheumatoid arthritis (RA) was admitted to our hospital because of a wet cough that persisted for 1 month. The patient had been taking methotrexate (MTX) and adalimumab (ADA) for the past 3 years, and disease activity of RA was low. Discontinuation of ADA and MTX and treatment with oral levofloxacin were not effective. On admission, laboratory examinations showed eosinophilia (2539/μL), elevated serum total immunoglobulin E (538.0 IU/ml) and Aspergillus-specific immunoglobulin E levels, and Aspergillus fumigatus serum precipitins. A chest radiograph revealed multiple bilateral pulmonary shadows, and computed tomography revealed multiple consolidations. Bronchoscopic examination showed mucous plugs. Pathological examination revealed diffuse infiltration of eosinophils and fungus in the plugs. These findings led to the diagnosis of allergic bronchopulmonary aspergillosis (ABPA). A combination of prednisolone (0.5 mg/kg/day) and itraconazole (200 mg/day) was administered. After 3 months, the pulmonary consolidations resolved. To our knowledge, this is the first report of ABPA in a patient with RA treated with ADA. If patients treated with biologic disease-modifying antirheumatic drugs present with eosinophilia and pulmonary consolidations, clinicians should consider ABPA in the differential diagnosis.

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