Systemic lupus erythematosus (SLE) is a prototypic systemic autoimmune disease that is characterized by the production of multiple autoantibodies and immune complex formation. Lupus nephritis (LN), which has various histological patterns and variable clinical outcomes, is one of the most important complications of SLE. Although this pathogenetic mechanism in each histologically different type of nephritis remains unclear, recent findings in LN elucidate an essential role for the Th1, IL-17 producing T cells and Th17 cells in the development of diffuse lupus nephritis (DLN), and Th2 cytokine in that of membranous lupus nephritis (MLN). These data support the hypothesis that individual Th1/Th2 balance is one of the critical determinants for histopathology of LN. Therefore the suppression of pivotal role cytokines in each pathological condition may support immunosuppressant strategy for LN.

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  Many recent clinical trials of immunotherapy for advanced tumors have reported remarkable results. For example, blockade of cytotoxic T-lymphocyte antigen 4 (CTLA-4) significantly improved median overall survival of melanoma patients. Blockade of programmed cell death 1 (PD-1) or programmed cell death 1 ligand 1 (PD-L1) induced durable tumor regression and prolonged disease stabilization in patients with advanced cancers, including melanoma, non-small-cell lung cancer, and renal cell cancer. In addition, adoptive cell transfer of tumor infiltrating lymphocytes (TILs) and T cells transduced with high avidity T cell receptor (TCR) genes have been reported to elicit marked durable tumor regression in melanoma patients. Further, clinical trials of cancer vaccines targeting various tumors have been conducted to prolong overall survival. In this review, some remarkable results achieved in recent clinical trials are summarized.

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  Systemic sclerosis (SSc) is a connective tissue disorder characterized by microvascular damage and excessive fibrosis of the skin and internal organs with autoimmune background. One representative feature of the immunological abnormalities in SSc patients is the presence of antinuclear antibodies (ANA). More than 90% of patients with SSc are positive for ANA. Although a role of ANA in the pathogenesis in SSc remains unclear, the particular ANA are often indicative of clinical feature, disease course, and overall severity. Therefore, subgrouping patients based on the type of autoantibodies present can be useful in diagnosis and management. Anticentromere antibody (ACA), anti-DNA topoisomerase I antibody (Ab), and anti-RNA polymerase Ab are the representative autoAbs found in patients with SSc. Other serum ANA found in SSc include anti-Th/To Ab, anti-U3RNP Ab, anit-human upstream-binding protein (hUBF) Ab, anti-centriole Ab, anti-U1RNP Ab, anti-Ku Ab, and anti-PM-Scl Ab. It is documented that the prevalence of SSc-related Abs and clinical characteristics of patients with SSc are influenced by ethnicity. Identifying several SSc-related Abs requires a complicated technique that include immunoprecipitation assay. Establishment of a system routinely available to screen ANA specificities such as enzyme-linked immunosorbent assay is needed.

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  Patients affected by primary immunodeficiency (PID) can be cured by allogeneic hematopoietic stem cell transplantation (HSCT). In the absence of HLA-matched donors, however, incidence of HSCT-related complications is observed. Therefore, gene therapy has been developed as a highly desirable alternative treatment for patients lacking suitable donors. Retrovirus-based gene therapy was begun in 1990 for the patients of adenosine deaminase deficiency, followed by X-linked severe combined immunodeficiency, Wiskott-Aldrich syndrome and chronic granulomatous disease. Although treated patients have had excellent immune reconstitution and resolution of ongoing infections, complications such as a lymphoproliferative syndrome and a disappearance of gene-modified cells were observed in some clinical trials. To overcome these, ongoing and upcoming clinical trials use some new strategies. The use of preconditioning chemotherapy makes space in the bone marrow for the gene-treated stem cells and allows engraftment of multi lineage stem/progenitor cells. Self-inactivating vectors in which strong enhancers of long terminal repeat are eliminated may reduce the risk of insertional activation of proto-oncogene resulting in leukemia. These modifications will surely increase the safety and efficacy of stem cell gene therapy for PID.

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  Acute inflammation, a physiologic response to protect cells from microbial infection and other stimuli, is automatically terminated by endogenous anti-inflammatory and pro-resolving mediators to restore homeostatic conditions. However, if timely resolution of inflammation is failed, inflammation persists and can progress to a chronic inflammation such as rheumatoid arthritis, interstitial pneumonitis. To prevent chronic inflammation, understanding the process that resolves inflammation is essential. Resolution of inflammation is an active coordinated process regulated by distinct anti-inflammatory and pro-resolving endogenous lipid mediators, such as lipoxins/ALX, chemerin/chemR23. In resolution of inflammation these resolving factors contribute a bridge between innate and adaptive immunity.

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  Denosumab (called RANMARK^® in Japan), an anti-bone resorptive drug, is a complete human type monoclonal antibody that targets the osteoclast differentiation factor receptor activator of NF-κB ligand (RANKL). Using advanced gene-engineering techniques, Amgen Inc. (USA) has developed the drug, and it is now utilized in Japan for treatment of cancerous bone lesions associated with multiple myeloma and bone metastasis. On the other hand, denosumab has also shown inhibitory effects on bone resorption seen in patients with osteoporosis, rheumatoid arthritis, and Paget's disease, thus its range of use for medical treatment is expected to widen. Because of its long half-life in the body, subcutaneous denosumab administrations every 6 months are sufficient to obtain inhibitory effects on bone resorption, suggesting that this agent is more efficacious than bisphosphonates, which are presently used as anti-bone resorptive drugs. However, hypocalcemia might develop in patients with massive renal dysfunction. Denosumab binds to a specific loop structure of the RANKL molecule and inhibits its interaction with its receptor RANK. When labeled with radioactivity, denosumab was detected in lymph nodes and the spleen after subcutaneous administration, indicating its binding to RANKL expressed in those tissues. Thus, many medical doctors and investigators are interested in the inhibitory effects of denosumab on bone resorption as well as its mode of action.

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  A 68-year-old female who had Raynaud phenomenon for a decade was admitted to our hospital in January 2012. She complained of sclerodactyly and scleroderma that did not extend past the elbows. She also had fingertip ulcers that repeatedly disappeared and recurred for several years. Blood tests showed that she was anti-centromere antibody positive. Therefore, she was diagnosed with limited cutaneous systemic sclerosis. Two months after diagnosis, she returned to our hospital because she experienced dyspnea on exertion and exacerbation of her fingertip ulcers. Chest X-rays revealed cardiac enlargement, an echocardiography showed tricuspid regurgitation with an increased tricuspid pressure gradient (91 mmHg) and right heart catheterization showed a mean pulmonary arterial pressure of 59 mmHg. Chest computed tomography and lung perfusion scintigraphy showed no abnormalities. She was then diagnosed with pulmonary arterial hypertension associated with systemic sclerosis. She improved rapidly with daily treatments of prednisolone in addition to warfarin, bosentan and beraprost sodium. This is a rare case of rapidly progressive pulmonary arterial hypertension associated with systemic sclerosis that can be markedly improved with early diagnosis and treatment.

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  Diagnosis of multiple sclerosis (MS) is difficult when the lesion mimics glioma or cerebral enchephalitis. We report a case of pediatric MS initially suspected as brain stem glioma. An 11-year-old boy developed left foot joint pain followed by progressive symptoms such as left arm and leg weakness, dysarthria, paraplegia, and decreased level of consciousness. He subsequently developed respiratory distress requiring endotracheal intubation and mechanical ventilation. Magnetic resonance imaging showed a mass measuring 2 cm in the medulla oblongata. Although this mass was initially suspected as a glioma, the patient's acutely progressive disease course was not consistent with this diagnosis. Open biopsy revealed inflammation and demyelination, but no malignant cells were detected. He was treated with steroid pulse therapy, which showed dramatic effects. Nine months later, he developed another episode characterized by several neurological symptoms, and the diagnosis of MS was clinically confirmed. Open brain stem biopsy is technically demanding, but this case demonstrates that appropriate neurosurgical evaluation can play an important role in diagnosis by ruling out glioma and confirming MS.

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