Regulatory T cells (Treg) are important mechanisms that regulate autoimmunity and CD4+CD25+Foxp3+ regulatory T cells (CD25+Treg) have been extensively investigated. Recently, we have identified CD4+CD25-LAG3+ regulatory T cells (LAG3+Treg) that express an anergy associated transcription factor Egr2. Egr2 regulates IL-10 production in response to IL-27, and Egr2-deficiency in T cells and B cells results in systemic autoimmunity with increased IL-17 production. Moreover, addition of Egr3 deficiency to Egr2-deficient mice significantly accelerates systemic autoimmunity without functional impairment of CD25+Treg, indicating cooperative autoimmune-regulation by Egr2 and Egr3. The linkage between Egr2 and systemic autoimmunity is also suggested by the fact that stimulation with Ly108, a candidate lupus susceptibility gene in lupus-prone NZM2410 mice, induces Egr2 expression in T cells. Collectively, LAG3+Treg and Egr2 are the unique regulators of autoimmunity and further examination may help to understand and control immune responses.

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  Uveitis is narrow-defined inflammation of the uvea, also clinically include all inflammatory conditions in the eye. Uveitis may occur as a consequence of various causes and background, such as autoimmune diseases, infections, and hematopoietic malignancy. We have to treat uveitis not only controlling the inflammation but also maintaining up the visual function of the eye because the most uveitis is chronic and relapsing inflammatory disorder. Behçét's disease is a systemic disease and results in loss of vision without adequate treatment. Behçét's disease was a representative of vision loss uveitis because Behçét's patient usually had treatment resistance of conventional treatment, such as colchicine and cyclosporine. However, biological therapy with TNF-α, which started from 2007, has revolutionized the treatment strategy of Behçét's disease. It is not too much to say that Behçét's patient is free from fear of vision loss by the dramatic decrease of ocular attach. Biological therapy is not approved as a treatment of uveitis except Behçét's disease. Some protracted cases of Sarcoidosis and Vogt-Koyanagi-Harada disease are resistant to corticosteroid therapy and require new treatment. In this review, we discuss the pathophysiology of uveitis and report new treatment of Behçét's disease by biological therapy.

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  Multiple Sclerosis (MS) is an autoimmune-mediated chronic demyelinating disease of the central nervous system. The role of CD4+ T helper T cells in the pathogenesis of this disease is established. CD4+ T cells comprise various Th subsets, including Th1 and Th17 cells. The contributution of each T cell subset to MS pathology is not fully elucidated. As each Th subset have characteristic chemokine receptor expression patterns, we compared the frequency of various inflammatory chemokine receptor positive Th cells in peripheral blood with those from cerebrospinal fluid (CSF) for each MS patient. CCR2+CCR5+CD4+ T cells were selectively enriched in the CSF of MS patients but not in other neurological diseases. Peripheral CCR2+CCR5+CD4+ Tcells produced both IFN-γ and IL-17, expressed Matrix Metalloproteinase-9 (MMP9) and Osteopontin, and transmigrated in an in vitro blood brain barrier model more efficiently than other Th cells, suggesting a BBB-invading mechanism and an important role in the relapse of MS. This study illustrates the potential of method in which examining the combination of chemokine receptors could reveal a Th subset with disease-relevant function.

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  Tumor immunology has been advancing after the great discovery of tumor-specific antigen MAGE in 1991, and a number of tumor antigens have been reported to date. We have also found novel tumor antigens through various methodologies such as gene expression cloning, bioinformatics, reverse immunology, transcriptome analysis and peptidome analysis. Recently, we made a success of defining cancer stem cell-specific antigens. The fruits of our basic research have been applied to clinical trials of cancer vaccine. The long path and future perspectives of innovative immunotherapeutic drug development are described.

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  A 73-year-old man with inflammatory abdominal aortic aneurysm was admitted with headache and fever. Chest computed tomography (CT) revealed pneumonia and antibiotic therapy was started. Short-term memory impairment was observed and his consciousness had been rapidly deteriorated with seazure. Fluid- attenuated inversion recovery (FLAIR) image and diffusion- weighted magnetic resonance image (DWI) showed high intensity signals around bilateral limbic areas and herpes simplex encephalitis was suspected. After human herpesvirus (HHV)-6 DNA was amplified from cerebrospinal fluid, he was diagnosed with HHV-6 encephalitis and treated with gancyclovir. Clinicians need to be aware that glucocorticoid treatment for elderly can cause HHV-6 encephalitis.

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  A 62-year-old-man presented to our hospital with complaints of coldness, numbness, pain, weakness and cyanosis on the fingers and toes in March 2010. Laboratory findings revealed marked eosinophilia (46.6%; WBC 20600/μl), an elevation of serum creatine kinase, proteinuria and hematuria. He was diagnosed as hypereosinophilic syndrome (HES) without evidence to support a diagnosis of underlying diseases causing eosinophilia. After the initiation of corticosteroid therapy, peripheral eosinophil count was dramatically decreased, and both serum CK value and urinary findings became normalized. However, his symptoms persisted and digital necrotic changes developed. Angiography of the bilateral upper and lower extremities showed multiple arterial occlusions with poor collaterals. The digital gangrenes were unresponsive to peripheral circulation ameliorators and gradually progressed. In July 2010, autologous transplantation of bone marrow mononuclear cells was performed for achievement of therapeutic angiogenesis. His digital skin color was ameliorated by the angiogenic therapy in two weeks, and digital gangrenes did not progress after that. After amputation of his fingers and toe, cut surfaces healed with favorable epithelization, and the symptoms were subsequently eliminated. Moreover, during three years after the therapy, as well as the effect on the skin lesion, the significant improvement in peripheral circulation was observed. Therefore, we proposed that therapeutic angiogenesis by autologous bone marrow mononuclear cells transplantation was a novel and effective treatment for intractable digital gangrene associated with HES.

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  We report a 68-years-old woman with systemic sclerosis and interstitial pneumonia (IP). She had developed subacute progressively encephalopathy and dementia while treated with oral cyclophosphamide and prednisolone. She admitted to our hospital because of syncope. Laboratory tests indicated slight elevated cerebrospinal fluid protein, and levels of serum C-reactive protein (CRP), levels of soluble IL-2 receptor was normal. But, magnetic resonance imaging (MRI) of the brain showed multiple infarct-like lesions mainly in the white matter, which mimics progressive multiple leukoencephalopathy (PML). Twenty days after admission, the retested MRI of the brain disclosed initial lesions progressively enlarged and numbers of the lesions were increased. The polymerase chain reaction (PCR) for JC virus of cerebrospinal fluid was negative. To make diagnosis, brain biopsy was performed. Microscopic examination revealed that small vessels were filled with lymphoma cells (CD20+, CD79+, CD3−), and intravascular lymphoma (IVL) was diagnosed. She treated with regimens of R-CHOP. After chemotherapy her consciousness and dementia were gradually improved. IVL of central nerve system (CNS) is a rare disease, and its common symptoms are ischemia, infarction and dementia. Diagnosis of IVL of CNS is difficult when the lesion mimics PML, and patient with similar laboratory examinations and radiographic findings of PML should undergo brain biopsy detected malignant cell in small vessels, which is a value of diagnosis.

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