Pulmonary hypertension is the most ominous complication of connective tissue diseases and its treatment has been a big challenge to clinicians. Vasodilators including epoprostenol (prostacyclin), bosentan (endothelin-receptor antagonist), and a sildenafil (phosphodiesterase type 5 inhibitor) have recently become available in Japan. These vasodilators may improve exercise tolerance, hemodynamics, activities of daily life, and the life span. In this article, we review an endothelin-receptor antagonist and phosphodiesterase type 5 inhibitor recently approved as treatment modalities for pulmonary hypertension in Japan.

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  Treatment with anti-CD3 antibodies appears promising to preserve residual beta-cell function in recent onset type 1 diabetes although many patients had therapy related adverse events. Insulin is an important islet antigen and autoimmunity to insulin may be central to disease pathogenesis of type 1 diabetes in man and NOD mouse. Evidence is strongest for the NOD mouse model, where blocking immune responses to insulin by amino acid substitution at positions B: 16, prevents diabetes. Insulin can be used to immunologically prevent diabetes of NOD mice, however, insulin-based preventive immunoregulation of diabetes in man is not yet possible. Treatment of NOD mice with insulin B-chain peptide and poly I: C, a Toll-like receptor 3 ligand, induces the pathogenic T cells as well as regulatory T cells and recruits them into the islets. Intranasal treatment with insulin B-chain analogue peptide with amino acid substitutions at positions B: 16 and 19 prevented the progression to diabetes and induced remission from hyperglycemia when co-administered with a mucosal adjuvant cholera toxin. Thus, an antigenic peptide vaccination with an alternative adjuvant or route might induce antigen-specific regulatory cell populations rather than pathogenic T cells. We believe that such an improved antigen specific therapy could provide more efficient and safer disease suppression and remission for human type 1 diabetes.

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  Sh2b3/Lnk consisting of an N-terminal proline-rich region, PH-, SH2-domains and a tyrosine phosphorylation site, forms an intracellular adaptor protein family conserved from drosophila to mammals, together with Sh2b1/SH2-B and Sh2b2/APS (adaptor protein with PH and SH2 domains). Lnk negatively regulates lymphopoiesis and early hematopoiesis. The lnk-deficiency results in enhanced production of B cells, and expansion as well as enhanced function of hematopoietic stem cells (HSCs), demonstrating negative regulatory functions of Sh2b3/Lnk in cytokine signaling. Our recent studies also revealed that Sh2b3/Lnk functions in responses controlled by cell adhesion and in crosstalk between integrin- and cytokine-mediated signaling. Importantly, recent genome-wide association studies of the autoimmune type 1 diabetes or celiac disease identified risk variants in the SH2B3/LNK region, indicating possible unrevealed functions mediated by this adaptor molecule. This review summarizes roles of Sh2b3/Lnk in the regulation of B-lymphopoiesis and HSCs expansion and function, and briefly introduces our approach for modulating HSCs function by targeting Sh2b3/Lnk-mediated pathways.

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  Human parvovirus B19 infection causes erythema infectiosum in child, aplastic crisis in patients with chronic hemolytic anemia, chronic pure red cell aplasia in immunocompromised patients and hydrops fetalis. Human parvovirus B19 causes arthritis and acute glomerulonephritis due to immunological mechanism. Other disorders, rheumatoid arthritis, vasculitis and thrombotic microangiopathy, are linked in human parvovirus B19 infection. Parvovirus B19 infection causes choronic rheumatoid-like arthropathy. Autoantibody and low complement were seen in acute human parvovirus infection, and parvovirus B19 infection present clinically lupus like tableau.

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  Pyoderma gangrenosum is a rare chronic ulcerative noninfectious disease of the skin. Half of patients are complicated with other autoimmune diseases, most commonly inflammatory bowel disease, Takayasu disease, and rheumatoid arthritis. It has been reported that approximately 4% of them were childhood-onset.
  The conventional treatments of pyoderma gangrenosum were described as systemic corticosteroids and cyclosporine. The combination of corticosteroids with immunosuppressants such as tacrolimus, mycophenolate mofetil has been reported as steroid-sparing modalities.
  We herein reported a girl, 12 years of age, having pyoderma gangrenosum refractory to the conventional combination of systemic prednisolone with cyclosporine, but successfully treated with infliximab, the anti-TNFα monoclonal antibody. Rapid improvement of pyoderma gangrenosum was seen within three doses of infliximab infusion. All skin lesions eventually healed completely and new skin ulcers were never coming out again. The dramatical improvement suggested that infliximab should be considered for patients with refractory pyoderma gangrenosum though further experiences and investigations are required to determine the mechanism of infliximab.

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  A 55-year-old woman developed bilateral leg edema in June 2006. Since the edema tended to worsen, she visited our hospital on November 11. Laboratory tests showed a serum albumin level of 2.5 g/dl with 3+ proteinuria, and suggested nephrotic syndrome, which led to her hospitalization on November 14. The findings of discoid erythema, an antinuclear antibody titer of 1: 640, anti-ds DNA antibody titer of 16.8 IU/ml, and ISN/RPS class III (A/C)+V lupus nephritis on kidney biopsy led to the diagnosis of systemic lupus erythematosus. Treatment with prednisolone at 1 mg/kg/day was initiated. Despite an increase in complement levels and decreases in anti-ds DNA antibody titers and immune complexes, proteinuria persisted; therefore, the patient was concomitantly given 125 mg/day of azathioprine, which was discontinued because of the poor improvement of proteinuria and development of myelosuppression, and replaced by 3 mg/day of tacrolimus (Tac), with a consequent marked improvement in proteinuria. We report a patient with refractory proteinuria due to class III/V lupus nephritis who achieved a Tac-induced complete remission.

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  We describe a case of systemic lupus erythematosus (SLE) complicated with multifocal leukoencephalopathy (PML). A 57-year old woman, who had a five-year history of SLE, was admitted to our hospital because of fever and multiple subcutaneous nodules. Diagnosis of disseminated cryptococcosis was made based on histological and bacteriological examinations, and she was successfully treated with anti-fungal drugs. Corticoteroids were increased for persistent lupus activities. One month later, however, she gradually developed disorientation and short-term memory loss. A brain magnetic resonance image (MRI) showed a focal lesion in the white matter of the right frontal lobe. Brain biopsy demonstrated demyelinating lesions with the presence of JC viral antigen. Polymerase chain reaction also revealed JC virus DNA in the cerebrospinal fluid. Her condition gradually progressed, and she died a year later due to pneumonia. Although acquired immunodeficiency syndrome is currently the most common disease associated with PML, patients with autoimmune diseases receiving immunosuppressive therapy also have risks for developing PML. In patients with SLE presenting with subacute neurological abnormalities and white matter lesions in the brain, PML should be considered in the differential diagnosis.

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