Semaphorins were identified originally as guidance cues for developing neuronal axons. However, it is becoming clear that several semaphorins play important roles in the immune system. For instance, Sema4D (CD100) enhances activation of B cells and dendritic cells through its receptor, CD72. Sema4A is crucially involved not only in T cell priming but also in Th1/Th2 regulation. Additional semaphorins and related molecules also have distinct biological activities in the immune system. We here review the current topic of immunoregulatory semaphorins which could be targets for potenciation of, and intervention for immune response.

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  Primary biliary cirrhosisis (PBC) is considered to be an autoimmune disease selectively targeted for interlobular bile ducts. While anti-mitochondrial antibodies are specifically detected in more than 90% of PBC patients, anti-nuclear envelope-gp210 antibodies are also specifically detected in 20-30% of PBC patients. In this review, we present 1, T cells specific for mitochondrial major epitope, PDC-E2 163-176, cross-react with peptides derived from nuclear envelope-gp210 protein, 2, PBC patients who have sustained high antibody titers to gp210 are at high risk for the progression to end-stage hepatic failure. These evidences may be very important for the epitope spreading of autoantigens from PDC-E2 to nuclear antigens and for the identification of target antigens on biliary epithelial cells which are recognized by cytotoxic T cells in PBC.

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  Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by the occurrence of numerous autoantibodies directed against nuclear antigens. Anti-histone antibodies (AHA) are as prevalent as their anti-dsDNA counterparts in SLE. Despite their frequency and potential importance, there have not been given much attention to AHA until recently. Nucleosomes, the fundamental repeating units of the chromatin, are formed of complexes of histones and DNA. The nucleosome core particle is composed of a central tetramer of 2 molecules each of H3 and H4 flanked by 2 dimers of H2A and H2B and surrounded by 2 superhelical turns of approximately 146 base pairs of DNA. The full nucleosome conatins a molecule of H1 located at the point where DNA enters and exits the nucleosome. Recent studies have shown that the post transcriptional modification of histone changes chromatin structure to regulate transcription and the concept of this mechanism “epigenetics” has become center of attention in the field of basic cell biology.
  There have been described diverging specificities of AHA. Many attempts to locate antigenic determinants recognized by AHA have been made and H1 and H2B have been thought as common targets in lupus patients. Studies on murine models of lupus have shown several intresting findings. The universal epitope is located on H2B in (NZBxNZW)F1 mice. In addition to core histones, MRL-MP/Fas^lpr mice develop high titers of autoantibodies to H1. Autoimmunity to chromatin regularly involves humoral immune responses directed against H1. These histones appear to be an early (possibly initial trigger) autoantigen for this autoimmune response in lupus.

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  The migration of leukocytes into inflamed peripheral tissues and lymphoid organs involves a cascade of molecular events finely regulated by cell adhesion molecules and chemokines. Fractalkine/CX3CL1 is a membrane-bound chemokine that functions not only as a chemoattractant but also as an adhesion molecule, and is expressed on endothelial cells activated by proinflammatory cytokines. The fractalkine receptor, CX3CR1, is expressed on cytotoxic effector lymphocytes including NK cells and cytotoxic effector T cells (T_CE), mature monocytes/macrophages, and mucosal dendritic cells, all of which play important roles in elimination of pathogens and cancer cells. Recently, accumulating evidence in both clinical studies and animal disease models has shown that fractalkine is also involved in the pathogenesis of various chronic inflammatory diseases, such as rheumatoid arthritis and atherosclerosis. This article reviews the unique functions of fractalkine and its pathophysiological roles in various clinical conditions.

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  The Wiskott-Aldrich syndrome (WAS) is an X-linked primary immunodeficiency caused by mutations in the gene encoding the WAS protein (WASP). WASP is predominantly expressed in hematopoietic cells and regulates the reorganization of the actin cytoskeleton in response to various important cell stimuli including T cell receptor signaling. WASP is localized at the immunological synapses between T cells and antigen presenting cells, NK cells and target cells. Here we focus on recent basic and clinical research advances for WAS, which has given great insight into the relevance of WASP, its related molecules and its interacting proteins to basic cell biology, actin cytoskeleton, immunological defects and prediction of clinical outcome in WAS patients. In particular, we have reported the significance of WIP (WASP-interacting protein) for molecular regulation of WASP. In addition, we discuss recent basic approaches to gene therapy for WAS.

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  A 46-year-old male demonstrated edematous fingers on both hands in November 2003, and interstitial pneumonia was noted on chest X-ray during a medical check-up in December 2003. Since muscular weakness and fever developed thereafter, and interstitial pneumonia was aggravated on chest X-ray and CT, the patient was admitted to our hospital on March 25, 2004. Heliotrope-like erythema, and Gottron's sign were noted. Laboratory findings showed the following ; LDH 876 U/l ; CK 224 U/l ; CRP 5.68 mg/dl ; and KL-6 3270 U/ml. Autoantibodies such as anti-Jo-1 antibody were all negative. Chest X-ray and CT showed ground-glass opacity in the bilateral lower dorsal regions of the lung, and reduced volume of the inferior lobe. He was diagnosed as having dermatomyositis (DM) associated with progressive interstitial pneumonia. Although a combination of steroid pulse theraphy and Cyclosporin-A were administered, the pulmonary lesions became aggravated. Additional intravenous Cyclophosphamide (IVCY) was intiated on the 6th hospital day, and interstitial pneumonia was markedly improved. Cases of progressive interstitial pneumonia associated with DM that are negative for anti-Jo-1 antibody and show a low ratio of CK/LDH are resistant to various treatments. Our case suggested that combination therapy with steroid, Cyclosporin-A, and IVCY is useful for the treatment of progressive interstitial pneumonia with DM.

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  A 10-year-old girl with autoimmune hepatitis (AIH) was reported. She was admitted to our hospital because of cholestasis and elevation of liver enzymes for 2 months. Laboratory examination revealed that EBV-DNA copy number in the PBMNC (peripheral mononuclear cells) was 1.2×10³ copies/microg of DNA, hypergammaglobulinemia, and positive antinuclear antibody, positive anti-smooth muscle antibody. The histology of her liver biopsy specimen revealed interface hepatitis, dense mononuclear cell infiltrates, mild fibrosis, and negative for EBV in situ hybridization assay indicating AIH and not EBV-associated hepatitis. She was treated firstly with methylprednisolone pulses, then will prednisolone p.o.+azathioprine p.o.. Intravenous cyclophosphamide pulse therapy was introduced because of her abnormal immune pathology. All abnormal laboratory parameters improved to normal levels within 2 months, and EBV-DNA copy number in the PBMNC became negative after 4 months. The histology of liver biopsy specimen was useful for the diagnosis of AIH in such a difficult case needed to be differentiated from EBV hepatitis.

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