Recent progress in immunology, utilizing molecular biology techniques, has elucidated the molecular mechanism of immune system. In the treatment of autoimmune diseases, molecular targeting therapies utilizing biologics such as monoclonal antibodies are now available. However, exact causes of the most autoimmune diseases are not known and there remain many issues which should be resolved.
  Interleukin-6 (IL-6) is a cytokine which regulates immune response and inflammation. Deregulated overproduction of IL-6 is involved in the immune-inflammatory diseases such as Castleman's disease and rheumatoid arthritis. A humanized anti-IL-6 receptor antibody tocilizumab has been proven to be therapeutically effective for the diseases. Simultaneously, we have learned new biological activities from the translational research. In this review, a study from bedside to bench is to be discussed.

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  We have demonstrated that IL-7 is produced by intestinal epithelial cells (IECs) and regulates the proliferation of IL-7R+ mucosal T cells. IEC-derived IL-7 is indispensable for both organization of mucosal lymphoid tissues and regulation of mucosal immune responses. Dysreguration of mucosal IL-7-dependent pathway leads to chronic intestinal inflammation. On the basis of the fact that IL-7R is expressed in both mucosal T cells and IECs, we found the crossing between mucosal immunity and epithelial regeneration/differentiation in human intestine. Human IECs are partly of bone marrow (BM) origin and BM-derived IECs promote the regeneration of the damaged intestinal epithelium. During regeneration following severe damage, BM-derived IECs trigger the change of IEC differentiation. BM-derived IECs mainly repopulate the absorptive IECs in normal condition, but IEC differentiation is changed toward the secretory lineage IECs during regeneration. Transcription regulation of IEC-derived IL-7 shows close relation to IEC cell specific lineage and is disturbed in chronic intestinal inflammation. Moreover, expression and function of transcription factors downstream of Notch signaling pathway that mediates IEC differentiation is changed in chronic intestinal inflammation. All these results indicated that the disorder of both IEC differentiation and mucosal immunity cause human inflammatory bowel disease.

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  Rheumatoid athritis (RA) is a disease full of variety. We need to elucidate various clinical doubts for the complete cure of RA. We observed a lot of patients with human parvovirus B19 (B19) infection who developed to RA till now. We investigated B19 infection in relation with RA etiology. B19 infects persistently to immune cells through cell surface Ku80 autoantigen as a cellular receptor. We are able to detect B19 in immune cells which infiltrate in synovial tissues of patients with RA. B19 is activated in infected cells, and functional viral protein NS1 induces over production of inflammatory cytokine TNFα As a result, it promotes a neutrophile activation and migration to the synovium where there are B19-infected immune cells. This may cause arthritis and create a vicious circle of chronic inflammation that develops into RA. As for the B19 persistent infection to immune cells, abnormality of anti-B19 humoral immunity may participate in imperfection of B19 neutralization of a host. It is expected the development of effective treatment that cure progressing RA from B19 infection. NS1 may be one of the candidates of therapeutic target.

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  Antiphospholipid antibodies (aPL) recognize phospholipid-binding proteins such as β₂-glycoprotein I (β₂-GPI) and prothrombin, inducing thrombosis and pregnancy morbidities. Pathogenicity of aPL has been established by many in vivo experiments in which administration of aPL resulted in pregnancy losses and/or thrombotic phenomena. The mechanisms how aPL cause such symptoms have been extensively investigated. aPL alters fibrinolysis/coagulation system by suppression of protein C/Z systems in the presence of β₂-GPI. B cell epitopes were also studied for specific therapies, resulting in diverse candidates such as domain I, IV or other domains. For T cells, importance of cryptic epitope on domain V was suggested. Recently, activation of endothelial cells, monocytes and thrombocytes by aPL with β₂-GPI has been reported. This activation is mainly mediated by p38MAP kinase activation and results in expression of tissue factor and adhesion molecules in endothelial cells and monocytes, thromboxane B2 in thrombocytes. Annexin II, toll-like receptor 4, LDL-receptor family members, and glycoprotein Ib are the candidates for cell surface ligands, suggesting the possibility of their blockades by monoclonal antibodies. Although treatment of APS is now limited to nonspecific anticoagulants or anti-platelet agents, based on these new insights, specific therapies targeting signal molecules and/or cell surface ligands for β₂-GPI should be introduced in near future.

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  Although corticosteroids and immunosuppressants are widely used for the treatments of autoimmune diseases such as systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA), we often experience patients who are resistant to these treatments. P-glycoprotein (P-gp) of membrane transporters, a product of the multiple drug resistance (MDR)-1 gene, plays a pivotal role in the acquisition of drug resistance. However, the relevance of MDR-1 and P-gp to resting and activated lymphocyte, major targets of the treatments in autoimmune diseases, remains unclear. We found that peripheral lymphocytes in patients with SLE and RA express P-gp on the surface and its expression is highly correlated with disease activity. P-gp on lymphocytes is induced by activation with cytokines such as IL-2, IL-4 and TNF-α, resulting in active efflux of corticosteroids from cytoplasm of lymphocytes, which mechanisms could lead to drug-resistance and high disease activity. However, the addition of P-gp antagonists such as ciclosporin A and inhibitors of P-gp synthesis successfully reduce efflux of corticosteroids from lymphocytes in vitro and these results imply that P-gp antagonists and P-gp synthesis inhibitors could work in order to overcome drug-resistance in vivo. Therefore, we propose that measurement of P-gp on lymphocytes is useful marker to indicate drug resistance and requirement of antagonists and/or intensive treatments to overcome drug resistance in active SLE and RA patients.

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  To form the human body and maintain the integrity of its complex tissues, individual cells need to hold tightly to each other. The desmosome is the major type of intercellular adhesive junction, and has desmoglein (Dsg), a cadherin type cell-cell adhesion molecule, as a transmembrane component. Dsg is now known to be targeted in autoimmune diseases, infectious diseases, as well as inherited diseases. Patients with pemphigus, an autoimmune blistering disease of the skin and mucous membrane, have IgG autoantibodies directed against Dsg1 and Dsg3. A subset of patients with pemphigus have Dsg1/Dsg4 crossreacting IgG autoantibodies. Exfoliative toxins produced by Staphylococcal aureus, which causes Staphylococcal Scalded Skin Syndrome (SSSS) and bullous impetigo, specifically digest Dsg1. A subset of patients with SSSS develop a low titer of anti-Dsg1 IgG autoantibodies. A mutation in DSG1 gene causes striate palmoplantar keratoderma and a mutation in DSG4 gene causes inherited hypotrichosis. It is not clear why so many diseases are clustered in desmogleins, but there must be a reason for this. Studies on desmogleins will provide an important framework to understand the mysteries between autoimmunity and infection.

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  Acute inflammatory responses are one of the major underlying mechanisms for tissue damage of multiple diseases, such as sepsis and acute lung injury. Inflammatory mediators released from a variety of cells in response to acute inflammations can interact with immune cells, microvascular endothelial cells and other tissue cells, to elicit a series of intracellular signaling reactions where activation of Src protein tyrosine kinase (PTK) family members is involved. Using cellular and molecular approaches and transgenic animals, Src PTK family members have been identified to be essential for the recruitment and activation of monocytes, macrophages, neutrophils and other immune cells. Src PTK family members also play a critical role in the regulation of vascular permeability and inflammatory responses in tissue cells. Importantly, animal studies have demonstrated that small chemical inhibitors for Src PTKs attenuated acute lung injury. Further investigation may lead to the clinical application of these inhibitors as drugs for acute lung injury.

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  We described a case of thrombotic thrombocytopenic purpura (TTP) with systemic lupus erythematosus (SLE). A-60-year old woman was admitted to our hospital because of fever, disconsciousness, and general fatigue. 32 years ago, she was diagnosed as SLE with Raynaud's phenomenon, rash, photosensitivity, arthritis, lymphocytopenia, and ANA. Her SLE was well controlled with 10 mg predonisolone as a maintance dose until several weeks ago. On admission, severe thrombocytopenia (0.7×10⁴/μl) and other laboratory data revealed microangiopathic hemolytic anemia and renal dysfunction, Immediately after diagnosed as TTP, plasma exchange and corticosteroid therapy started. In spite of the treatment, disconsciousness progressed and systemic convulsion occurred and died 4 days after admission. Autopsied examination revealed diffuse microvascular hyalinized thrombi in heart, kidney, liver, spleen, and pancreas. Some microvascular thrombi were detected in lymph nodes, bone marrow, intestine. Pathological diagnosis of TTP was made on microvascular hyalinized platelet thrombi in organs. Von Willebrand factor-cleaving protease (VWF-CP) activity in plasma on set is less than 0.5 percent of normal and inhibitor for VWF-CP was detected. We here report a valuable case for analysis of pathogenesis in SLE-TTP.

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