Chronic sialadenitis in Sjögren's syndrome (SS) is associated with cell death induced by Fas or cytotoxic granules. Furthermore, tumor necrosis factor-related apoptosis inducing ligand or toll-like receptor3 are known to induce apoptosis in the salivary gland epithelial cells (SGECs) derived from patients with SS. Anti-apoptotic molecules that are closely related to epidermal growth factor are known to inhibit apoptosis. Epidemiologically, high prevalence of HTLV-I in primary Sjögren's syndrome (SS) patients has been found in an endemic area. However, by comparison of radiographic imaging with mononuclear cells (MNCs) infiltration of LSGs, we have found that there are significantly fewer abnormalities determined by sialography in HTLV-I-seropositive SS patients in comparison with HTLV-I-seronegative SS patients irrespective of similar grade of MNCs infiltration. In HTLV-I-seropositive SS patients, low frequency of salivary gland destruction was observed and this phenomenon was associated with frequency of the ectopic germinal center (GC). Then, we show cytokine profile in culture supernatant of salivary gland epithelial cells co-cultured with HCT-5 established from spinal fluid of patients with HAM. Up-regulation of adhesion molecule or migration factor was observed in culture supernatant. On the other hand, co-cultured cell lysate showed apoptotic and anti-apoptotic molecules without increase of apoptosis. Detailed molecular mechanisms in these processes are under study.

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  Cell death process can be involved in the development, differentiation, inflammation, immunity and tumorigenesis. Molecular mechanism of apoptotic cell death has been unveiled while molecular mechanisms of the other programmed cell death, especially necroptosis and autophagy, also have been elucidated. Autophagy is a highly conserved lysosome-mediated catabolic process and a homeostatic process to degrade unnecessary or dysfunctional cellular organelles and to recycle nutrients. The relation between autophagy and human disease has been reported. Here, we describe about the role of autophagy in autoimmune disease.

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  Negative selection induces central tolerance in which self-reactive T cells are deleted by medullary thymic epithelial cells (mTECs) to prevent autoimmunity. The transcriptional factor, autoimmune regulator (Aire), controls the expression of tissue-specific antigens (TSAs) by mTECs for negative selection. The mechanisms by which Aire targets loci which encode TSAs are unknown in detail; recently, however, the ATF7ip-MBD1 complex was identified as an Aire-interacting transcriptional protein complex required for its targeting the loci. Lineage tracing of Aire⁺ mTECs identified that mTECs have a post-Aire stage during the development, where they lost maturation markers but maintained intermediate TSA expression, and Aire is required for the terminal differentiation of mTEC's. Extrathymic Aire-expressing cells (eTACs) are identified in murine and human secondary lymphoid organs. eTACs express major histocompatibility complex class II^hi, CD80^lo, CD86^lo, epithelial cell adhesion molecule^hi, CD45^lo bone marrow-derived peripheral antigen-presenting cell population, which is distinct from mTECs and dendritic cells. They can induce activation-induced cell death of self-reactive CD8⁺ T cells and unresponsiveness of self-reactive CD4⁺ T cells through a mechanism that does not require regulatory T cells, suggesting that peripheral Aire plays a complementary role for central tolerance.

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  Allograft inflammatory factor-1 is the protein that expressed in the macrophages around the coronary arteries in rat ectopic cardiac allograft model. AIF-1 is produced mainly by macrophages and regulated by interferon-gamma (IFN-γ). There are various splicing valiants in AIF-1, and the functions are different. AIF-1 has Ca-binding EF-hand motif that induces cell proliferation and migration by structural features. Besides cell proliferation and migration, AIF-1 contributes to secretion of inflammatory cytokines and chemokines such as IL-6, IL-10, IL-12, and transforming growth factor-beta (TGF-β), insulin resistance by downregulation of GLUT4 or IRS-1, and fibrosis process by upregulation of collagen production. It has been elucidated that AIF-1 is responsible for the onset of various diseases such as rheumatoid arthritis and systemic sclerosis, atherosclerotic disease, diabetes mellitus. AIF-1 may have the therapeutic potential for chronic inflammatory diseases by elucidation of the mechanism.

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  The immune network is a complex system comprising several types of inflammatory and regulatory cells. Autoimmune diseases occur because of dysregulation in host defenses caused by a cellular imbalance. The pattern of imbalance depends on the disease. Most autoimmune diseases are chronic, and the mechanism underlying this chronic nature is yet to be determined. Monoclonal antibody therapy is highly specific to the molecules targeted and is therefore highly effective. However, this therapy cannot be applied to all autoimmune diseases, since even the most effective therapy is incapable of completely inhibiting disease activity. Antigen-specific therapies have the ability to inhibit disease activity; however, their application is limited because of the presence of various disease-specific antigens. Regulatory cell therapies also have potential, but pose a plasticity problem. By focusing our research on experimental autoimmune encephalomyelitis (EAE), which is a multiple sclerosis (MS) model and normally initially has a relapse or remission course, followed by a progressive course, we can develop alternative therapies for the treatment of autoimmune diseases by exploring the mechanism of relapse and remission. It is safe to say that immunologic history is paced with EAE on which autoimmune disease therapy is based.

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  Rheumatoid arthritis (RA) is one of the representative auto-immune diseases, characterized by systemic inflammatory synovitis. Various genetic and environmental factors which contribute to RA pathogenesis, has been suggested, however, detailed mechanism remained unknown. While around 100 genetic risk factors for RA have been reported, Peptidylarginine deiminase type4 (PADI4) was firstly identified as a non-MHC RA genetic risk factor. Furthermore, PADI4 risk allele possessed the association with bone damage regardless of anti citrullinated peptide antibody (ACPA) positivity in Asian RA patients. PADI4 gene codes PAD4 protein which has post-translational modification activity (citrullination). Padi4 is mainly expressed in myeloid cells and granulocytes. PADI4 RA risk haplotype showed an increase of mRNA stability, which resulted in excess translation into PAD4 protein. According to ACPA specificity for RA, increasing PADI4 mRNA stability suggested a hypothesis that excess expression of PAD4 induces a large amount of citrullinated protein, which causes the induction of ACPA. On the other hand, PADI4 has nuclear trans-locational signals and is associated with regulation of various gene expression and formation of neutrophil extracellular traps. These information provide the possibility that PADI4 contributes to not only excess citrullinated protein production, but also various roles in the immune system. We summarize PADI4 function in the immune system and discuss PADI4 roles in RA.

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  Flaky tail mice possess two distinct autosomal recessive mutations, hair abnormality (matted: ma) and stratum corneum layer abnormality (flaky tail: ft), and develop dermatitis spontaneously with high serum IgE even under specific pathogen free condition. We demonstrated that flaky tail mice possess loss of function mutation in Filaggrin (Flg) which is one of the major component of stratum corneum, and showed skin barrier abnormality, although our genetically engineered Flg null mice did not develop dermatitis spontaneously. As a result of segregation of ft and ma mutations, we identified that ma mutation is responsible for the dermatitis phenotype in flaky tail mice, and Tmem79 nonsense mutation (Tmem79^ma) is corresponding to the ma mutation. Tmem79 is expressed in outermost cell of stratum granulosum layer, and ma mice showed abnormal lamellar granule secretory system and abnormal formation of stratum corneum. Thus, Tmem79^ma/ma mice provides a useful mouse model for spontaneous dermatitis caused by skin barrier gene deficiency. Further analysis for Tmem79^ma/ma mice would elucidate important mechanisms for development of atopic dermatitis.

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  Takayasu arteritis (TAK) is a systemic vasculitis affecting aorta and its large branches which were firstly reported from Japan. TAK develops mainly in young females and the number of patients with TAK in Japan is estimated about 6,000 to 10,000. This low prevalence has made genetic studies of TAK difficult to elucidate its genetic background. The HLA region, especially HLA-B locus, is the strongest susceptibility locus to TAK. The association between TAK and HLA-B*52:01 has been established beyond ethnicity. Recently, two different Japanese research groups identified HLA-B67:01, a relatively rare allele in East Asian population, as a novel susceptibility allele. At the same time, two amino acid variations, namely, histidine at position 171 and phenylalanine at position 67 were reported as susceptibility and protective variations, respectively. Since these positions of amino acid are in the peptide binding grooves of HLA-B protein, changes of peptide-binding in MHC class I seem to play a critical role on susceptibility to TAK. Furthermore, the importance of these two amino acid variations would explain the lack of susceptibility effect of HLA-B*51:01 to TAK, which shares most of amino acid sequences with HLA-B*52:01 except for two amino acids including the position 67.

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  αEβ7 (CD103), one of integrin family molecules, is a heterodimer consisting of an αE subunit and a β7 subunit. αEβ7 is expressed in several subsets of lymphocytes including T cells, intestinal intraepithelial lymphocytes and lamina propria lymphocytes. αEβ7 a ligand for E-cadherin, which is mainly expressed in epithelial cells, and an interaction between αEβ7 and E-cadherin results in adhesion of lymphocytes to epithelial cells. We found that EC5 domain, one of domains consisting E-cadherin, was indispensable for binding of E-cadherin with αEβ7. Accumulating evidence suggests that αEβ7 is not only involved in intestinal immune responses but also tissue damages associated with inflammatory diseases including autoimmune diseases. While E-cadherin is constitutively expressed in epithelial cells, the expression of αEβ7 is induced in T cells upon inflammatory stimulation in vitro. In addition, TGF-β1 induces the expression of αEβ7 via a pathway including Smad. These findings raise the possibility that αEβ7 is a potential therapeutic target for inflammatory diseases. We postulate that molecules that interfere with interaction between αEβ7 and E-cadherin are drug candidates for the diseases. We have been focusing on αEβ7 and vigorously investigating the mechanism that underlies the pathogenesis of autoimmune diseases.

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  A 14-year-old boy was admitted in the former hospital with remittent fever, erythematous rash, joint pain, and muscle pain. Antibiotics were ineffectively administered and then, methylprednisolone (mPSL) pulse therapy with methotrexate was introduced under the diagnosis of suspected systemic juvenile idiopathic arthritis (JIA). However, he still had clinical symptoms and signs, and was transferred to our hospital. Re-examination revealed no malignancies including acute leukemia by bone marrow aspiration, no infectious agents by septic work, and no significant increases of antibodies against several viruses including CMV, EBV, HSV, Parvovirus B19, adenovirus, and so forth. FDG-PET demonstrated the accumulation of ¹⁸F-FDG in bone marrows suggesting systemic JIA. Laboratory findings were leukocytosis and granulocytosis, elevated levels of C-reactive protein, D-dimer, ferritin, and interleukin-6. He was finally diagnosed as having severe systemic JIA. Thus, soon after the additional mPSL pulse therapy, tocilizumab (TCZ) was successfully introduced. In conclusion, for systemic JIA patients with severe systemic inflammation, it will be reasonable to introduce tocilizumab earlier than the guideline suggested to reduce side effects of long-term and large amounts of steroids and to protect the transition to macrophage activation syndrome. Further studies will be needed to recommend appropriate timing of tocilizumab introduction.

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  A 44-year-old woman was admitted to our hospital with shock, massive pneumonia and respiratory failure, liver and renal dysfunction, and cerebral infarction. Based on these symptoms, we suspected the presence of disseminated intravascular coagulation and multiple organ dysfunctions due to massive pneumonia or catastrophic antiphospholipid syndrome (CAPS). Therefore, the patient was placed on a respirator and was administered ciprofloxacin, doripenem hydrate, thrombomodulin, antithrombin III, and methylprednisolone pulse therapy. Because the patient's antiphospholipid antibody titer was low on the day of admission (day 1), we did not include CAPS in the differential diagnosis and discontinued prednisolone treatment on day 6. However, the anticardiolipin immunoglobulin M antibody titer was found to be elevated on day 7; in addition, a transient increase in the anticardiolipin anti-β2 glycoprotein antibody titer was noted on re-examination. Moreover, on day 8, the thrombopenia and alveolar hemorrhage suddenly exacerbated. We finally diagnosed the patient with CAPS, and therefore resumed methylprednisolone therapy. Subsequently, the inflammation, respiratory failure, and thrombopenia rapidly improved, and the patient was extubated on day 12.

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