Mikulicz's disease represents a unique condition involving enlargement of the lacrimal and salivary glands. Mikulicz's disease has been considered part of primary Sjögren's syndrome because both diseases were histologically similar. However, the gland swellings in Mikulicz's disease are persistent, and its decreased secretional function is good responsiveness to glucocorticoid. Serologically, Mikulicz's disease is characterized by few autoantibody including anti-SS-A and anti-SS-B antibodies. Recently, it is revealed elevated IgG4 concentrations in the serum and prominent infiltration by plasmacytes expressing IgG4 in the lacrimal and salivary glands in Mikulicz's disease. Prominent IgG4-positive plasma cells are also detected in systemic lymph tissues. We cannot detect the phenomenon in Sjögren's syndrome. In complications with Mikulicz's disease, there are autoimmune pancreatitis, retroperitoneal fibrosis, tubulointerstitial nephritis, autoimmune hypophysitis, Riedel's thyroiditis, which are related to IgG4 in its pathogenesis. Mikulicz's disease is different from Sjögren's syndrome, and may be a systemic IgG4-related plasmacytic disease.

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  Central tolerance is established by the repertoire selection of immature T lymphocytes in the thymus, avoiding autoimmune responses to self-antigens. Differential ligand-TCR interactions that result in positive and negative selection initiate differential intracellular signals that, in turn, lead to the survival-or-death decision of immature thymocytes. TCR signal dysregulation due to the mutation of ZAP-70 or defective apoptosis of autoreactive thymocytes due to the deficiency of pro-apoptotic protein Bim impair tolerance and cause autoimmunity. Thymic repertoire selection also induces the development of CD25⁺CD4⁺ regulatory T cells, which play important roles for maintaining peripheral tolerance. Furthermore, the establishment of central tolerance requires the development of thymic medulla that is mediated by the activation of NF-κB signaling pathway, promiscuous expression of tissue-specific self-antigens by medullary epithelial cells that is regulated by AIRE, and cortex-to-medulla migration of developing thymocytes that is regulated by CCR7-mediated chemokine signals.

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  The mucosal surface of the body is exposed to a vast array of exogenous antigens and microorganisms. Epithelial cells evoke minimal immune response to food ingredients and commensal bacteria, while they release an array of antimicrobial peptides and CXC chemokines in response to bacterial invasion or inflammatory stimuli. The mucosal antigens are transported from the gut lumen to organized lymphoid follicles by specialized epithelial M cells residing in follicle-associated epithelium (FAE). An alternative pathway of antigen uptake with neonatal Fc receptor (FcRn) is also reported. Furthermore, intestinal dendritic cells underneath epithelium directly take up luminal antigens, where epithelial fractalkine expression plays a critical role in the guidance of dendrite extrusion. Epithelial cells express polymeric Ig receptor (pIgR) that is essential for the luminal secretion of dimeric IgA produced in the lamina propria. Furthermore, soluble factors released by mucosal epithelial cells condition dendritic cells, which in turn promote Th2 response. These multiple lines of evidence clearly suggest the significant role of epithelial cells at the front line of mucosal immune defense.

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  iNKT cells are a unique subset of CD1-restricted T lymphocytes that express T cell receptor (TCR) and some NK receptors. iNKT cells express an invariant TCRα chain composed of Vα14-Jα18 segments in mice and Vα24-Jα18 segments in humans associated with TCRβ chains using a restricted set of Vβ. iNKT cells recognize glycolipid antigens such as α-galactosylceramide (α-GC) presented by CD1d, non-pormorphic MHC class I-like molecule, and rapidly secrete large amounts of cytokines including IL-4 and IFN-γ upon activation. Due to its potent ability to produce a variety of cytokines, iNKT cells are involved in a various kinds of immunoregulation. iNKT cells play a regulatory role in some disease models such as type I diabetes in NOD mice. In contrast, iNKT cells exaggerate the pathogenesis such as arthritis, allergic airway inflammation and atherosclerosis. In addition, iNKT cells are an attractive target for immunotherapy because several different synthetic glycolipid antigens to modify the function of iNKT cells are available. In this review, we examine the potential roles of NKT cells in the pathogenesis of a variety of diseases including autoimmunity , allergy, infection and cancer. Additionally, we discuss on the recent advances in glycolipid therapy for these disease models.

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  CD4⁺CD25⁺ regulatory T cells play an important role in preventing autoimmunity. We investigated the presence of CD4⁺CD25⁺ regulatory T cells in the peripheral blood of patients with rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and systemic sclerosis (SSc), using flow cytometry. The percentage of CD4⁺CD25⁺ regulatory T cells was significantly decreased in RA, especially in patients with high serum levels of either CRP or MMP-3. In SSc and SLE, the percentage of CD4⁺CD25⁺ regulatory T cells was higher in patients than in controls, but not significant. We also investigated the serum levels of IL-10, which influences the function of CD4⁺CD25⁺ regulatory T cells and other regulatory T cells. In RA, on contrast to CD4⁺CD25⁺ regulatory T cells, the serum levels of IL-10 increased in patients with higher serum levels of CRP, or MMP-3. In SLE and SSc, the serum level of IL-10 increased significantly in patients than in controls. These data thus indicated that CD4⁺CD25⁺ regulatory T cells contributes to occurrence and progression of RA, and other regulatory T cells or cytokines contribute to occurrence and progression of SSc and SLE.

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  A 48-year-old woman presented to our hospital with epigastralgia and erythema on the left dorsalis pedis. Her medical history included deep venous thrombosis three months prior to admission to our hospital. Upon admission it was determined that she had severe anemia (hemoglobin level 4.6 g/dl). Bone marrow analysis indicated a markedly decreased number of erythroid progenitor cells. A skin biopsy specimen of the erythema revealed microthrombus. Anticardiolipin-β2GPI antibody and lupus anticoagulant were positive. The patient was diagnosed with pure red cell aplasia (PRCA) and antiphospholipid syndrome (APS). After steroid pulse therapy and warfarinization, her anemia and purpura improved. Three months later she developed depression with positive anti-ribosomal P protein antibody that was indicative of central nervous system lupus. Although her psychometric condition did not respond to steroid pulse therapy, improvement was seen after she received three courses of cyclophosphamide pulse therapy. We report a rare case of CNS lupus that developed during corticosteroid therapy and warfarinization in a patient with PRCA and APS.

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