CD25+CD4+ regulatory T cells are naturally anergic and suppressive. They differentiate through thymus as professional regulator to control immunological self-tolerance in the periphery. When they are depleted from normal animals, various organ-specific autoimmune diseases spontaneously develop, and reconstitution of regulatory T cells prevents the diseases. Transcriptional factor FoxP3 is the master gene for differentiation and function of regulatory T cells. Mutation of FoxP3 gene causes development of autoimmune disease in both human and mouse. There are accumulating reports that regulatory T cells are abnormal in their number or function in several animal models and also patients with autoimmune diseases. These findings indicate that regulatory T cells are involved in the pathogenesis of many autoimmune diseases. Regulatory T cells can also be employed for the treatment of autoimmune diseases. Further studies of regulatory T cells, especially the detection of their specific markers and the development of the method to propagate them in an antigen-specific manner, will facilitate their clinical application.

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  Recent studies have revealed that B cells play a critical role in autoimmunity and disease expression through various functions, including autoantibody production, cytokine secretion, antigen presentation, and co-stimulatory effect. Selective targeting of B cells has been recently achieved using a chimeric monoclonal antibody against CD20 (Rituximab). Significant clinical efficacy has been demonstrated in several autoimmune diseases including rheumatoid arthritis and systemic lupus erythematosus by the infusion of this antibody. Rituxumab significantly improves the symptoms during the long period of complete B cell depletion. Understanding the dynamics of B cell involvement in autoimmune diseases will be crucial to the development of B cell-targeted strategies. Conversely, the findings derived from studies of anti-B cell therapy provide us a lot of important clues to clarify the pathogenesis of autoimmune diseases. This review focuses on recent data demonstrating the roles of B cells in autoimmune diseases as well as the current studies concerning the treatment of autoimmune diseases by Rituximab.

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  Toll-like receptors (TLRs) have been revealed to recognize specific patterns of microbial components. Recognition of microbial components by TLRs initiates signal transduction pathways, triggering expression of genes, which products control innate immune responses and further instruct development of antigen-specific acquired immunity. TIR domain-containing adaptors, such as MyD88, TIRAP, TRIF, and TRAM, play pivotal roles in TLR signaling pathways. Differential utilization of these TIR domain-containing adaptors provides specificity of individual TLR-mediated signaling pathways. TLR-mediated activation of innate immunity, when in excess, leads to immune disorders such as inflammatory bowel diseases. Therefore, several mechanisms that negatively control TLR signaling pathways and thereby prevent overactivation of innate immunity have been elucidated. Nuclear IκB proteins, such as Bcl-3 and IκBNS, have been revealed to be responsible for this process, by differentially inhibiting TLR-dependent cytokine production.

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  The activation threshold of cells in the immune system is often tuned by cell surface molecules. The Fc receptors expressed on various hematopoietic cells constitute critical elements for activating or down-modulating immune responses and combines humoral and cell-mediated immunity. Thus, Fc receptors are the intelligent sensors of the immune status in the individual. However, impaired regulation by Fc receptors will lead to unresponsiveness or hyperreactivity to foreign as well as self antigens. Murine models for autoimmune disease indicate the indispensable roles of the inhibitory Fc receptor in the suppression of such disorders, whereas activating-type FcRs are crucial for the onset and exacerbation of the disease. The development of many autoimmune diseases in humans may be caused by impairment of the human Fc receptor regulatory system. This review is aimed at providing a current overview of the mechanism of Fc receptor-based immune regulation and the possible scenario of how immunological disorders might result from their dysfunction.

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  Semaphorins were identified originally as guidance cues for developing axons. However, it is becoming clear that several semaphorins are crucially involved in the immune system. For instance, Sema4D (CD100) enhances activation of B cells and dendritic cells, and Sema4A is involved in T cell priming and Th1/Th2 regulation. In addition, recent cumulative evidence reveals their importance in immunological homeostasis. We here focus on our current understanding of the roles of semaphorins in autoimmunity.

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  B cell activating factor belonging to the tumor necrosis factor family (BAFF) is a tumor necrosis factor (TNF) superfamily member best known for its role in the survival and maturation of B cells. BAFF is a ligand for three TNF receptor superfamily members : B-cell maturation antigen (BCMA), transmembrane activator and calcium-modulator and cyclophilin ligand interactor (TACI), and BAFF receptor (BAFF-R). Among them, BAFF-R plays the central role in the BAFF system, whereas TACI plays the inhibitory role. BAFF/BAFF receptors appear to span nearly all stages of B-lineage differentiation, ranging from the development, selection, and homeostasis of naive primary B cells to the maintenance of long-lived bone marrow plasma cells. Furthermore, excessive BAFF rescues self-reactive B cells from anergy, which may play a crucial role in the induction and development of autoimmunity. Mice overexpressing BAFF exhibit increased B cell numbers in spleen and lymph node and autoimmune phenotype similar to patients with systemic lupus erythematosus (SLE) and Sjögren's syndrome. Furthermore, inhibition of BAFF by TACI-Ig and BAFFR-Ig has been successful in treating murine models of SLE and rheumatoid arthritis. In humans, previous reports have shown elevated serum BAFF levels in SLE, rheumatoid arthritis, Sjögren's syndrome, and systemic sclerosis patients. Thus, the dysregulation of BAFF/BAFF receptor system may contribute to induction and development of autoimmune diseases and become one of important therapeutic targets.

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  We reported three cases of childhood-onset male systemic lupus erythematosus (SLE), all of whom successfully treated with a combination of pulse methylprednisolone (mPSL) and pulse cyclophosphamide (IVCY). All of them had severe lupus nephritis and were complicated with other collagen diseases. Two cases were complicated with Sjögren syndrome (SS) and the other was complicated with both SS and anti-phospholipid syndrome (APS). After a combination of pulse mPSL and IVCY for a year, followed by oral predonisolone (PSL) and azathioprine (AZA), following up renal biopsy were performed in all cases, which showed histological improvement in glomerulonephritis. One case had flares a year later, but no flares were observed either in clinical symptoms or in laboratory examinations in the others. Their autoantibodies except anti-nuclear antibody (ANA) were eliminated.
  We suggest a combination of pulse mPSL and IVCY is effective for the patients who are suffering with severe lupus nephritis complicated with the other collagen diseases.

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  A 73-year-old woman had experienced dry mouth and swellings of both upper eyelids from 1998. In October 2003, she also developed bilateral submandibular swellings, and was diagnosed with diabetes mellitus and prescribed antidiabetic medication. She consulted our hospital in the summer of 2004 due to the exacerbation of eyelid swelling, and was admitted in October 2004. Keratoconjunctivitis sicca was not present. CT and MRI of the head showed bilateral enlargement of the lacrimal and submandibular glands. Serological investigations revealed hypergammaglobulinemia, but as antinuclear antibody and anti-SS-A antibody were absent, further investigation was performed. Serum concentrations of IgG4 were elevated and biopsy of the minor salivary gland revealed a severe infiltration of IgG4-positive plasmacytes. The patient was therefore diagnosed with Mikulicz's disease. Abdominal CT demonstrated diffuse pancreatic swelling, and endoscopic retrograde cholangio-pancreatography revealed stricture of the common bile duct and main pancreatic duct, suggesting the complication of autoimmune pancreatitis. Treatment was commenced with 40 mg/day of prednisolone. This resulted in rapid resolution of the lacrimal and submandibular gland swellings and recovery of salivary gland function. Diffuse swelling of the pancreas and stricture of the common bile duct and main pancreatic duct also improved, and endogenous insulin secretion increased. Both Mikulicz's disease and autoimmune pancreatitis presented with elevated serum IgG4 and infiltration of IgG4-expressing plasma cells into the glandular tissues. We recently proposed the new diagnostic entity of “IgG4-related plasmacytic exocrinopathy” ; however, if diabetes mellitus in autoimmune pancreatitis was caused by direct dysfunction of pancreatic ? cells, we must reconsider this pathogenesis and consider a wider concept including exocrine as well as endocrine glands. This case, in which both types of glands were affected, is therefore of considerable interest.

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