Lupus nephritis is a major cause of morbidity and mortality among patients with systemic lupus erythematosus (SLE). In these patients, treatment with immunosuppressive agents can significantly improve the outcome of lupus nephritis. However, these agents have severe adverse reactions and some patients are refractory to those therapies. Retinoids, a group of natural and synthetic derivatives of vitamin A, play important regulatory roles of cellular proliferation, differentiation and apoptosis. They have been used for the treatment of acute promyelocytic leukemia and inflammatory disorders such as psoriasis and acne. It has also been shown that retinoids have therapeutic effects in various animal models of kidney disease, including lupus nephritis. Based on these findings, retinoids are a promising agent for the treatment of lupus nephritis. We studied the clinical effects of retinoid therapy in patients with lupus nephritis. In open clinical trial, 7 patients with active lupus nephritis that was refractory to steroid therapy were studied. In all these patients, retinoid was added to the immunosuppressive therapy and its therapeutic effects were evaluated. As a result, 4 out of 7 patients showed improvement of the clinical symptoms and laboratory findings, including urinary protein and anti-dsDNA antibody levels. No important adverse effects of ATRA therapy were observed in all patients. Thus, retinoids might be indicated in cases of lupus nephritis that are refractory to conventional immunosuppressive therapy.

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  Rheumatic diseases are chronic inflammatory disorders, and many of them are autoimmune diseases. Class I phosphatidylinositol-3 kinases (PI3Ks) are enzymes that phosphorylate phosphoinositides in response to extracellular stimuli and regulates cellular activation, proliferation, and migration, in a variety of cell types, suggesting that they play critical roles in the development of inflammation. In patients with rheumatic diseases, such as systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA), recent reports have shown convincing pathogenic evidence for the involvement of PI3K/Akt signaling pathways in chronic inflammation. Moreover, selective inhibition of PI3K γ reduced incidence and severity of the renal disease. More recently, the kinome array analysis revealed particular up-regulation of PI3K in B cells from patients with SLE in comparison with matched controls. Up-regulation of PI3K in T cells was also reported in patients with SLE. Further, we have demonstrated anti-rheumatic effects of a novel PI3K-specific inhibitor, ZSTK474, in mouse collagen-induced arthritis (CIA). Administration of ZSTK474, even if started after the development of arthritis, ameliorated CIA with no apparent adverse effect. Proliferation of B lymphocytes and synovial fibroblasts were inhibited by ZSTK474 in vitro. ZSTK474 suppressed osteoclast formation in vitro and also in the joints of CIA mice. These findings indicate that PI3K might be a potential therapeutic target of rheumatic diseases.

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  Common variable immunodeficiency is one of the most common primary immunodeficiency that is categorized into primary antibody deficiency. The responsible genes identified so far include ICOS, TACI, CD19, CD20, CD21, CD81 and BAFF-R; and most of the CVID-causing genes are yet to be identified. TACI mutation is the most common one; however the direct contribution of TACI mutation to pathogenesis of CVID is not yet clear. One third to a half of the patients with CVID shows autoimmunity as well as malignancy in their course. It is of importance to develop diagnostic measure, to identify the disease causing genes, and to develop the optimal therapy.

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  Cryopyrin-associated periodic syndrome (CAPS) comprises a group of rare, but severe, autoinflammatory syndrome, and includes 3 distinct conditions, familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), and neonatal-onset multisystem inflammatory disease (MONID). These syndromes are characterized by urticarial-like rash, periodic fever, central nervous system inflammation, an arthropathy, and the risk of amyloidosis. About 20% die by age 20 years in the most severe cases. The disease is associated with mutations in the NLRP3 gene that encodes for the protein cryopyrin, a component of the inflammasome complex that regulates the production and secretion of IL-1β. Canakinumab is a human IgG monoclonal antibody targeting IL-1β. The clinical trials of canakinumab for patients with CAPS in both western countries and Japan were well-tolerated in most patients, and provided significant advantages over existing competitive therapies. Although no serious adverse effects have been reported, the frequencies of common infectious diseases including nasopharyngitis, upper respiratory tract infections, and gastroenteritis were reported presumably due to the blockade of proinflammatory cytokine, IL-1β. For us pediatrician, it will be important to be more careful for infectious diseases to provide the maximum safety of canakinumab for these patients.

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  IgG4-related disease is a chronic disorder, which is characterized with elevated levels of serum immunoglobulin (Ig)G4 and abundant infiltration of IgG4-positive plasmacyte and storiform fibrosis in the enlarged organs. It includes Mikulicz's disease (IgG4-related dacryoadenitis and sialadenitis), autoimmune pancreatitis type I, and so on. In Japan, we have been able to measure the IgG4 levels in our clinic since 2010, and we knew that various diseases except IgG4-related disease, also presented with elevated levels of serum IgG4. Eosinopihic disorders, such as Chrug-Strauss syndrome, a part of rheumatoid arthritis and systemic sclerosis can present with high levels of serum IgG4. So the confusion is seen in some clinicians, but we have to recognize that only serological findings cannot lead to the correct diagnosis in IgG4-related disease. The pathological and image findings also are needed. With regard of the treatments for IgG4-related disease, the levels of serum IgG4 often reflected with the therapeutic response, and were also the markers, which predicted the relapse. We describe herein the significance of measuring serum IgG4 levels in the diagnosis and during the treatment for IgG4-related disease.

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  Systemic lupus erythematosus (SLE) is a prototypic systemic autoimmune disease with multiple organ disorders. Although the prognosis of SLE has been recently improved, corticosteroid and immunosuppressive agents are still main treatment used in medical practice. Refractory disease and complications by the conventional drugs still remain. RP105 (CD180) is one of the toll-like receptor associated molecules. The molecule is expressed on mature B cells. Significantly increased population of RP105-negative [RP105(−)] B cells is found in SLE. RP105(−) B cells belong to highly activated and differentiated late B cells and produce autoantibodies including anti-dsDNA antibodies. RP105(−) B cells are further divided into at least 5 subsets that include novel human B cell subsets. In active SLE, subset 1 (activated B cells) and 3 (early-plasmablasts) are significantly increased compared to inactive SLE patients. Especially, subset 3 RP105(−) B cells may play an important role in pathophysiology of SLE. RP105(−) B cells from active SLE patients express preferentially BCMA (B-cell maturation antigen) compared to BAFF-R (B-cell activating factor-receptor) than normal subjects and other autoimmune diseases. In SLE, it is suggested that BAFF/APRIL (a proliferation-inducing ligand) maintain chronic activation and survival of RP105(−) B cells. The increased RP105(−) B cells may reflect the breaking of tolerance checkpoint for autoreactive B cells and finally affect autoimmunity in SLE. For the B cell therapy, especially targeting of autoantibody-producing B cells, including subset 3 of RP105(−) B cells, BCMA and RP105(−) B cell itself may be an ideal target.

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  Immunoglobulin Binding Protein (BiP) is a member of heat shock protein 70 famaily, and is also known as an autoantigen in rheumatoid arthritis (RA) patients. Serum anti-BiP antibody is detected up to 60% of RA patients, and recent reports demonstrated that serum anti-BiP antibody is also detected in systemic lupus erythematosus patients. Notably, anti-citrullinated BiP antibody is revealed as another member of anti-citrullinated protein/peptide antibodies (ACPAs). Since ACPAs are supposed to be closely associated with RA pathogenesis, immune responses to citrullinated BiP could play an important role in RA. Indeed, immunization of citrullinated BiP exacerbated inflammatory arthritis in mice. Moreover, T cell responses to BiP were reported in human RA and mice models. In mice models, native BiP administration induced IL-4 and IL-10 producing CD4⁺ T cells and regulated inflammatory arthritis. In this way, immune responses to BiP are various, and dysregulation of the balances between pro-inflammatory and regulatory responses to BiP could lead to the autoimmune responses and diseases.

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  Rheumatoid arthritis (RA) is a chronic inflammatory disorder with a variable disease outcome, and is characterized by inflammation of multiple joints. Proinflammtory cytokines, such as tumor necrosis factor alpha (TNFα), interleukin-6 (IL-6) are thought to play crucial roles in the pathology of RA. The prognosis of patients with RA has improved significantly with the recent availability of biologics targeting TNFα and IL-6. Immunization of DBA/1 mice with glucose-6-phosphate isomerase (GPI) induces severe acute arthritis. This arthritis can be controlled by TNFα antagonists, suggesting similar etiology to RA. We performed GeneChip analysis using splenocytes of mice with GPI-induced arthritis. Among the arrayed TNFα-related genes, the expression of TNFα-induced adipose-related protein (TIARP) mRNA was the highest. TIARP was detected specifically in joints and spleens of arthritic mice. Among the splenocytes, CD11b⁺ cells were the main source of TIARP mRNA. STEAP4 (the human ortholog of TIARP) was highly upregulated in joints of patients with RA and especially co-localized with CD68⁺ macrophages. In this study, we discuss the role of TIARP in the generation of experimental autoimmune arthritis and the possible clinical application of for the treatment of RA.

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  Biological products have proven its high efficacy on autoimmune disease such as rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). Meanwhile, small molecular drugs have attracted attention over the years because of its availability of oral administration and cost effectiveness. Spleen tyrosine kinase (Syk) is a 72 kDa protein tyrosine kinase widely expressed on cells that are involved in the immune system and inflammation such as B cells, T cells, macrophages and synovial fibroblast. Syk is involved in intracellular signaling of the multi-chain immune receptors, including B cell receptor (BCR), ζchain of T-cell receptor (TCR), FcR and integrins, which contains the immune-receptor tyrosine-based activation motif (ITAM). Recently, Syk inhibitor fostamatinib has exerted potent therapeutic efficacy against autoimmune and allergic diseases such as rheumatoid arthritis (RA), bronchial asthma and thrombocytopenic purpura (ITP). Moreover, Syk blockade prevented the development of skin and kidney lesions in lupus-prone mice, however the mechanism of action is unclear. We have revealed that Syk-mediated BCR-signaling is prerequisite for optimal induction of toll-like receptor (TLR)-9, thereby allowing efficient propagation of CD40- and TLR9- signaling in human B cells. These results indicate that inhibition of Syk have a potential to regulate B-cell mediated inflammatory diseases such as SLE. We here document the in vitro and in vivo effects of a Syk inhibitor for the treatment of autoimmune diseases, mainly in RA and SLE.

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  Dendritic cells (DCs) is the cell that act as source of the immune response by exquisitely presenting antigens to acquired immunity such as the T cells. Janus kinase (JAK) is a tyrosine kinase that is activated immediately after the cytokine binds to its unique receptor expressed on the cell surface. Among the JAKs, expression of JAK3 is limited on heamatopoietic cells and is indispensable for lymphocyte development and proliferation. We have demonstrated that JAK3-deficient DCs normally develop, uptake antigens, produce inflammatory cytokines and function as an antigen-presenting cell, although they over-produce IL-10. Among the transcription factors that are known to be activated by JAK3, we explored the phenotype of Stat6-deficient DCs which is a transcription factor specifically activated by JAK3. Interestingly, development, function and inflammatory cytokine production was normal with over-production of IL-10 which was in line with the JAK3-deficient DCs. IL-4 is well known to activate JAK3-Stat6 in the cytoplasm and has been reported to be produced in the synovial fluid of rheumatoid arthritis patients. Hence the suppression of IL-10 production by IL-4 can be considered as one of the inflammatory process of arthritis. Moreover, induction of IL-10 production by DCs can be one mechanism of action of the JAK inhibitor (tofacitinib) which have shown high efficiency on active rheumatoid arthritis in clinical trials.

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  MicroRNAs (miRNAs) are endogenous non-coding small RNAs of approximately 22 nucleotides in length. miRNAs repress expression of target genes at the posttranscription level. Biological relevance of miRNAs have been investigated in physiological and pathological conditions, revealing their involvement in fine tuning of the biological events, such as cell proliferation, differentiation and cell death. In 2008, miR-146a and miR-155 were reported to be involved in the pathology of rheumatoid arthritis. Subsequently, expression and function of other miRNAs in rheumatoid arthritis have been reported. These reports suggest that miRNAs could be novel candidates for the therapeutic target or biomarker of rheumatoid arthritis. Further investigations are required to identify, characterize and modulate the key miRNA in the pathology of rheumatoid arthritis.

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  Sjögren's syndrome (SS) is a systemic autoimmune disorder characterized by profound lymphocytic infiltration into the lacrimal and salivary glands, thereby diminished secretory function. B cell hyper-activation is a predominant feature of SS related to hypergammaglobulinemia and production of autoantibodies.
  The adaptor molecule NF-kB activator 1 (Act1) plays an important role in the homeostasis of B cells by attenuating CD40 and B cell-activating factor belonging to the tumor necrosis factor family receptor (BAFFR) signaling. Act1-deficient mice develop autoimmune manifestations similar to SS, which are hypergammaglobulinemia, high levels of anti-SSA and anti-SSB autoantibodies. In this study, to investigate the role of Act1 in the pathogenesis of SS, we examined Act1mRNA expressions in B cells from patients with SS and discussed the association of Act1 with parameters and clinical manifestations of SS.
  We showed the low level of Act1mRNA expression in patients with SS and reciprocal association of Act1 with serum IgG level. Diminished Act1mRNA expression in SS may be associated with B cell hyperactivity and elevated immunoglobulin production in SS by uncontrolled B cell activation signal through CD40 and BAFFR.

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  Triggering receptor expressed on myeloid cells (TREM)-1 belongs to an immunoglobulin super family and is expressed on neutrophils, mature monocytes and macrophages. The engagement of TREM-1 synergizes with several Toll Like Receptors (TLR) activation in amplifying the inflammatory response. TREM-1 blockade using a fusion protein containing murine TREM-1 extracellular domain and human immunoglobulin Fc portion was reported to prevent death in mouse models of microbial peritonitis and protect from organ damage during other inflammatory diseases. There are many reports suggesting the involvement of TREM-1 in the pathogenesis of rheumatoid arthritis. Blockade of TREM-1 could be a new therapeutic target in rheumatoid arthritis without impairing the host defense against microbes. In this report, we outline the role of TREM-1 and the trial of developing anti-rheumatic drugs by targeting its ligand.

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  A 14-day-old neonate was transferred to our university hospital because of respiratory distress and mild disturbance of consciousness. He had no history of abnormal pregnancy or delivery, but had developed apnea at 6 days old. Thereafter, respiratory distress progressed and his condition deteriorated. On admission to our hospital, several vesicles were found on the left upper arm, and moderate hepatomegaly was also present. Herpes simplex virus (HSV) type II genome was detected from serum, spinal fluid, and bone marrow. Laboratory examinations revealed typical abnormalities of disseminated intravascular coagulation, increased levels of serum ferritin, aspartate aminotransferase, and lactate dehydrogenase. Bone marrow aspiration demonstrated activated macrophages and hemophagocytosis. Spinal tap revealed numerous mononuclear cells. Meningitis and virus-associated hemophagocytic syndrome (VAHS) due to systemic HSV type II infection were thus diagnosed. Acyclovir (60 mg/kg/day) and vidarabine were promptly administered. Dexamethasone palmitate and intravenous cyclosporine were also administered for systemic inflammation due to VAHS. Finally, these aggressive therapies rescued the patient without any sequelae. In general, neonatal systemic HSV infection is life-threatening and results in poor intact survival. Our case report suggests that not only antiviral treatment for HSV, but also anti-inflammatory treatment including steroid and cyclosporine should be considered from the early phase of neonatal systemic HSV infection.

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  We report a 53-year-old male with Cogan's syndrome. He was admitted to our hospital because of a fever of 2-weeks duration, blurred vision for 10 days, hypoacusis, and numbness of the left hand for 3 days. In addition to uveitis, hypoacusis, and aseptic meningitis, multiple mononeuropathy was diagnosed based on a nerve conduction study. Furthermore, positron emission tomography/computed tomography (PET/CT) revealed diffuse aortitis. Accordingly, the patient was diagnosed with Cogan's syndrome. After starting steroid-pulse therapy followed by 1 mg oral prednisolone/kg/day, the uveitis and hypoacusis improved immediately, while the peripheral neuropathy persisted until effectively treated with intravenous gamma globulin therapy. Prompt steroid therapy for Cogan's syndrome based on a diagnosis made using PET/CT prevented progression of the hypoacusis.

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