A5090289912- T-cell and B-cell Immunology
- Systemic Lupus Erythematosus Research
- Immune Cell Function and Interaction
- Axon Guidance and Neuronal Signaling
- Amino Acid Enzymes and Metabolism
- Cytokine Signaling Pathways and Interactions
- Renal and related cancers
- Renal Diseases and Glomerulopathies
- Angiogenesis and VEGF in Cancer
- Chronic Kidney Disease and Diabetes
- RNA Interference and Gene Delivery
- Immunodeficiency and Autoimmune Disorders
- Metabolism and Genetic Disorders
- Zebrafish Biomedical Research Applications
- Monoclonal and Polyclonal Antibodies Research
- Diet and metabolism studies
- Eosinophilic Disorders and Syndromes
- Dialysis and Renal Disease Management
- Psoriasis: Treatment and Pathogenesis
- Cell Adhesion Molecules Research
- Cardiac Valve Diseases and Treatments
- Galectins and Cancer Biology
- Renal Transplantation Outcomes and Treatments
- Biochemical effects in animals
- Atherosclerosis and Cardiovascular Diseases
Osaka University
2016-2025
Hadassah Medical Center
2012-2024
Harvard University
2011-2020
Beth Israel Deaconess Medical Center
2011-2020
Harvard University Press
2014-2016
Osaka International University
2008-2010
Japan Science and Technology Agency
2008
Niigata University
2004
Ludwig-Maximilians-Universität München
2003
LMU Klinikum
2003
Tissue inflammation in several autoimmune diseases, including SLE and MS, has been linked to an imbalance of IL-17–producing Th (Th17) cells Tregs; however, the factors that promote Th17-driven autoimmunity are unclear. Here, we present evidence calcium/calmodulin-dependent protein kinase IV (CaMK4) is increased required during Th17 cell differentiation. Isolation naive T from a murine model lupus revealed levels CaMK4 following stimulation with Th17-inducing cytokines but not Treg, Th1, or...
Patients with systemic lupus erythematosus (SLE) suffer frequent infections that account for significant morbidity and mortality. T cell cytotoxic responses are decreased in patients SLE, yet the responsible molecular events largely unknown. We find an expanded CD8CD38high subset a subgroup of increased rates infections. cells from healthy subjects SLE display capacity, degranulation, expression granzymes A B perforin. The key cytotoxicity-related transcription factors T-bet, RUNX3, EOMES...
IL-2, a cytokine with pleiotropic effects, is critical for immune cell activation and peripheral tolerance. Although the therapeutic potential of IL-2 has been previously suggested in autoimmune diseases, mechanisms whereby mitigates autoimmunity prevents organ damage remain unclear. Using an inducible recombinant adeno-associated virus vector, we investigated effect low systemic levels lupus-prone MRL/Fas(lpr/lpr) (MRL/lpr) mice. Treatment mice after onset disease IL-2-recombinant resulted...
DNA hypomethylation is a characteristic feature of systemic lupus erythematosus (SLE) immune cells. Numerous reports have implicated the involvement MEK/ERK pathway in reduction methyltransferase (DNMT) expression, hence inducing transcription methylation-sensitive genes SLE patients. However, molecular mechanisms involved remain unclear. Here, we investigated whether catalytic subunit protein phosphatase 2A (PP2Ac), which overexpressed T-cells, contributes to reduced methylation. We show...
Abstract The activity of calcium/calmodulin-dependent protein kinase IV (CaMK4) is increased in T cells from patients with systemic lupus erythematosus (SLE) and has been shown to reduce IL-2 production by promoting the effect transcriptional repressor cAMP responsive element modulator-α on IL2 promoter. In this article, we demonstrate that MRL/lpr mice display levels CaMK4 nucleus, genetic deletion Camk4 results improved survival. We absence restores production, curbs cell activation,...
Inducible cAMP early repressor (ICER) has been described as a transcriptional isoform of the response element modulator (CREM). Here we report that ICER is predominantly expressed in Th17 cells through IL-6-STAT3 pathway and binds to Il17a promoter, where it facilitates accumulation canonical enhancer RORγt. In vitro differentiation from naive ICER/CREM-deficient CD4+ T impaired but can be rescued by forced overexpression ICER. Consistent with role autoimmune inflammatory diseases, B6.lpr...
Alterations in the apoptosis of immune cells have been associated with autoimmunity. Here, we identified a homozygous missense mutation gene encoding base excision repair enzyme Nei endonuclease VIII-like 3 (NEIL3) that abolished enzymatic activity siblings from consanguineous family. The NEIL3 was fatal recurrent infections, severe autoimmunity, hypogammaglobulinemia, and impaired B cell function these individuals. same also an asymptomatic individual who exhibited elevated levels serum...
Systemic lupus erythematosus (SLE) is a devastating multisystemic autoimmune disorder. However, the molecular mechanisms underlying its pathogenesis remain elusive. Some patients with Noonan syndrome, congenital disorder predominantly caused by gain-of-function mutations in protein tyrosine phosphatase SH2 domain–containing PTP (SHP2), have been shown to develop SLE, suggesting functional correlation between activity and systemic autoimmunity. To test this directly, we measured SHP2 spleen...
Key Points Restarting renin-angiotensin system inhibitor after discontinuation was associated with a lower risk of kidney outcomes and mortality but not related to hyperkalemia. Our findings support proactive approach restarting among patients CKD. Background While inhibitors (RASi) have been the mainstream treatment for CKD, they are often discontinued because adverse effects such as hyperkalemia AKI. It is unknown whether RASi improves clinical outcomes. Methods Using Osaka Consortium...
Semaphorins and their receptors play crucial roles not only in axon guidance during neuronal development but also the regulation of immune responses. Plexin-A4, a member plexin-A subfamily, forms receptor complex with neuropilins transduces signals for class III semaphorins nervous system. Although plexin-A4 is expressed lymphoid tissues, involvement responses remains unknown. To explore role system, we analyzed plexin-A4-deficient (plexin-A4-/-) mice. Among cells, mRNA was detected T...
Abstract Renal involvement in systemic lupus erythematosus remains a major cause of morbidity and mortality. Although immune parameters that instigate renal damage have been characterized, their link to local processes, which execute tissue damage, is poorly understood. Using genetic-deletion pharmacological-inhibition approaches, we demonstrated calcium/calmodulin-dependent protein kinase type IV, contributes altered cytokine production patients, controls spontaneous platelet-derived growth...
Objective: Foxp3+ regulatory T cells (Treg) are pivotal for the maintenance of peripheral tolerance and prevent development autoimmune diseases. We have reported that calcium/calmodulin-dependent protein kinase IV (CaMK4) deficient MRL/lpr mice display less disease activity by promoting IL-2 production increasing Treg cells. To further define mechanism CaMK4 on in systemic lupus erythematosus (SLE), we used Foxp3-GFP reporter treated them with KN-93, an inhibitor CaMK4. Methods: generated to...
Abstract Treatment of autoimmune diseases is still largely based on the use systemically acting immunosuppressive drugs, which invariably cause severe side effects. Calcium/calmodulin-dependent protein kinase IV involved in suppression IL-2 and production IL-17. Its pharmacologic or genetic inhibition limits disease mice. In this study, we demonstrate that KN93, a small-molecule inhibitor calcium/calmodulin-dependent IV, targeted to CD4+ T cells via nanolipogel delivery system, markedly...
The recruitment of interleukin-17 (IL-17)-producing T helper (Th17) cells to inflammatory sites has been implicated in the development organ damage and autoimmune diseases including systemic lupus erythematosus (SLE). To define mechanism calcium/calmodulin-dependent kinase IV (CaMKIV) activation Th17 cell target tissues, we performed anti-glomerular basement membrane antibody-induced glomerulonephritis (AIGN) experiments mice studied samples from patients with SLE.We induced experimental...
T cell Ig and mucin domain (TIM)-4 is preferentially expressed on antigen-presenting cells, its counter-ligand, TIM-1, thought to deliver co-stimulating signals cells. However, the physiological functions of TIM-4 remain unclear. Here, we demonstrate that inhibits naive activation through a ligand other than TIM-1. The inhibitory effect was specific cells which do not express disappeared in pre-activated Conversely, antibody-mediated blockade vivo substantially suppressed cell-mediated...