Rheumatoid Arthritis: Matsushita S

Nakano K, Matsushita S, Saito K, Yamaoka K, Tanaka Y. · The first dept. of Internal Medicine, University of Occupational & Environmental Health, Kitakyushu, Japan. · Nihon Rinsho Meneki Gakkai Kaishi. · Pubmed #19252371 links to  free full text

Abstract: The nerve systems affect immune functions by releasing neurotransmitters through lymphocyte cell-surface receptors. A major neurotransmitter dopamine transmits signals via five different seven-transmembrane G protein-coupled receptors termed D1 to D5. There is wide evidence for a decreased risk of rheumatoid arthritis (RA) in patients with schizophrenia which is associated with the excessive stimulation of D2-like receptors by dopamine. However, the reason for the negative association between RA and schizophrenia is unknown. We previously demonstrated that dendritic cells (DCs) could synthesize and store dopamine, DC released dopamine to naive CD4 T cells upon DC-T cell interaction and affected helper T-cell differentiation. Because DCs have been proposed to play a pivotal role in the initiation and perpetuation of RA by presentation of arthritogenic antigens to T cells, we here assessed effects and functions of dopamine on immune cells during the pathogenesis of RA. In this paper, we overview the series of our research findings, and present the possibility of drug discovery which target at dopamine receptors.

Matsushita S, Higashi T. · Department of Allergy and Immunology, Faculty of Medicine, Saitama Medical University, Saitama, Japan. · Allergol Int. · Pubmed #18427166 No free full text.

Abstract: Immunomodulators such as lipopolysaccharides (LPS) and forskolin change the nature of dendritic cells (DCs) to induce Th1 and Th2 cells, respectively, thereby designated Th1 or Th2 adjuvants. Recent studies showed that Th17-inducing activity can be carried by certain polysaccharides such as beta-glucan derived from Candia albicans. Such activities can be scrutinized by using MLR, cAMP and possibly, differential expression of Notch ligand isoforms. In this review article, we also introduce an effective method to establish human Th17 cell clones and a transcriptome analysis using human Th subpopulations. In vivo relevance to human Th17 responses is discussed.

Takagi R, Higashi T, Hashimoto K, Nakano K, Mizuno Y, Okazaki Y, Matsushita S. · Department of Allergy and Immunology, Faculty of Medicine, Saitama Medical University Saitama, Japan. · J Immunol. · Pubmed #18566383 links to  free full text

Abstract: Th 17 cells represent a novel subset of CD4+ T cells that have a protective effect against extracellular microbes, while they are also responsible for autoimmune disorders in mice. However, the protein expression profile of Th17 cells remains to be clarified. In this study, we report an effective method to establish human allo-reactive Th17 cell clones and demonstrate that human Th17, but not Th1 or Th2, cells express B cell chemoattractant CXCL13, by using DNA chips, RT-PCR, and ELISA. Such a pattern was also the case in Candida albicans-specific Th17 clones and synovial fluid specimens obtained from patients with rheumatoid arthritis. The biological implication of this finding is discussed.

Nakano K, Saito K, Mine S, Matsushita S, Tanaka Y. · Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan. · Apoptosis. · Pubmed #17136494 No free full text.

Abstract: Activation-induced cell death (AICD) plays a pivotal role in self-tolerance by deleting autoreactive T cells, but a defect of AICD results in expansion of autoreactive T cells and is deeply involved in the pathogenesis of rheumatoid arthritis. Although the process of AICD is mainly mediated by Fas Ligand (FasL)/Fas signaling, it remains unclear what induces FasL expression on T cells. In the present study, we found that CD44 was the most potent stimulator of FasL expression on human peripheral T cells. CD44 cross-linking rapidly up-regulated FasL expression on the T cell surface by delivery from the cytoplasm without new FasL protein synthesis. This up-regulation of FasL was mediated by activation of a tyrosine kinase, IP3 receptor-dependent Ca(2+) mobilization and actin cytoskeletal rearrangements. Furthermore, AICD induced by CD3 restimulation was inhibited by hyaluronidase as well as by soluble Fas, indicating an interaction between membrane-bound hyaluronan and the cell surface CD44 was involved in the up-regulation of FasL expression on T cells and subsequent AICD. We therefore propose that the engagement of CD44 on T cells can eliminate autoreactive T cells by expression of FasL and FasL-mediated AICD.