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Takeshi Tsubata 대한면역학회 2019 Immune Network Vol.19 No.1
Systemic lupus erythematosus (SLE) is the prototypic systemic autoimmune disease characterized by production of autoantibodies to various nuclear antigens and overexpression of genes regulated by IFN-I called IFN signature. Genetic studies on SLE patients and mutational analyses of mouse models demonstrate crucial roles of nucleic acid (NA) sensors in development of SLE. Although NA sensors are involved in induction of anti-microbial immune responses by recognizing microbial NAs, recognition of self NAs by NA sensors induces production of autoantibodies to NAs in B cells and production of IFN-I in plasmacytoid dendritic cells. Among various NA sensors, the endosomal RNA sensor TLR7 plays an essential role in development of SLE at least in mouse models. CD72 is an inhibitory B cell co-receptor containing an immunoreceptor tyrosine-based inhibition motif (ITIM) in the cytoplasmic region and a C-type lectin like-domain (CTLD) in the extracellular region. CD72 is known to regulate development of SLE because CD72 polymorphisms associate with SLE in both human and mice and CD72−/− mice develop relatively severe lupus-like disease. CD72 specifically recognizes the RNA-containing endogenous TLR7 ligand Sm/RNP by its extracellular CTLD, and inhibits B cell responses to Sm/RNP by ITIM-mediated signal inhibition. These findings indicate that CD72 inhibits development of SLE by suppressing TLR7-dependent B cell response to self NAs. CD72 is thus involved in discrimination of self-NAs from microbial NAs by specifically suppressing autoimmune responses to self-NAs.
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Synthesis and biological evaluation of the mimics of cis ligand for CD22
Yuki Sugamuna,Naoko Matsubara,Yuki Iwayama,Akiharu Ueki,Akihiro Imamura,Hiromune Ando,Takeshi Tsubata,Hideharu Ishida,Makoto Kiso 한국당과학회 2012 한국당과학회 학술대회 Vol.2012 No.1
CD22 (siglec-2) is an accessory molecule of the B-cell receptor complex (BCR) that exertsnegative effects on receptor signaling. It is also well-documented that CD22 is a regulatoryprotein that sets a threshold for immune responses. The carbohydrate ligand recognized byCD22 is the sequence Neuα(2,6)Galβ(1,4)GlcNAc found on both neighboringglycoconjugate of the same cell (cis ligand) and on other cells that interact with B cells (transligands). Recently, we have reported that the C-9 amido derivative of sialic acid (GSC718;9-(4’-hydroxy-4-biphenyl)acetamido-9-deoxy-Neu5Gc-OBn) show a potent affinity andselectivity for CD22 than other siglecs such as MAG [1]. Moreover, the compoundpromoted the proliferation of B cells in vitro. As next step of our investigation, we intend toreinforce the promoting activity of GSC718 for B cell growth by chemical modification.Herein, we report the efficient synthesis of GSC718 analogs which have varied aglyconmoieties. To achieve the comprehensive synthesis of GSC718 analogs having varied aglycons, wereexamined every synthetic process to obtain a fine target compound. In case of thesialoside synthesis, the most time-consuming and troublesome process is thechromatographic separation of α-sialoside from other byproducts such as β−isomer, 2,3-enederivative etc. after glycosylation reaction with aglycon part. To improve this process, weemployed 1,5-lactam formation as the key step for separation because the lactam formation isknown to proceed only in α-sialoside [2]. At the beginning of the synthesis of targetmolecules, we synthesized a suitably modified sialic acid donor in good yields. Then, thesialyl donor was reacted with various 2-substituted-ethanols to give the mixtures of α- and β-glycosides and 2,3-ene derivative, which were subsequently advanced to 1,5-lactamformation. As we anticipated, 1,5-lactamized α-sialosides became isolable from themixtures due to its different polarity from the other byproducts. Finally, the obtained 1,5-lactamized silaosides were successfully converted into target structures via reaction sequenceincluding C9-midification with biphenyl amide group, lactam opening and globaldeprotection. The synthesized analogs were advanced to biological assay using B cells. In this poster presentation, we will also discuss the structure-activity relationships of thesynthesized analogs. [1] H. H. M. Abdu-Allah et al, Bioorg. Med. Chem. Lett. 2011, 19, 1966-1971. [2] H. Tanaka et al, Tetrahedron Lett. 2009, 50, 4478-4481.
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