CD22-Binding Synthetic Sialosides Regulate B Lymphocyte Proliferation Through CD22 Ligand-Dependent and Independent Pathways, and Enhance Antibody Production in Mice.
CD22-Binding Synthetic Sialosides Regulate B Lymphocyte Proliferation Through CD22 Ligand-Dependent and Independent Pathways, and Enhance Antibody Production in Mice.
复制标题
DOI：
10.3389/fimmu.2018.00820
复制
发表时间：
2018
影响因子：
7.3
通讯作者：
Tsubata T
中科院分区：
文献类型：
--
作者：
Matsubara N;Imamura A;Yonemizu T;Akatsu C;Yang H;Ueki A;Watanabe N;Abdu-Allah H;Numoto N;Takematsu H;Kitazume S;Tedder TF;Marth JD;Ito N;Ando H;Ishida H;Kiso M;Tsubata T
唾液酸结合免疫球蛋白样凝集素（Siglecs）在各种免疫细胞中表达，并且它们中的大多数携带信号传导功能。已经开发了用于各种Siglecs的高亲和力合成唾液酸糖苷配体。已经证明了纳米颗粒和含有多个这些唾液酸苷和其他试剂如毒素和抗原的化合物的治疗潜力。然而，免疫反应是否可以调节单体唾液酸苷配体尚未知道。CD 22（也称为Siglec-2）是一种优先在B淋巴细胞（B细胞）中表达的抑制性分子，并由同一细胞上表达的α 2，6唾液酸（顺式配体）组成性结合和功能性调节。在这里，我们开发了合成的唾液酸苷GSC 718和GSC 839，它们以高亲和力（IC 50 ~100 nM）结合CD 22，并抑制CD 22的配体结合。当B细胞被B细胞抗原受体（BCR）连接激活时，GSC 718和GSC 839均下调B细胞的增殖，并且该调节需要CD 22和α 2，6唾液酸。该结果表明，这些唾液酸苷通过逆转内源性配体介导的CD 22调节来调节BCR连接诱导的B细胞活化。相比之下，GSC 718和GSC 839增强TLR配体或CD 40连接诱导的B细胞增殖，并且这种增强需要CD 22而不是α 2，6唾液酸。因此，这些唾液酸糖苷似乎通过直接抑制CD 22的抑制功能而增强B细胞活化，而不依赖于内源性配体介导的调节。此外，GSC 839增强依赖于BCR连接和CD 40连接的B细胞增殖，如体内B细胞对抗原的应答的情况，并增强抗体产生至与CpG寡核苷酸或少量明矾相当的程度。尽管这些已知的佐剂诱导炎性细胞因子的产生或炎性细胞的积累，但结合CD 22的唾液酸糖苷不会。因此，以高亲和力结合CD 22的合成唾液酸糖苷通过内源性配体依赖性和非依赖性途径调节B细胞活化，并携带佐剂活性而不诱导炎症。
Sialic acid-binding immunoglobulin-like lectins (Siglecs) are expressed in various immune cells and most of them carry signaling functions. High-affinity synthetic sialoside ligands have been developed for various Siglecs. Therapeutic potentials of the nanoparticles and compounds that contain multiple numbers of these sialosides and other reagents such as toxins and antigens have been demonstrated. However, whether immune responses can be regulated by monomeric sialoside ligands has not yet been known. CD22 (also known as Siglec-2) is an inhibitory molecule preferentially expressed in B lymphocytes (B cells) and is constitutively bound and functionally regulated by α2,6 sialic acids expressed on the same cell (cis-ligands). Here, we developed synthetic sialosides GSC718 and GSC839 that bind to CD22 with high affinity (IC50 ~100 nM), and inhibit ligand binding of CD22. When B cells are activated by B cell antigen receptor (BCR) ligation, both GSC718 and GSC839 downregulate proliferation of B cells, and this regulation requires both CD22 and α2,6 sialic acids. This result suggests that these sialosides regulate BCR ligation-induced B cell activation by reversing endogenous ligand-mediated regulation of CD22. By contrast, GSC718 and GSC839 augment B cell proliferation induced by TLR ligands or CD40 ligation, and this augmentation requires CD22 but not α2,6 sialic acids. Thus, these sialosides appear to enhance B cell activation by directly suppressing the inhibitory function of CD22 independently of endogenous ligand-mediated regulation. Moreover, GSC839 augments B cell proliferation that depends on both BCR ligation and CD40 ligation as is the case for in vivo B cell responses to antigens, and enhanced antibody production to the extent comparable to CpG oligonuleotides or a small amount of alum. Although these known adjuvants induce production of the inflammatory cytokines or accumulation of inflammatory cells, CD22-binding sialosides do not. Thus, synthetic sialosides that bind to CD22 with high-affinity modulate B cell activation through endogenous ligand-dependent and independent pathways, and carry an adjuvant activity without inducing inflammation.
登录
查看更多内容
影响因子：
6.2
作者：
Bode C;Zhao G;Steinhagen F;Kinjo T;Klinman DM
通讯作者：
Klinman DM
影响因子：
32.4
作者：
Hou B;Saudan P;Ott G;Wheeler ML;Ji M;Kuzmich L;Lee LM;Coffman RL;Bachmann MF;DeFranco AL
通讯作者：
DeFranco AL
影响因子：
3.5
作者：
Abdu-Allah, Hajjaj H. M.;Watanabe, Kozo;Completo, Gladys C.;Sadagopan, Magesh;Hayashizaki, Koji;Takaku, Chiaki;Tamanaka, Taichi;Takematsu, Hiromu;Kozutsumi, Yasunori;Paulson, James C.;Tsubata, Takeshi;Ando, Hiromune;Ishida, Hideharu;Kiso, Makoto
通讯作者：
Kiso, Makoto
影响因子：
56.9
作者：
Garside, P;Ingulli, E;Jenkins, MK
通讯作者：
Jenkins, MK
影响因子：
7.3
作者：
Abdui-Allah, Hajaj H. M.;Tainanaka, Taichi;Kiso, Makoto
通讯作者：
Kiso, Makoto