臨床検査52巻4号

2008年04月発行

シリーズ最新医学講座・Ⅰ 糖鎖と臨床検査・4

セレクチンと糖鎖

著者： 内村健治¹

所属機関： ¹国立長寿医療センター研究所

ページ範囲：P.465 - P.471

はじめに

　リンパ球のリンパ節へのホーミングおよび白血球の末梢炎症部位への血行性移入は，1991年に提唱された多段階の分子シグナルによって厳密に制御されている(図1)^1,2)．すなわち，ターゲットとなる組織の血管内で血液中を流れる細胞は，セレクチンとその認識リガンドである細胞表面糖鎖の蛋白質-糖鎖の比較的弱い相互作用を利用し，血管内皮細胞上でローリングと呼ばれる現象を示し流速を減少させる(第1段階)．その後，内皮細胞上に提示されたケモカインとローリング細胞上のケモカイン受容体が結合し，ローリング細胞に活性化シグナルが入る(第2段階)．このシグナルがローリング細胞上のインテグリンを活性化し，内皮細胞上の細胞接着分子との蛋白質-蛋白質の結合を利用し強固な接着を引き起こす(第3段階)．最終的に細胞は，血管内皮細胞層をすり抜けて血管外遊走し組織内へ移入する(第4段階)．本稿では，この多段階モデルの最初のステップであるセレクチンとそのリガンド糖鎖について述べる．ケモカインのシグナル機構，およびインテグリンの活性化については他の総説³⁾に詳しい．

参考文献

１) von Andrian UH, Mempel TR：Homing and cellular traffic in lymph nodes. Nat Rev Immunol　3：867-878, 2003

２) Luster AD, Alon R, von Andrian UH：Immune cell migration in inflammation：present and future therapeutic targets. Nat Immunol　6：1182-1190, 2005

３) Kinashi T：Intracellular signalling controlling integrin activation in lymphocytes. Nat Rev Immunol　5：546-559, 2005

４) Kannagi R：Regulatory roles of carbohydrate ligands for selectins in the homing of lymphocytes. Curr Opin Struct Biol　12：599-608, 2002

５) Sako D, Comess KM, Barone KM, et al：A sulfated peptide segment at the amino terminus of PSGL-1 is critical for P-selectin binding. Cell　83：323-331, 1995

６) Miyasaka M, Tanaka T：Lymphocyte trafficking across high endothelial venules：dogmas and enigmas. Nat Rev Immunol　4：360-370, 2004

７) Sperandio M, Smith ML, Forlow SB, et al：P-selectin glycoprotein ligand-1 mediates L-selectin-dependent leukocyte rolling in venules. J Exp Med　197：1355-1363, 2003

８) Ley K, Laudanna C, Cybulsky MI, et al：Getting to the site of inflammation：the leukocyte adhesion cascade updated. Nat Rev Immunol　7：678-689, 2007

９) Uchimura K, Rosen SD：Sulfated L-selectin ligands as a therapeutic target in chronic inflammation. Trends Immunol　27：559-565, 2006

10) Rosen SD：Ligands for L-selectin：homing, inflammation, and beyond. Annu Rev Immunol　22：129-156, 2004

11) Mitsuoka C, Sawada-Kasugai M, Ando-Furui K, et al：Identification of a major carbohydrate capping group of the L-selectin ligand on high endothelial venules in human lymph nodes as 6-sulfo sialyl Lewis X. J Biol Chem　273：11225-11233, 1998

12) Yeh JC, Hiraoka N, Petryniak B, et al：Novel sulfated lymphocyte homing receptors and their control by a Core1 extension beta 1,3-N-acetylglucosaminyltransferase. Cell　105：957-969, 2001

13) Mitoma J, Bao X, Petryanik B, et al：Critical functions of N-glycans in L-selectin-mediated lymphocyte homing and recruitment. Nat Immunol　8：409-418, 2007

14) Hiraoka N, Kawashima H, Petryniak B, et al：Core 2 branching beta1, 6-N-acetylglucosaminyltransferase and high endothelial venule-restricted sulfotransferase collaboratively control lymphocyte homing. J Biol Chem　279：3058-3067, 2004

15) M'Rini C, Cheng G, Schweitzer C, et al：A novel endothelial L-selectin ligand activity in lymph node medulla that is regulated by alpha (1,3)-fucosyltransferase-IV. J Exp Med　198：1301-1312, 2003

16) Maly P, Thall A, Petryniak B, et al：The alpha (1,3) fucosyltransferase Fuc-TVII controls leukocyte trafficking through an essential role in L-, E-, and P-selectin ligand biosynthesis. Cell　86：643-653, 1996

17) Harduin-Lepers A, Vallejo-Ruiz V, Krzewinski-Recchi MA, et al：The human sialyltransferase family. Biochimie 83：727-737, 2001

18) Sperandio M, Frommhold D, Babushkina I, et al：alpha 2,3-Sialyltransferase-IV is essential for L-selectin ligand function in inflammation. Eur J Immunol　36：3207-3215, 2006

19) Hemmerich S, Bistrup A, Singer MS, et al：Sulfation of L-selectin ligands by an HEV-restricted sulfotransferase regulates lymphocyte homing to lymph nodes. Immunity　15：237-247, 2001

20) Uchimura K, Kadomatsu K, El-Fasakhany FM, et al：N-acetylglucosamine 6-O-sulfotransferase-1 regulates expression of L-selectin ligands and lymphocyte homing. J Biol Chem　279：35001-35008, 2004

21) Uchimura K, El-Fasakhany FM, Hori M, et al：Specificities of N-acetylglucosamine-6-O-sulfotransferases in relation to L-selectin ligand synthesis and tumor-associated enzyme expression. J Biol Chem　277：3979-3984, 2002

22) de Graffenried CL, Bertozzi CR：Golgi localization of carbohydrate sulfotransferases is a determinant of L-selectin ligand biosynthesis. J Biol Chem　278：40282-40295, 2003

23) Uchimura K, Gauguet JM, Singer MS, et al：A major class of L-selectin ligands is eliminated in mice deficient in two sulfotransferases expressed in high endothelial venules. Nat Immunol　6：1105-1113, 2005

24) Kawashima H, Petryniak B, Hiraoka N, et al：N-acetylglucosamine-6-O-sulfotransferases 1 and 2 cooperatively control lymphocyte homing through L-selectin ligand biosynthesis in high endothelial venules. Nat Immunol　6：1096-1104, 2005

25) Kobayashi M, Mitoma J, Nakamura N, et al：Induction of peripheral lymph node addressin in human gastric mucosa infected by Helicobacter pylori. Proc Natl Acad Sci USA　101：17807-17812, 2004

26) Suzawa K, Kobayashi M, Sakai Y, et al：Preferential induction of peripheral lymph node addressin on high endothelial venule-like vessels in the active phase of ulcerative colitis. Am J Gastroenterol　102：1499-1509, 2007

27) Iwata M, Hirakiyama A, Eshima Y, et al：Retinoic acid imprints gut-homing specificity on T cells. Immunity　21：527-538, 2004

28) Bonasio R, Scimone ML, Schaerli P, et al：Clonal deletion of thymocytes by circulating dendritic cells homing to the thymus. Nat Immunol　7：1092-1100, 2006

29) Cavanagh LL, Bonasio R, Mazo IB, et al：Activation of bone marrow-resident memory T cells by circulating, antigen-bearing dendritic cells. Nat Immunol　6：1029-1037, 2005

30) Sackstein R, Merzaban JS, Cain DW, et al：Ex vivo glycan engineering of CD44 programs human multipotent mesenchymal stromal cell trafficking to bone. Nat Med　14：181-187, 2008

31) Huehn J, Hamann A：Homing to suppress：address codes for Treg migration. Trends Immunol　26：632-636, 2005

32) Veerman KM, Williams MJ, Uchimura K, et al：Interaction of the selectin ligand PSGL-1 with chemokines CCL21 and CCL19 facilitates efficient homing of T cells to secondary lymphoid organs. Nat Immunol　8：532-539, 2007