CD19 has a potential CD77 (globotriaosyl ceramide)-binding site with sequence similarity to verotoxin B-subunits: implications of molecular mimicry for B cell adhesion and enterohemorrhagic Escherichia coli pathogenesis.
CD19 has a potential CD77 (globotriaosyl ceramide)-binding site with sequence similarity to verotoxin B-subunits: implications of molecular mimicry for B cell adhesion and enterohemorrhagic Escherichia coli pathogenesis.
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DOI：
10.1084/jem.180.1.191
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发表时间：
1994-07-01
期刊：
影响因子：
--
通讯作者：
Lingwood CA
中科院分区：
文献类型：
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作者：
Maloney MD;Lingwood CA
鞘糖脂globotriaosyl神经酰胺（CD 77）和其它含有末端半乳糖（Gal）α 1-4Gal残基的globo系列糖脂作为大肠杆菌精心制作的毒素的verotoxin（志贺样毒素）家族的受体发挥作用。CD 77也是生殖中心B淋巴细胞和伯基特淋巴瘤细胞的标志物。泛B细胞标志物CD 19是一种95-kD的膜蛋白，其在B细胞分化早期出现，并且仅在终末分化为浆细胞时丢失。CD 19参与信号转导，并在体外应答活化的B细胞增殖和分化中具有调节作用。然而，尚未鉴定出CD 19的内源性配体。我们在此报告，CD 19的细胞外结构域有一个潜在的CD 77结合位点与广泛的序列相似性的verotoxin B-亚基。CD 19上的这些B亚基样序列在将间插氨基酸组织成二硫键连接的结构域后非常接近。用抗-CD 19抗体对伯基特淋巴瘤衍生的Daudi细胞上的CD 19和CD 77进行Cocapping表明CD 19和CD 77在B细胞表面上缔合。抗CD 19抗体的细胞表面结合在CD 77缺陷型突变型Daudi细胞上降低，表明CD 77表达影响CD 19的表面表达。野生型Daudi细胞，而不是CD 19/CD 77缺陷型突变体，结合表达CD 77或其他含Gal α 1-4Gal糖脂的碳水化合物部分的基质。这种结合可被抗CD 77抗体、CD 77结合verotoxin B亚基或抗CD 19抗体抑制。Daudi细胞在培养中表现出一定程度的自发同型粘附，而CD 77/CD 19缺陷型Daudi突变体作为单细胞生长。在抗体连接CD 19后，在B细胞中发生的更强的同型粘附在某种程度上涉及整联蛋白系统，相对于亲本细胞系，突变细胞中的同型粘附也显著降低。然而，用CD 77重建突变细胞将抗CD 19 mAb诱导的粘附恢复至野生型Daudi细胞水平。这些研究代表了第一次在低应答B细胞系中重建CD 19介导的信号传导。这些一致的观察结果提供了令人信服的证据，即CD 19/CD 77相互作用在B细胞发育的特定阶段的粘附和信号转导中起作用，并表明这种相互作用在体内B淋巴细胞归巢和生发中心形成中起作用。通过靶向CD 77 + B细胞，verotoxins可抑制感染期间免疫应答的体液分支。（400字处截断摘要）
The glycosphingolipid globotriaosyl ceramide (CD77) and other globo- series glycolipids containing terminal galactose (Gal)alpha 1-4Gal residues function as receptors for the verotoxin (Shiga-like toxin) family of Escherichia coli-elaborated toxins. CD77 is also a marker for germinal center B lymphocytes and Burkitt's lymphoma cells. The pan B cell marker CD19 is a 95-kD membrane protein that appears early in B cell differentiation and is only lost upon terminal differentiation to plasma cells. CD19 is involved in signal transduction and has a regulatory role in B cell proliferation and differentiation in response to activation in vitro. However, an endogenous ligand for CD19 has not yet been identified. We report herein that the extracellular domain of CD19 has a potential CD77-binding site with extensive sequence similarity to the verotoxin B-subunits. These B-subunit-like sequences on CD19 are in close proximity following the organization of intervening amino acids into disulfide-linked domains. Cocapping of CD19 and CD77 on Burkitt's lymphoma-derived Daudi cells with anti-CD19 antibodies indicates that CD19 and CD77 are associated on the B cell surface. Cell surface binding of anti-CD19 antibodies is decreased on CD77-deficient mutant Daudi cells, suggesting that CD77 expression influences the surface expression of CD19. Wild-type Daudi cells, but not the CD19/CD77-deficient mutants, bind to matrices expressing the carbohydrate moiety of CD77 or other Gal alpha 1-4Gal containing glycolipids. This binding can be inhibited by anti-CD77 antibodies, the CD77-binding verotoxin B-subunit or anti-CD19 antibodies. Daudi cells exhibit a degree of spontaneous homotypic adhesion in culture while the CD77/CD19-deficient Daudi mutants grow as single cells. The stronger homotypic adhesion that occurs in B cells after antibody ligation of CD19 and that involves, to some extent, the integrin system, is also dramatically lower in the mutant cells relative to the parent cell line. However, reconstitution of mutant cells with CD77 restores the anti-CD19 mAb-induced adhesion to wild-type Daudi cell levels. These studies represent the first time that CD19-mediated signaling has been reconstituted in a low-responder B cell line. These convergent observations provide compelling evidence that CD19/CD77 interactions function in adhesion and signal transduction at a specific stage in B cell development and suggest that such interactions have a role in B lymphocyte homing and germinal center formation in vivo. By targeting CD77+ B cells, verotoxins may suppress the humoral arm of the immune response during infection.(ABSTRACT TRUNCATED AT 400 WORDS)