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首页> 外文期刊>Biochemistry >Humoral Immune Response to Fibrillar beta-Amyloid Peptide.
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Humoral Immune Response to Fibrillar beta-Amyloid Peptide.

机译：对原纤维β淀粉样肽的体液免疫反应。

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摘要

The beta-amyloid peptide (Abeta) is a normal product of the proteolytic processing of its precursor (beta-APP). Normally, it elicits a very low humoral immune response; however, the aggregation of monomeric Abeta to form fibrillar Abeta amyloid creates a neo-epitope, to which antibodies are generated. Rabbits were injected with fibrillar human Abeta(1)(-)(42), and the resultant antibodies were purified and their binding properties characterized. The antibodies bound to an epitope in the first eight residues of Abeta and required a free amino terminus. Additional residues did not affect the affinity of the epitope as long as the peptide was unaggregated; the antibody bound Abeta residues 1-8, 1-11, 1-16, 1-28, 1-40, and 1-42 with similar affinities. In contrast, the antibodies bound approximately 1000-fold more tightly to fibrillar Abeta(1)(-)(42). Their enhanced affinity did not result from their bivalent nature: monovalent Fab fragments exhibited a similar affinity for the fibrils. Nor did it result from the particulate nature of the epitope: monomeric Abeta(1)(-)(16) immobilized on agarose and soluble Abeta(1)(-)(16) exhibited similar affinities for the antifibrillar antibodies. In addition, antibodies raised to four nonfibrillar peptides corresponding to internal Abeta sequences did not exhibit enhanced affinity for fibrillar Abeta(1)(-)(42). Antibodies directed to the C-terminus of Abeta bound poorly to fibrillar Abeta(1)(-)(42), which is consistent with models where the carboxyl terminus is buried in the interior of the fibril and the amino terminus is on the surface. When used as an immunohistochemical probe, the antifibrillar Abeta(1)(-)(42) IgG exhibited enhanced affinity for amyloid deposits in the cerebrovasculature. We hypothesize either that the antibodies recognize a specific conformation of the eight amino-terminal residues of Abeta, which is at least 1000-fold more favored in the fibril than in monomeric peptides, or that affinity maturation of the antibodies produces an additional binding site for the amino-terminal residues of an adjacent Abeta monomer. In vivo this specificity would direct the antibody primarily to fibrillar vascular amyloid deposits even in the presence of a large excess of monomeric Abeta or its precursor. This observation may explain the vascular meningeal inflammation that developed in Alzheimer's disease patients immunized with fibrillar Abeta. Passive immunization with an antibody directed to an epitope hidden in fibrillar Abeta and in the transmembrane region of APP might be a better choice in the search for an intervention to remove Abeta monomers without provoking an inflammatory response.
机译：β-淀粉样肽（Abeta）是其前体（beta-APP）进行蛋白水解加工的正常产物。通常，它引起非常低的体液免疫反应。但是，单体Abeta的聚集形成原纤维Abeta淀粉样蛋白会产生新表位，并产生抗体。给兔子注射原纤维状人Abeta（1）（-）（42），纯化所得抗体，并鉴定其结合特性。抗体与Abeta的前八个残基中的表位结合，需要一个游离氨基末端。只要肽未聚集，其他残基就不会影响表位的亲和力。抗体以相似的亲和力结合Abeta残基1-8、1-11、1-16、1-28、1-40和1-42。相比之下，抗体与原纤维Abeta（1）（-）（42）的结合更紧密约1000倍。它们的亲和力增强不是由于其二价性质：单价Fab片段对原纤维表现出相似的亲和力。它也不是由表位的颗粒性质引起的：固定在琼脂糖上的单体Abeta（1）（-）（16）和可溶性Abe​​ta（1）（-）（16）对抗原纤维抗体表现出相似的亲和力。此外，针对对应于内部Abeta序列的四个非原纤维肽的抗体并未表现出对原纤维Abeta（1）（-）（42）的增强亲和力。针对Abeta C末端的抗体与原纤维Abeta（1）（-）（42）的结合较弱，这与羧基末端埋在原纤维内部且氨基末端位于表面的模型相符。当用作免疫组织化学探针时，抗原纤维Abeta（1）（-）（42）IgG对脑血管系统中的淀粉样蛋白沉积物显示出增强的亲和力。我们假设要么抗体识别Abeta的八个氨基末端残基的特定构象，其在原纤维中的亲和力至少比在单体肽中高1000倍，或者抗体的亲和力成熟产生额外的结合位点相邻Abeta单体的氨基末端残基。在体内，即使在存在大量过量的单体Abeta或其前体的情况下，这种特异性也可以将抗体主要引导至原纤维状血管淀粉样蛋白沉积物。该观察结果可以解释在用纤维状Abeta免疫的阿尔茨海默氏病患者中发生的血管性脑膜炎症。用针对隐藏在纤维状Abeta和APP跨膜区域中的表位的抗体进行被动免疫可能是寻找去除Abeta单体而不引起炎症反应的干预措施的更好选择。

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