Circulating immune complexes in IgA nephropathy consist of IgA1 with galactose-deficient hinge region and antiglycan antibodies
Circulating immune complexes in IgA nephropathy consist of IgA1 with galactose-deficient hinge region and antiglycan antibodies
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DOI：
10.1172/jci5535
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发表时间：
1999-07-01
影响因子：
15.9
通讯作者：
Mestecky, J
中科院分区：
文献类型：
--
作者：
Tomana, M;Novak, J;Mestecky, J
从 IgA 肾病 (IgAN) 患者血清中分离的循环免疫复合物 (CIC) 由半乳糖基化的、大部分是聚合的、含有 J 链的 IgA1 和 IgG 抗体组成，这些抗体对 IgA1 重链铰链区 O 连接聚糖中的 N-乙酰半乳糖胺 (GalNAc) 残基具有特异性。具有这种特异性的抗体存在于 IgAN 患者的血清中，并且在非 IgA 增殖性肾小球肾炎患者和健康对照者的血清中存在少量抗体；它们主要存在于 IgG（主要是 IgG2 亚类）中，较少出现在 IgA1 同型中。它们对 GalNAc 的特异性是通过与 IgA1 骨髓瘤蛋白的反应性来确定的，其中酶法去除了 N-乙酰神经氨酸 (NeuNAc) 和半乳糖 (Gal)；去除 IgA1 的 O 连接聚糖会导致反应性显着降低。此外，缺少 O 连接聚糖铰链区但在其他结构上与 IgA1 相似的 IgA2 蛋白不会与 IgG 或 IgA1 抗体发生反应。缺乏 NeuNAc 和 Gal 的 IgA1 比完整的 IgA1 更能有效地抑制分离的和酸解离的 CIC 的重新形成。固定化 GalNAc 和脱唾液酸绵羊颌下粘蛋白（富含 O 连接聚糖）也是有效的抑制剂。我们的结果表明，IgA1 分子铰链区 Gal 的缺陷导致产生含有 GalNAc 残基的抗原决定簇，这些残基可被天然存在的 IgG 和 IgA1 抗体识别。
Circulating immune complexes (CICs) isolated from sera of patients with IgA nephropathy (IgAN) consist of undergalactosylated, mostly polymeric, and J chain-containing IgA1 and IgG antibodies specific for N-acetylgalactosamine (GalNAc) residues in O-linked glycans of the hinge region of IgA1 heavy chains. Antibodies with such specificity occur in sera of IgAN patients, and in smaller quantities in patients with non-IgA proliferative glomerulonephritis and in healthy controls; they are present mainly in the IgG (predominantly IgG2 subclass), and less frequently in the IgA1 isotype. Their specificity for GalNAc was determined by reactivity with IgA1 myeloma proteins with enzymatically removed N-acetylneuraminic acid (NeuNAc) and gallactose (Gal); removal of the O-linked glycans of IgA1 resulted in significantly decreased reactivity. Furthermore, IgA2 proteins that lack the hinge region with O-linked glycans but are otherwise structurally similar to IgA1 did not react with IgG or IgA1 antibodies. The re-formation of isolated and acid-dissociated CICs was inhibited more effectively by IgA1 lacking NeuNAc and Gal than by intact IgA1. Immobilized GalNAc and asialo-ovine submaxillary mucin (rich in O-linked glycans) were also effective inhibitors. Our results suggest that the deficiency of Gal in the hinge region of IgA1 molecules results in the generation of antigenic determinants containing GalNAc residues that are recognized by naturally occurring IgG and IgA1 antibodies.