Igs as Substrates for Transglutaminase 2: Implications for Autoantibody Production in Celiac Disease
Igs as Substrates for Transglutaminase 2: Implications for Autoantibody Production in Celiac Disease
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DOI：
10.4049/jimmunol.1501363
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发表时间：
2015-12-01
影响因子：
4.4
通讯作者：
Sollid, Ludvig M.
中科院分区：
文献类型：
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作者：
Iversen, Rasmus;du Pre, M. Fleur;Sollid, Ludvig M.
转谷氨酰胺酶 2 (TG2) 特异性自身抗体是麸质敏感性肠病乳糜泻的标志。抗体的产生严格依赖于膳食麸质蛋白的摄入，因此提出了外来抗原（麸质）如何诱导自身免疫反应的问题。有人提出，TG2 反应性 B 细胞在受体介导的 TG2-麸质复合物摄取后被麸质反应性 T 细胞激活。在这项研究中，我们提出了一个修订模型，该模型基于 BCR 作为 TG2 底物并与麸质衍生肽交联的能力。我们表明，TG2 特异性 IgD 分子在反应中是优选的，并且 TG2 通过使用 IgH 可变基因片段 (IGHV) 5-51 的细胞靶向的共同表位进行结合，导致更有效的交联。基于这些发现，我们假设使用 IGHV5-51 的表达 IgD 的 B 细胞被优先激活，我们认为这一特性可以解释之前报道的体细胞突变数量较少以及乳糜泻病变中 TG2 特异性浆细胞中 IGHV5-51 的过度表达。该模型还将 TG2 反应性 B 细胞对麸质肽的摄取直接与肽脱酰胺结合起来，这对于麸质反应性 T 细胞的激活是必要的。因此，它提供了麸质脱酰胺、T 细胞激活和 TG2 特异性抗体产生之间的联系。这些都是乳糜泻发展过程中的关键事件，通过将它们联系起来，该模型可以解释为什么催化麸质脱酰胺的同一种酶也是一种自身抗原，这绝非巧合。
Autoantibodies specific for the enzyme transglutaminase 2 (TG2) are a hallmark of the gluten-sensitive enteropathy celiac disease. Production of the Abs is strictly dependent on exposure to dietary gluten proteins, thus raising the question how a foreign Ag (gluten) can induce an autoimmune response. It has been suggested that TG2-reactive B cells are activated by gluten-reactive T cells following receptor-mediated uptake of TG2-gluten complexes. In this study, we propose a revised model that is based on the ability of the BCR to serve as a substrate to TG2 and become cross-linked to gluten-derived peptides. We show that TG2-specific IgD molecules are preferred in the reaction and that binding of TG2 via a common epitope targeted by cells using the IgH variable gene segment (IGHV) 5-51 results in more efficient cross-linking. Based on these findings we hypothesize that IgD-expressing B cells using IGHV5-51 are preferentially activated, and we suggest that this property can explain the previously reported low number of somatic mutations as well as the overrepresentation of IGHV5-51 among TG2-specific plasma cells in the celiac lesion. The model also couples gluten peptide uptake by TG2-reactive B cells directly to peptide deamidation, which is necessary for the activation of gluten-reactive T cells. It thereby provides a link between gluten deamidation, T cell activation, and the production of TG2-specific Abs. These are all key events in the development of celiac disease, and by connecting them the model may explain why the same enzyme that catalyzes gluten deamidation is also an autoantigen, something that is hardly coincidental.