St Thomas' Hospital, Guy's & St Thomas' NHS Foundation Trust, London, UK.
Waksman Institute of Microbiology, Rutgers University, Piscataway, NJ08854, USA.
Br J Nutr. 2020 Jun 28;123(12):1382-1389. doi: 10.1017/S0007114520000768. Epub 2020 Feb 26.
The only generally accepted treatment of coeliac disease (CD) is a lifelong gluten-free diet. Wheat gluten proteins include gliadins, low and high molecular weight glutenins. However, we have found significant structural variations within these protein families among different cultivars. To determine which structural motifs might be less toxic than others, we assessed five variants of α-gliadin immunodominant CD-toxic peptides synthesised as 16mers in CD T cell stimulation assays with gluten-sensitive T cell lines generated from duodenal biopsies from CD-affected individuals. The peptides harboured the overlapping T cell epitopes DQ 2.5-glia-α-2 and naturally occurring variants that differed in certain amino acids (AA). The results revealed that introduction of two selected AA substitutions in α-gliadin peptides reduced immunogenicity. A peptide with three AA substitutions involving two glutamic acids (E) and one glutamine residue (G) revealed the peptide was negative in 5:5 samples. We used CD small-intestinal organ culture to assess CD toxicity that revealed two peptides with selected substitution of both glutamic acid (E) and proline (P) residues abrogated evidence of CD toxicity.
乳糜泻（CD）的唯一公认的治疗方法是终生无麸质饮食。小麦面筋蛋白包括麦醇溶蛋白、低分子量和高分子量麦谷蛋白。然而，我们在不同品种的这些蛋白家族中发现了显著的结构变异。为了确定哪些结构基序可能比其他结构基序毒性更小，我们评估了五种α-麦醇溶蛋白免疫显性 CD 毒性肽的变体，这些变体作为 16 -mer 在 CD 细胞刺激测定中合成，使用来自 CD 个体十二指肠活检的麸质敏感 T 细胞系进行刺激。这些肽含有重叠的 T 细胞表位 DQ2.5- 谷氨酰胺-α-2 和天然存在的变异体，在某些氨基酸（AA）上存在差异。结果表明，在 α-麦醇溶蛋白肽中引入两个选定的 AA 取代可降低免疫原性。一个含有两个谷氨酸（E）和一个谷氨酰胺残基（G）的三个 AA 取代的肽在 5:5 样本中呈阴性。我们使用 CD 小肠器官培养来评估 CD 毒性，结果显示，两种具有选定取代的谷氨酸（E）和脯氨酸（P）残基的肽消除了 CD 毒性的证据。
