Maiuri Luigi, Ciacci Carolina, Ricciardelli Ida, Vacca Loredana, Raia Valeria, Auricchio Salvatore, Picard Jean, Osman Mohamed, Quaratino Sonia, Londei Marco
Institute of Child Health, University College London, London, UK.
Lancet. 2003 Jul 5;362(9377):30-7. doi: 10.1016/S0140-6736(03)13803-2.
The adaptive immune system is central to the development of coeliac disease. Adaptive immune responses are, however, controlled by a preceding activation of the innate immune system. We investigated whether gliadin, a protein present in wheat flour, could activate an innate as well as an adaptive immune response in patients with coeliac disease.
Duodenal biopsy samples from 42 patients with untreated coeliac disease, 37 treated patients, and 18 controls, were cultured in vitro for 3 h or 24 h, in the presence of either immunodominant gliadin epitopes (p(alpha)-2 and p(alpha)-9) or a non-immunodominant peptide (p31-43) known to induce small intestine damage in coeliac disease. We also incubated biopsy samples from nine untreated and six treated patients with a non-immunodominant peptide for 3 h, before incubation with immunodominant gliadin epitopes. Different combinations of interleukin-15 or signal transduction inhibitors were added to selected incubations.
Only the non-immunodominant peptide induced rapid expression of interleukin-15, CD83, cyclo-oxygenase (COX)-2, and CD25 by CD3- cells (p=0.005 vs medium alone) and enterocyte apoptosis (p<0.0001). Only the non-immunodominant peptide induced p38 MAP kinase activation in CD3- cells. Pre-incubation with the non-immunodominant peptide enabled immunodominant epitopes to induce T-cell activation (p=0.001) and enterocyte apoptosis. Inhibition of interleukin-15 or of p38 MAP kinase controlled such activity.
A gliadin fragment can activate the innate immune system, affecting the in situ T-cell recognition of dominant gliadin epitopes. Although our findings emphasise the key role of gliadin-specific T cells, they suggest a complex pathogenic situation, and show that inhibition of interleukin-15 or p38 MAP kinase might have the potential to control coeliac disease.
适应性免疫系统在乳糜泻的发展过程中起核心作用。然而，适应性免疫反应受先天性免疫系统先前激活的控制。我们研究了小麦粉中的一种蛋白质——麦醇溶蛋白，是否能在乳糜泻患者中激活先天性免疫反应和适应性免疫反应。
将42例未经治疗的乳糜泻患者、37例已治疗患者和18例对照的十二指肠活检样本，在体外分别培养3小时或24小时，培养环境中加入免疫显性麦醇溶蛋白表位（p(α)-2和p(α)-9）或一种已知可在乳糜泻中诱导小肠损伤的非免疫显性肽（p31-43）。我们还将9例未经治疗患者和6例已治疗患者的活检样本先与一种非免疫显性肽孵育3小时，然后再与免疫显性麦醇溶蛋白表位孵育。在选定的孵育过程中加入白细胞介素-15或信号转导抑制剂的不同组合。
仅非免疫显性肽能诱导CD3-细胞快速表达白细胞介素-15、CD83、环氧化酶（COX）-2和CD25（与单独培养基相比，p = 0.005）以及肠上皮细胞凋亡（p < 0.0001）。仅非免疫显性肽能诱导CD3-细胞中的p38丝裂原活化蛋白激酶激活。先用非免疫显性肽预孵育能使免疫显性表位诱导T细胞活化（p = 0.001）和肠上皮细胞凋亡。抑制白细胞介素-15或p38丝裂原活化蛋白激酶可控制这种活性。
一种麦醇溶蛋白片段可激活先天性免疫系统，影响原位T细胞对显性麦醇溶蛋白表位的识别。虽然我们的研究结果强调了麦醇溶蛋白特异性T细胞的关键作用，但它们提示了一种复杂的致病情况，并表明抑制白细胞介素-15或p38丝裂原活化蛋白激酶可能有控制乳糜泻的潜力。
