Dieterich Walburga, Esslinger Birgit, Schuppan Detlef
Medical Department I, University of Erlangen-Nürnberg, Erlangen, Germany.
Int Arch Allergy Immunol. 2003 Oct;132(2):98-108. doi: 10.1159/000073710.
Celiac disease is a complex autoimmune disease which is characterized by a strong genetic association (HLA-DQ2 or -DQ8), gluten as nutritional etiological factor, and the enzyme tissue transglutaminase as endomysial autoantigen. Patients develop highly predictive IgA autoantibodies to tTG. Certain gluten peptides are presented by the disease-associated HLA-DQ2/DQ8 molecules leading to stimulation of gluten-specific T cells. This immune response which is driven in the lamina propria causes the mucosal transformation characteristic for celiac disease. Increased intestinal expression of tTG in patients with CD appears to play an important role in the pathogenesis of CD. Thus, modification of gluten peptides by tTG, especially deamidation of certain glutamine residues, can enhance their binding to HLA-DQ2 or -DQ8 and potentiate T cell stimulation. Furthermore, tTG-catalyzed cross-linking and consequent haptenization of gluten with extracellular matrix proteins allows for storage and extended availability of gluten in the mucosa. New therapeutic approaches aim at proteolytic destruction of immunodominant gliadin peptides that are resistant to intestinal enzymes by bacterial prolyl endopeptidases, the inhibition of tTG activity with highly specific enzyme inhibitors or at HLA-DQ2/DQ8 blocking peptide analogues.
乳糜泻是一种复杂的自身免疫性疾病，其特征为存在强遗传关联（HLA - DQ2或 - DQ8）、麸质作为营养病因因素以及酶组织转谷氨酰胺酶作为肌内膜自身抗原。患者会产生针对组织转谷氨酰胺酶的高度预测性IgA自身抗体。某些麸质肽由疾病相关的HLA - DQ2/DQ8分子呈递，从而导致麸质特异性T细胞受到刺激。这种在固有层中驱动的免疫反应导致了乳糜泻特有的黏膜转变。乳糜泻患者中组织转谷氨酰胺酶在肠道中的表达增加似乎在乳糜泻的发病机制中起重要作用。因此，组织转谷氨酰胺酶对麸质肽的修饰，尤其是某些谷氨酰胺残基的脱酰胺作用，可增强它们与HLA - DQ2或 - DQ8的结合并增强T细胞刺激。此外，组织转谷氨酰胺酶催化的交联以及随之而来的麸质与细胞外基质蛋白的半抗原化，使得麸质能够在黏膜中储存并延长其可用性。新的治疗方法旨在通过细菌脯氨酰内肽酶对抵抗肠道酶的免疫显性麦醇溶蛋白肽进行蛋白水解破坏，用高度特异性的酶抑制剂抑制组织转谷氨酰胺酶的活性，或使用HLA - DQ2/DQ8阻断肽类似物。
