Sollid L M, McAdam S N, Molberg O, Quarsten H, Arentz-Hansen H, Louka A S, Lundin K E
Institute of Immunology and Medical Department, Rikshospitalet, University of Oslo, Norway.
Acta Odontol Scand. 2001 Jun;59(3):183-6. doi: 10.1080/000163501750266792.
Celiac disease is an intestinal disorder that develops as a result of interplay between genetic and environmental factors. HLA genes along with non-HLA genes predispose to the disease. Linkage studies have failed to identify chromosomal regions other than the HLA region which have major effects, indicating the existence of multiple non-HLA predisposing genes with modest effects. Association studies have shown that CTLA4 or a closely located gene is one of these genes. The primary HLA association in the majority of celiac disease patients is with DQ2 (DQA105/DQB102) and in the minority of patients with DQ8 (DQA10301/DQB10302). Gluten reactive CD4+ T cells can be isolated from small intestinal biopsies of celiac patients but not from controls. DQ2 or DQ8, but not other HLA molecules carried by patients, present peptides to these T cells. A number of distinct T cell gluten epitopes exist, most of them posttranslationally modified by deamidation. DQ2 and DQ8 bind the epitopes such that the glutamic acid residues created by deamidation are accommodated in pockets that have a preference for negatively charged side chains. There is evidence that deamidation in vivo is mediated by the enzyme tissue transglutaminase (tTG). Overall, the results point to control of the immune response to gluten by intestinal T cells restricted by the DQ2 or DQ8 molecules. This is likely to be a critical checkpoint for the development of celiac disease and could explain the dominant genetic role of HLA in this disorder. The products of the other predisposing genes may participate in pathway(s) that lead(s) to lesion formation. The minor genetic effects of the non-HLA genes could indicate a lack of critical checkpoints along these pathways, or that there are several pathways leading to the lesion formation.
乳糜泻是一种由于遗传和环境因素相互作用而引发的肠道疾病。HLA基因以及非HLA基因使人易患此病。连锁研究未能确定除HLA区域外具有主要影响的染色体区域，这表明存在多个具有适度影响的非HLA易感基因。关联研究表明，CTLA4或与之紧密相邻的一个基因就是其中之一。大多数乳糜泻患者中主要的HLA关联是与DQ2（DQA105/DQB102）相关，少数患者则与DQ8（DQA10301/DQB10302）相关。可从乳糜泻患者的小肠活检组织中分离出对麸质有反应的CD4+ T细胞，而对照样本中则无法分离出。患者携带的DQ2或DQ8，而非其他HLA分子，将肽段呈递给这些T细胞。存在许多不同的T细胞麸质表位，其中大多数在翻译后通过脱酰胺作用进行了修饰。DQ2和DQ8结合这些表位，使得脱酰胺作用产生的谷氨酸残基能够容纳在偏好带负电荷侧链的口袋中。有证据表明，体内的脱酰胺作用是由组织转谷氨酰胺酶（tTG）介导的。总体而言，这些结果表明，由DQ2或DQ8分子限制的肠道T细胞控制着对麸质的免疫反应。这可能是乳糜泻发病的关键检查点，并且可以解释HLA在这种疾病中的主要遗传作用。其他易感基因的产物可能参与导致病变形成的途径。非HLA基因的微小遗传效应可能表明这些途径缺乏关键检查点，或者存在多条导致病变形成的途径。
