摘要

Celiac disease is a small intestine inflammatory disorder with multiple organ involvement, sustained by an inappropriate immune response to dietary gluten. Anti-transglutaminase antibodies are a typical serological marker in patients with active disease, and may disappear during a gluten-free diet treatment. Involvement of infectious agents and innate immunity has been suggested but never proven. Molecular mimicry is one of the mechanisms that links infection and autoimmunity.In our attempt to clarify the pathogenesis of celiac disease, we screened a random peptide library with pooled sera of patients affected by active disease after a pre-screening with the sera of the same patients on a gluten-free diet. We identified a peptide recognized by serum immunoglobulins of patients with active disease, but not by those of patients on a gluten-free diet. This peptide shares homology with the rotavirus major neutralizing protein VP-7 and with the self-antigens tissue transglutaminase, human heat shock protein 60, desmoglein 1, and Toll-like receptor 4. We show that antibodies against the peptide affinity-purified from the sera of patients with active disease recognize the viral product and self-antigens in ELISA and Western blot. These antibodies were able to induce increased epithelial cell permeability evaluated by transepithelial flux of [(3)H] mannitol in the T84 human intestinal epithelial cell line. Finally, the purified antibodies induced monocyte activation upon binding Toll-like receptor 4, evaluated both by surface expression of activation markers and by production of pro-inflammatory cytokines.Our findings show that in active celiac disease, a subset of anti-transglutaminase IgA antibodies recognize the viral protein VP-7, suggesting a possible involvement of rotavirus infection in the pathogenesis of the disease, through a mechanism of molecular mimicry. Moreover, such antibodies recognize self-antigens and are functionally active, able to increase intestinal permeability and induce monocyte activation. We therefore provide evidence for the involvement of innate immunity in the pathogenesis of celiac disease through a previously unknown mechanism of engagement of Toll-like receptor 4.

译文

乳糜泻是一种多器官受累的小肠炎症性疾病,由对膳食麸质的不适当免疫反应维持。抗转谷氨酰胺酶抗体是活动性疾病患者的典型血清学标记,在无麸质饮食治疗期间可能会消失。传染性病原体和先天免疫的参与已经被提出,但从未被证实。分子模拟是联系感染和自身免疫的机制之一。在我们试图阐明乳糜泻的发病机制时, 在对相同无麸质饮食患者的血清进行预筛选后,我们用合并的活动性疾病患者血清筛选了一个随机肽库。我们鉴定了一种肽,这种肽是由活动性疾病患者的血清免疫球蛋白识别的,但不是由无麸质饮食患者的血清免疫球蛋白识别的。该肽与轮状病毒主要中和蛋白 VP-7 以及自身抗原组织转谷氨酰胺酶、人热休克蛋白 60 、桥粒蛋白 1 和 Toll 样受体 4 具有相同的同源性。我们表明,在 ELISA 和 Western 印迹中,来自活性疾病患者血清的针对肽亲和纯化的抗体识别病毒产物和自身抗原。这些抗体能够诱导通过 T84 人肠上皮细胞系中 [(3) H] 甘露醇的跨上皮通量评估的上皮细胞通透性增加。最后,纯化的抗体在结合 Toll 样受体 4 时诱导单核细胞活化,通过活化标记物的表面表达和促炎细胞因子的产生进行评估。我们的研究结果表明,在活动性乳糜泻中,抗转谷氨酰胺酶 IgA 抗体的一个子集识别病毒蛋白 VP-7,表明轮状病毒感染可能通过分子模拟机制参与疾病的发病机制。此外,这种抗体识别自身抗原并具有功能性活性,能够增加肠道通透性并诱导单核细胞活化。因此,我们通过先前未知的 Toll 样受体 4 参与的机制,为固有免疫参与乳糜泻的发病机制提供了证据。

Celiac Disease

儿科 自身免疫性肠病 疾病
概述  :  

乳糜泻是一种携带有遗传易感基因的个体因摄入含麸质蛋白的谷物及其制品而诱发的自身免疫性肠病,又称为麦胶性肠病、非热带口炎性腹泻。乳糜泻的发病率在欧洲白种人中达1%。在中国曾被认为极为罕见,但近几年来接连报道了多例乳糜泻病例,且从中国人群乳糜泻易感基因携带率和小麦消费量等方面分析,结果显示中国人群患病风险远比原先预计的高。临床症状乳糜泻患者因摄入麸质蛋白激发自身免疫性反应导致小肠损伤,绒毛萎缩,而引起营养物质吸收不良,长期的营养不良进而影响到机体的其他组织器官,如皮肤、骨骼、肌肉、关节、肝脏、心

celiac  英 /ˈsiːliæk/美 /ˈsiːliæk/

释    义   adj. 腹的;[解剖] 腹腔的

例    句   Traditionally, "classic" celiac disease was diagnosed when babies and young children developed symptoms like chronic diarrhea and significant weight loss. 通常情况下,当幼儿和小孩出现慢性腹泻和显著的体重下降时,“典型”的腹腔疾病才会被诊断出。

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