Association of a syndrome resembling Wegener's granulomatosis with low surface expression of HLA class-I molecules
Association of a syndrome resembling Wegener's granulomatosis with low surface expression of HLA class-I molecules
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DOI：
10.1016/s0140-6736(99)04206-3
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发表时间：
1999-11-06
期刊：
影响因子：
168.9
通讯作者：
Cerundolo, V
中科院分区：
文献类型：
--
作者：
Moins-Teisserenc, HT;Gadola, SD;Cerundolo, V
背景肉芽肿综合征，如韦格纳肉芽肿病，是根据复杂的标准定义的，但其根本原因很少被确定。我们提出了一个新的病因慢性肉芽肿性病变与隐性遗传缺陷，这是与人类白细胞抗原（HLA）locus.Methods五个成年人坏死性肉芽肿性病变在上呼吸道和皮肤，与反复细菌性呼吸道感染和皮肤血管炎，被确定的证据。所有患者均考虑诊断为韦格纳肉芽肿病，但由于病程不相容和免疫抑制治疗耐药而放弃。采集外周血样本，并通过免疫组织化学和荧光激活细胞分选仪分析进行分析。由于所有5例患者的HLA基因座纯合，我们寻找位于HLA基因座内的遗传缺陷与PCR和限制性片段长度polymorphism.Findings一个严重的减少细胞表面表达的HLA I类分子被认为是在所有患者。与抗原呈递相关的转运蛋白（TAP）基因的表达缺陷是导致HLA I类下调的原因，在2例患者中，我们发现TAP 2基因突变导致TAP复合物表达缺陷。我们发现，在两名患者的外周血细胞中存在自身反应性自然杀伤（NK）细胞和γ δ T淋巴细胞。体外遗传缺陷的纠正恢复了HLA I类分子的正常表达，并防止了患者细胞的自身反应。肉芽肿性病变的组织学表现出的激活NK细胞的大比例的存在下。解释我们的研究结果定义的原因和发病机制的一个新的综合征，影响患者有缺陷的表面表达的HLA I类分子。该综合征在临床和组织学上都类似于韦格纳肉芽肿病。患者上呼吸道和皮肤有慢性坏死性肉芽肿性病变，呼吸道复发性感染和皮肤血管炎。肉芽肿性病变内的主要NK细胞群表明皮肤病变的病理生理学可能与HLA I类分子无法关闭NK细胞应答有关。对一个确定的综合征进行精确的遗传分析可以更好地了解疾病的病因和发病机制。
Background Granulomatous syndromes, such as Wegener's granulomatosis, are defined according to complex criteria, but the underlying cause is rarely identified. We present evidence for a new aetiology for chronic granulomatous lesions associated with a recessive genetic defect, which is linked to the human leucocyte antigen (HLA) locus.Methods Five adults with necrotising granulomatous lesions in the upper respiratory tract and skin, associated with recurrent bacterial respiratory infections and skin vasculitis, were identified. A diagnosis of Wegener's granulomatosis was considered in all of them, but abandoned because of an incompatible disease course and resistance to immunosuppressive treatments. Peripheral-blood samples were taken and analysed by immunohistochemistry and fluorescent-activated-cell-sorter analysis. Since all five patients were homozygous for the HLA locus, we looked for genetic defects located within the HLA-locus with PCR and restriction fragment length polymorphism.Findings A severe decrease in cell-surface expression of HLA class-I molecule was seen in all patients. Defective expression of the transporter associated with antigen presentation (TAP) genes was responsible for the HLA class-I down-regulation, and in two patients we identified a mutation in the TAP2 gene responsible for the defective expression of the TAP complex. We showed the presence of autoreactive natural killer (NK) cells and gamma delta T lymphocytes in the peripheral blood cells of two patients. Correction of the genetic defect in vitro restored normal expression of HLA class-I molecules and prevented self-reactivity in the patients' cells. Histology of granulomatous lesions showed the presence of a large proportion of activated NK cells.Interpretation Our findings define the cause and pathogenesis of a new syndrome that affects patients with a defective surface expression of HLA class-I molecules. The syndrome resembles Wegener's granulomatosis both clinically and histologically. Patients have chronic necrotising granulomatous lesions in the upper respiratory tract and skin, recurrent infections of the respiratory tract, and skin vasculitis. A predominant NK population within the granulomatous lesions suggests that the pathophysiology of the skin lesions may relate to the inability of HLA class-I molecules to turn off NK cell responses. Accurate genetic analysis of a defined syndrome can provide a better understanding of the cause and pathogenesis of a disease.