Secretion of tumour necrosis factor alpha and lymphotoxin alpha in relation to polymorphisms in the TNF genes and HLA-DR alleles. Relevance for inflammatory bowel disease
Secretion of tumour necrosis factor alpha and lymphotoxin alpha in relation to polymorphisms in the TNF genes and HLA-DR alleles. Relevance for inflammatory bowel disease
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DOI：
10.1046/j.1365-3083.1996.d01-65.x
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发表时间：
1996-04-01
影响因子：
3.7
通讯作者：
Pena, AS
中科院分区：
文献类型：
--
作者：
Bouma, G;Crusius, JBA;Pena, AS
肿瘤坏死因子α (TNF α)和淋巴毒素α (LT α; TNF β)基因串联排列在MHC的中心区域。因此，它们可能对mhc相关疾病的病因学有重要意义。作者在30名慢性炎症性肠病（IBD）患者和12名健康对照者中前瞻性研究了TNF - α和LT - α的分泌与TNF - α基因(TNFA) -308和-238位点多态性、LT - α基因第一个内含子（LTA）的两个多态性以及HLA-DR的关系。在荷兰人群中，这四种多态性的等位基因只出现在五种组合中，称为tnf -单倍型：TNF-C， -E, -H， -I和-P。当与t细胞激活剂一起培养PBMC时，发现TNF单倍型与TNF α和LT α分泌之间存在显著关联，与疾病无关。携带HLA-DR3相关TNF- e单倍型的个体的平均TNF- α分泌量显著高于不携带该单倍型的个体（26 441 pg/ml vs 19 629 pg/ml; P = 0.014）。携带TNF- c单倍型的个体产生最低量的TNF- α (17 408 pg/ml; P = 0.022)。TNF-C和TNF-E单倍型仅在TNFA启动子的-308位置不同。携带HLA-DR1相关的tnf - 1单倍型的个体与缺乏这种单倍型的个体相比，产生的LT α显著减少（1979 pg/ml vs 3462 pg/ml; P = 0.006）。由于TNF- 1单倍型也与低TNF- α分泌相关，因此该单倍型定义为“低分泌表型”。总之，这是第一个显示使用t细胞刺激剂时TNF单倍型与TNF α和LT α分泌之间存在关联的研究。这些发现将有助于定义IBD的疾病异质性，并可能与理解自身免疫性疾病的发病机制相关。
The genes for tumour necrosis factor alpha (TNF alpha) and lymphotoxin alpha (LT alpha; TNF beta) are tandemly arranged in the central region of the MHC. They may, therefore, be of importance for the aetiology of MHC-associated diseases. The authors have prospectively studied the secretion of TNF alpha and LT alpha in relation to polymorphisms at positions-308 and -238 in the TNF alpha gene (TNFA), and two polymorphisms in the first intron of the LT alpha gene (LTA), as well as HLA-DR in 30 patients with chronic inflammatory bowel diseases (IBD) and 12 healthy controls. In the Dutch population, the alleles of these four polymorphisms are present in only five combinations, called TNF-haplotypes: TNF-C, -E, -H, -I, and -P. Significant associations between TNF haplotypes and TNF alpha and LT alpha secretion were found when PBMC were cultured with T-cell activators, irrespective of disease. Mean TNF alpha secretion of individuals carrying the HLA-DR3 associated TNF-E haplotype was significantly higher, as compared to individuals without this haplotype (26 441 pg/ml versus 19 629 pg/ml; P = 0.014). Individuals carrying the TNF-C haplotype produced the lowest amount of TNF alpha (17 408 pg/ml; P = 0.022). The TNF-C and TNF-E haplotypes differ only at position -308 in the promoter of TNFA. Individuals carrying the HLA-DR1 associated TNF-I haplotype produced significantly less LT alpha when compared to those who lack this haplotype (1979 pg/ml versus 3462 pg/ml; P = 0.006). As the TNF-I haplotype is also associated with low TNF alpha secretion, this haplotype thus defines a 'low secretor phenotype'. In conclusion, this is the first study to show associations between TNF haplotypes and TNF alpha and LT alpha secretion when T-cell stimulators are used. These findings will contribute to define disease heterogeneity in IBD and may be of relevance for understanding the pathogenesis of autoimmune diseases.