Paulsen G, Lundin K E, Gjertsen H A, Hansen T, Sollid L M, Thorsby E
Institute of Transplantation Immunology, National Hospital, Oslo, Norway.
Hum Immunol. 1995 Feb;42(2):145-53. doi: 10.1016/0198-8859(94)00086-6.
CD is precipitated in susceptible individuals by ingestion of wheat gluten. The disease is strongly associated to the HLA-DQ(alpha 10501, beta 10201) (DQ2) heterodimer, where both the DQ alpha and DQ beta chains are required for susceptibility. We have recently shown that gluten-specific CD4+ T cells from the small intestinal mucosa of CD patients are predominantly restricted by the CD-associated HLA-DQ(alpha 10501, beta 10201) heterodimer. Here we report studies on the influence of aa substitutions in the DQ beta 10201 chain on DQ2-restricted T-cell recognition of gluten antigens. A B-LCL expressing the DQ(alpha 1501, beta 10301) heterodimer was transfected with the DQB10201 gene, or with DQB10201 genes altered by site-directed mutagenesis. Surface expression of the wild-type or mutated DQ(alpha 10501, beta 10201) heterodimers was observed in the transfectants. Seven DQ2-restricted, gluten-specific TCCs were then investigated with respect to their ability to recognize antigen presented by the transfectants. All TCCs were sensitive to one or more of the aa substitutions induced but showed different response patterns. The results demonstrate that single aa substitutions of the DQ beta 10201 chain at positions in the peptide-binding cleft of DQ(alpha 10501, beta 10201) may affect binding of gluten-derived peptides and/or interfere with T-cell recognition. Because all seven TCCs studied were differently affected, they probably differ with respect to glutenpeptide and/or DQ(alpha 10501, beta 10201) restriction fine specificity.
在易感个体中，摄入小麦麸质会引发乳糜泻。该疾病与HLA - DQ（α1 * 0501，β1 * 0201）（DQ2）异二聚体密切相关，其中DQα链和DQβ链对于易感性均是必需的。我们最近表明，来自乳糜泻患者小肠黏膜的麸质特异性CD4 + T细胞主要受与乳糜泻相关的HLA - DQ（α1 * 0501，β1 * 0201）异二聚体的限制。在此，我们报告关于DQβ1 * 0201链中的氨基酸取代对DQ2限制的T细胞识别麸质抗原的影响的研究。一个表达DQ（α1 * 501，β1 * 0301）异二聚体的B - LCL用DQB1 * 0201基因或通过定点诱变改变的DQB1 * 0201基因进行转染。在转染子中观察到野生型或突变型DQ（α1 * 0501，β1 * 0201）异二聚体的表面表达。然后研究了七个DQ2限制的、麸质特异性的TCC识别转染子呈递的抗原的能力。所有TCC对诱导产生的一个或多个氨基酸取代敏感，但表现出不同的反应模式。结果表明，在DQ（α1 * 0501，β1 * 0201）的肽结合裂隙位置处的DQβ1 * 0201链的单个氨基酸取代可能影响麸质衍生肽的结合和/或干扰T细胞识别。因为所研究的所有七个TCC受到不同影响，它们在麸质肽和/或DQ（α1 * 0501，β1 * 0201）限制精细特异性方面可能存在差异。
