Naturally processed and presented epitopes of the islet cell autoantigen IA-2 eluted from HLA-DR4
Naturally processed and presented epitopes of the islet cell autoantigen IA-2 eluted from HLA-DR4
复制标题
DOI：
10.1172/jci7936
复制
发表时间：
1999-11-01
影响因子：
15.9
通讯作者：
Chicz, RM
中科院分区：
文献类型：
--
作者：
Peakman, M;Stevens, EJ;Chicz, RM
在免疫应答过程中，抗原提呈细胞（APCs）加工抗原并呈递与人白细胞抗原（HLA）分子复合物的肽表位。CD4细胞识别这些与HLA II类分子结合的自然加工和呈递的表位（nppe）。表位鉴定对于开发免疫介导疾病的诊断和治疗工具以及了解其病因非常重要，但目前的方法忽略了自然加工对表位选择的影响。我们已经开发了一种使用基于凝集素的抗原递送系统（ADS）将抗原靶向到apc上后，使用质谱（MS）鉴定nppe的技术。我们应用该技术鉴定了1型糖尿病相关（1型dm相关）自身抗原胰岛素瘤相关-2 （IA-2ic）细胞内结构域的npe，该抗原由HLA-DR4（0401）呈现。从HLA-DR4中洗脱的ia -2ic衍生的NPPEs构成6组嵌套在不同核心区域周围的肽。基于这些区域的合成肽结合HLA-DR4并在HLA-DR4阳性的1型糖尿病患者中经常引起原代t细胞增殖，但在非HLA-DR4患者中很少，在我们测试的HLA-DR4非糖尿病对照组中也没有。这种灵活、直接的方法可以识别HLA II类分子中任何抗原的NPPEs等位基因特异性图谱。这种方法应该能够更好地理解表位选择，并导致产生用于检测自身反应性T细胞的敏感和特异性试剂。
During immune responses, antigen-presenting cells (APCs) process antigens and present peptide epitopes complexed with human leukocyte antigen (HLA) molecules. CD4 cells recognize these naturally processed and presented epitopes (NPPEs) bound to HLA class II molecules. Epitope identification is important for developing diagnostic and therapeutic tools for immune-mediated diseases and providing insight into their etiology, but current approaches overlook effects of natural processing on epitope selection. We have developed a technique to identify NPPEs using mass spectrometry (MS) after antigen is targeted onto APCs using a lectin-based antigen delivery system (ADS). We applied the technique to identify NPPEs of the intracellular domain of the type 1 diabetes mellitus-associated (type 1 DM-associated) autoantigen insulinoma-associated-2 (IA-2ic), presented by HLA-DR4 (0401). IA-2ic-derived NPPEs eluted from HLA-DR4 constitute 6 sets of peptides nested around distinct core regions. Synthetic peptides based on these regions bind HLA-DR4 and elicit primary T-cell proliferation frequently in HLA-DR4-positive type 1 DM patients, but rarely in non-HLA-DR4 patients, and in none of the HLA-DR4 nondiabetic controls we tested. This flexible, direct approach identifies an HLA allele-specific map of NPPEs for any antigen, presented by any HLA class II molecule. This method should enable a greater understanding of epitope selection and lead to the generation of sensitive and specific reagents for detecting autoreactive T cells.