Burkhart C, Britschgi M, Strasser I, Depta J P H, von Greyerz S, Barnaba V, Pichler W J
Clinic of Rheumatology and Clinical Immunology/Allergology, Inselspital, Bern, Switzerland.
Clin Exp Allergy. 2002 Nov;32(11):1635-43. doi: 10.1046/j.1365-2222.2002.01513.x.
It has been shown that drugs comprise a group of non-peptide antigens that can be recognized by human T cells in the context of HLA class II and that this recognition is involved in allergic reactions. Recent studies have demonstrated a MHC-restricted but processing- and metabolism-independent pathway for the presentation of allergenic drugs such as lidocaine and sulfamethoxazole (SMX) to drug-specific T cells. However, there is little information so far on the precise molecular mechanisms of this non-covalent drug presentation.
The aim of this study was to evaluate the requirements for a specific peptide occupying the groove of the MHC class II molecule for the efficient presentation of non-covalently bound drugs to CD4+ T cells.
We analysed the effect of coincubation or prepulse of antigen presenting cells (APC) with different peptides on the proliferative responses of SMX-specific CD4+ T cell clones. In a second series of experiments, we eluted HLA-bound peptides from the surface of antigen presenting cells by mild acid treatment. Successful removal of peptides was tested directly using labelled peptides and functionally by monitoring activation and proliferation of peptide-specific T cell clones. Finally, the presentation of SMX to SMX-specific T cell clones before and after elution of MHC class II bound peptides was tested.
We found that neither peptide coincubation nor peptide prepulse of APC altered the proliferative response of SMX-specific T cells. APC treated with the acid for a short time retained cell viability, MHC class II expression and antigen presenting cell function. However, defined peptides could be eluted from surface MHC class II molecules nearly quantitatively. Nevertheless, the chemically non-reactive drug SMX could still be presented to specific T cells independent of the presence of distinct self-peptides.
Our data suggest that small molecules like drugs can bind to a multitude of HLA-bound peptides or that, similar to superantigens, they might bind directly to HLA.
研究表明，药物属于一组非肽类抗原，在 HLA Ⅱ类分子的环境中可被人类 T 细胞识别，且这种识别参与过敏反应。最近的研究已经证明，存在一条 MHC 限制但不依赖加工和代谢的途径，可将诸如利多卡因和磺胺甲恶唑（SMX）等致敏药物呈递给药物特异性 T 细胞。然而，迄今为止，关于这种非共价药物呈递的确切分子机制的信息很少。
本研究旨在评估 MHC Ⅱ类分子凹槽中占据特定肽段对于将非共价结合药物有效呈递给 CD4⁺ T 细胞的要求。
我们分析了抗原呈递细胞（APC）与不同肽段共孵育或预脉冲对 SMX 特异性 CD4⁺ T 细胞克隆增殖反应的影响。在第二系列实验中，我们通过温和酸处理从抗原呈递细胞表面洗脱 HLA 结合的肽段。使用标记肽段直接测试肽段的成功去除情况，并通过监测肽段特异性 T 细胞克隆的激活和增殖进行功能测试。最后测试了 MHC Ⅱ类结合肽段洗脱前后 SMX 向 SMX 特异性 T 细胞克隆的呈递情况。
我们发现，APC 与肽段共孵育或预脉冲均未改变 SMX 特异性 T 细胞的增殖反应。短时间用酸处理的 APC 保留了细胞活力、MHC Ⅱ类表达和抗原呈递细胞功能。然而，特定肽段可几乎定量地从表面 MHC Ⅱ类分子上洗脱下来。尽管如此，化学性质不活泼的药物 SMX 仍可独立于特定自身肽段的存在而呈递给特异性 T 细胞。
我们的数据表明，像药物这样的小分子可以与多种 HLA 结合的肽段结合，或者类似于超抗原，它们可能直接与 HLA 结合。
