Heavy Metal Induced Autoimmunity

重金属诱发的自身免疫

• 批准号: 9245299
• 负责人: SHAODONG DAI
• 金额: $ 23.78万
• 依托单位: NATIONAL JEWISH HEALTH
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-05-01 至 2018-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9245299
• 关键词: Affinity; Alleles; Allergic Disease; Amino Acids; Animal Model; Animals; Antigen Receptors; Antigen-Presenting Cells; Antigens; Autoantibodies; Autoantigens; Autoimmune Diseases; Autoimmune Process; Autoimmune Responses; Autoimmunity; B-Lymphocytes; Beryllium; Binding; Binding Sites; C57BL/6 Mouse; Cadmium; Calcium; Categories; Cells; Complex; Crystallization; Data; Development; Disease; Environmental Exposure; Environmental Risk Factor; Exposure to; Genes; Genetic; Genetic Predisposition to Disease; Gold; Half-Life; Heart Diseases; Heavy Metals; Histocompatibility Antigens Class II; Hypersensitivity; Immune System Diseases; Immune system; Ions; Knowledge; Ligands; Light; Link; Major Histocompatibility Complex; Malignant Neoplasms; Mediating; Mercury; Metals; Modeling; Molecular; Mus; Mutation; NMR Spectroscopy; Nature; Nickel; Peptides; Play; Population; Production; Proteins; Research; Role; Silver; Site; Structure; Symptoms; T cell response; T-Cell Activation; T-Lymphocyte; TCR Activation; Testing; Therapeutic; Toxic effect; Transgenic Organisms; United States; Variant; autoreactive B cell; cell transformation; chemical property; design; immunogenic; in vivo; novel; prevent; small molecule; tool

PROJECT SUMMARY/ABSTRACT This proposal will investigate the role of heavy metals in autoimmunity. Autoimmune diseases are the third most common category of disease in the United States after cancer and heart disease. They occur when the immune system erroneously attacks the cells in the body that are normally recognized as “self”. Although there is a genetic component to autoimmune disease, the rapid increase in these diseases in recent years suggests that environmental factors are also important in their development. While, despite much research, these factors remain elusive. There is some evidence that exposure to heavy metals may play a role in the induction or exacerbation of several autoimmune diseases. For example, in some animal models, mercury, silver, gold and cadmium (Cd2+) induce autoimmunity. Loss of T cell tolerance to key self-antigens is critical in many autoimmune diseases, since the T cells can act both as direct effectors of autoimmune damage and as well as helpers in B cell auto-antibody production. The exact mechanisms linking metals to autoimmunity are not as yet well understood. It is likely that the toxic effects of these metals contribute to some extent. However, T cell mediated allergies to these metals are common. Given that major histocompatibility complex (MHC) class II genes are often linked to the development of autoimmunity, an attractive hypothesis is that these metals may interact with MHC/self-peptide complexes to enhance the activation of self-reactive T cells. αβ T cells bearing antigen receptors (TCRs) usually recognize antigen in the form of peptides bound to MHC (pMHC). However, metals, for example nickel, and other small molecules can be unconventional components of TCR ligands and, in this form, can cause some of the most common allergic diseases. Recently we identified a novel calcium (Ca2+) coordination site on mouse MHCII, IAb, bound to an immunogenic peptide variant (3K) of a dominant self-peptide derived from the MHCII Eα protein (Eα). Binding of Ca2+ to IAb-3K modulated the binding affinity of one of the IAb-3K reactive TCRs, 2W20 for its ligand. Additionally, we discovered that Cd2+ can replace the Ca2+ ion and significantly enhance the binding affinity between the TCR and pMHCII, dramatically prolonging the binding half-life. We also demonstrated that Cd2+ can directly increase the activation and proliferation of 2W20 cells. A crystal structure confirmed that Cd2+ is ligated to acidic residues in the Ca2+ binding site composed of amino acids from both IAb and pEα. Our data suggest a model in which Cd2+ binding converts a self MHC/self-peptide combination against which the host T cells are normally tolerant into a neoantigen. Such a model is similar to that we recently proposed for allergies to beryllium. The heavy metal distorts the MHC/self-peptide combination, thus stimulates T cell responses to this now foreign antigen. We hypothesize that the metal ion continues to be there throughout the course of the disease therefore the disease is actually always driven by T cells responding to this self-MHC /self-peptide/heavy metal combination. The metal specific T cells could still help truly autoreactive B cells secrete autoantibodies. This proposal will investigate the possible molecular mechanism responsible for Cd2+ induced T cell activation and proliferation as a neoantigen. Our results could provide a plausible explanation of the role of heavy metals in autoimmune disease. We will elucidate the mechanism of presentation of IAb-3K/ Cd2+ to T cells, and test the impact of Cd2+ in IAb/single peptide mice. Our results could provide a plausible explanation of the role of heavy metals in autoimmune disease.

项目总结/摘要 本提案将调查重金属在自身免疫中的作用。自身免疫性疾病是第三大 在美国仅次于癌症和心脏病的常见疾病。当免疫系统 系统错误地攻击身体中通常被认为是“自我”的细胞。虽然有 自身免疫性疾病的遗传成分，近年来这些疾病的快速增加表明， 环境因素在其发展中也很重要。尽管有很多研究，这些因素 仍然难以捉摸有一些证据表明，暴露于重金属可能在诱导或 几种自身免疫性疾病的恶化。例如，在一些动物模型中，汞、银、金和 镉（Cd ~（2+））诱导自身免疫。T细胞对关键自身抗原耐受性的丧失在许多自身免疫性疾病中是至关重要的。 由于T细胞既可以作为自身免疫损伤的直接效应物，也可以作为B中的辅助物， 细胞自身抗体产生。金属与自身免疫的确切机制还不清楚 明白这些金属的毒性作用可能在一定程度上起作用。然而，T细胞介导的 对这些金属过敏是常见的。鉴于主要组织相容性复合体（MHC）II类基因是 通常与自身免疫的发展有关，一个有吸引力的假设是，这些金属可能与 MHC/自身肽复合物增强自身反应性T细胞的活化。携带抗原的αβ T细胞 受体（TCR）通常识别与MHC结合的肽（pMHC）形式的抗原。然而，金属， 例如镍和其它小分子可以是TCR配体的非常规组分，在这种形式中， 会导致一些最常见的过敏性疾病最近，我们发现了一种新的钙（Ca 2+） 小鼠MHCII，IAb上的配位位点，与显性自身肽的免疫原性肽变体（3 K）结合 MHCII Eα蛋白（Eα）。Ca ~（2+）与IAb-3 K的结合调节了其中一种蛋白的结合亲和力。 IAb-3 K反应性TCR，2 W20为其配体。此外，我们发现Cd 2+可以取代Ca 2+离子， 显著增强TCR与pMHCII之间的结合亲和力，显著延长TCR与pMHCII之间的结合时间， 半衰期我们还证实了Cd ~（2+）可以直接增加2 W20细胞的活化和增殖。一 晶体结构证实Cd 2+连接在由氨基酸组成的Ca 2+结合位点的酸性残基上 从Iab和pEα。我们的数据表明了一个模型，其中Cd 2+结合将自身MHC/自身肽 宿主T细胞通常耐受该组合的新抗原。这种模式类似于 我们最近提出了铍过敏症重金属扭曲了MHC/自身肽的结合， 刺激T细胞对外来抗原的反应我们假设金属离子继续存在 因此，在整个疾病过程中，疾病实际上总是由T细胞对此做出反应而驱动的。 自身-MHC/自身肽/重金属组合。金属特异性T细胞仍然可以帮助真正的自身反应性B 细胞分泌自身抗体。这项提案将调查可能的分子机制负责 Cd ~（2+）作为新抗原诱导T细胞活化和增殖。我们的结果可以提供一个合理的解释 重金属在自身免疫性疾病中的作用我们将阐明IAb-3 K/ Cd 2+对T细胞的影响，并检测Cd 2+对IAb/单肽小鼠的影响。我们的研究结果可以提供一个合理的 解释重金属在自身免疫性疾病中的作用。