Heavy Metal Induced Autoimmunity

项目摘要/摘要 这项提案将调查重金属在自身免疫中的作用。自身免疫性疾病排在第三位。 美国仅次于癌症和心脏病的常见疾病类别。它们发生在免疫的时候 系统错误地攻击身体中通常被识别为“自我”的细胞。尽管有一种 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 环境因素在它们的发展中也是重要的。尽管进行了大量研究，但这些因素 仍然难以捉摸。有一些证据表明，接触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的耐受性丧失在许多自身免疫中是至关重要的 疾病，因为T细胞既可以是自身免疫损伤的直接效应者，也可以是B细胞的帮助者 细胞自身抗体的产生。将金属与自身免疫联系起来的确切机制尚不清楚。 明白了。这些金属的毒性效应很可能在一定程度上起到了作用。然而，T细胞介导的 对这些金属过敏是很常见的。鉴于主要组织相容性复合体(MHC)II类基因 通常与自身免疫的发展有关，一个吸引人的假说是，这些金属可能与 MHC/自体多肽复合体增强自身反应性T细胞的活化。携带抗原的αβT细胞 受体(TCR)通常以与MHC结合的多肽(PMHC)的形式识别抗原。然而，金属，用于 例如镍和其他小分子可以是TCR配体的非传统成分，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(钙离子)。 小鼠MHCII，IAb上的配位位点，与优势自体多肽的免疫原性多肽变体(3K)结合 来源于MHCII Eα蛋白(Eα)。钙离子与IAB-3K的结合调节其中一种细胞的结合亲和力 IAB-3K反应性TCRs，2W20为其配体。此外，我们还发现，Cd~(2+)可以取代钙离子，并且 显著增强TCR与pMHCII之间的结合亲和力，显著延长结合时间 半衰期。我们还证实了Cd~(2+)可以直接促进2W20细胞的激活和增殖。一个 晶体结构证实，Cd~(2+)与氨基酸组成的Ca~(2+)结合部位的酸性残基相连 来自IAB和Peα。我们的数据提示了一种模型，在该模型中，CD2+结合将自身MHC/自体肽转化为 宿主T细胞通常能耐受成新抗原的一种组合。这样的模型类似于 我们最近提出了治疗铍过敏的建议。重金属扭曲了MHC/自体肽的结合，因此 刺激T细胞对这种现在的外来抗原的反应。我们假设金属离子仍在那里 因此，在整个疾病过程中，疾病实际上总是由对此做出反应的T细胞驱动的 自身MHC/自体肽/重金属结合。金属特异性T细胞仍然可以帮助真正的自体反应性B细胞 细胞分泌自身抗体。这项提议将调查可能的分子机制 CD2+作为一种新抗原，可诱导T细胞活化和增殖。我们的结果可能会提供一个可信的解释 重金属在自身免疫性疾病中的作用。我们将阐明IAB-3K/的呈递机制。 CD2+对T细胞的影响，并检测CD2+对IAB/单肽小鼠的影响。我们的结果可能会提供一个可信的 解释重金属在自身免疫性疾病中的作用。

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.