Division of Rheumatology, Allergy and Clinical Immunology, University of California, Davis, CA, 95616, USA; Center for Autoimmune Diseases Research (CREA), School of Medicine and Health Sciences, Universidad del Rosario, Bogota, Colombia.
Center for Autoimmune Diseases Research (CREA), School of Medicine and Health Sciences, Universidad del Rosario, Bogota, Colombia.
J Autoimmun. 2024 Sep;148:103303. doi: 10.1016/j.jaut.2024.103303. Epub 2024 Aug 13.
Autoimmune diseases (ADs) showcase the intricate balance between the immune system's protective functions and its potential for self-inflicted damage. These disorders arise from the immune system's erroneous targeting of the body's tissues, resulting in damage and disease. The ability of T cells to distinguish between self and non-self-antigens is pivotal to averting autoimmune reactions. Perturbations in this process contribute to AD development. Autoreactive T cells that elude thymic elimination are activated by mimics of self-antigens or are erroneously activated by self-antigens can trigger autoimmune responses. Various mechanisms, including molecular mimicry and bystander activation, contribute to AD initiation, with specific triggers and processes varying across the different ADs. In addition, the formation of neo-epitopes could also be implicated in the emergence of autoreactivity. The specificity of T cell responses centers on the antigen recognition sequences expressed by T cell receptors (TCRs), which recognize peptide fragments displayed by major histocompatibility complex (MHC) molecules. The assortment of TCR gene combinations yields a diverse array of T cell populations, each with distinct affinities for self and non-self antigens. However, new evidence challenges the traditional notion that clonal expansion solely steers the selection of higher-affinity T cells. Lower-affinity T cells also play a substantial role, prompting the "two-hit" hypothesis. High-affinity T cells incite initial responses, while their lower-affinity counterparts perpetuate autoimmunity. Precision treatments that target antigen-specific T cells hold promise for avoiding widespread immunosuppression. Nevertheless, detection of such antigen-specific T cells remains a challenge, and multiple technologies have been developed with different sensitivities while still harboring several drawbacks. In addition, elements such as human leukocyte antigen (HLA) haplotypes and validation through animal models are pivotal for advancing these strategies. In brief, this review delves into the intricate mechanisms contributing to ADs, accentuating the pivotal role(s) of antigen-specific T cells in steering immune responses and disease progression, as well as the novel strategies for the identification of antigen-specific cells and their possible future use in humans. Grasping the mechanisms behind ADs paves the way for targeted therapeutic interventions, potentially enhancing treatment choices while minimizing the risk of systemic immunosuppression.
自身免疫性疾病（AD）展示了免疫系统的保护功能与其自我伤害潜力之间的复杂平衡。这些疾病是由于免疫系统错误地针对身体组织而引起的，导致损伤和疾病。T 细胞区分自身和非自身抗原的能力对于避免自身免疫反应至关重要。这个过程的紊乱导致 AD 的发展。逃避胸腺清除的自身反应性 T 细胞可被自身抗原的模拟物激活，或被自身抗原错误激活，从而引发自身免疫反应。多种机制，包括分子模拟和旁观者激活，有助于 AD 的启动，不同的 AD 有不同的特定触发因素和过程。此外，新表位的形成也可能与自身反应性的出现有关。T 细胞反应的特异性集中在 T 细胞受体（TCR）表达的抗原识别序列上，TCR 识别主要组织相容性复合体（MHC）分子呈现的肽片段。TCR 基因组合的多样性产生了多样化的 T 细胞群体，每个群体对自身和非自身抗原都有不同的亲和力。然而，新的证据挑战了传统观念，即克隆扩增仅指导高亲和力 T 细胞的选择。低亲和力 T 细胞也发挥着重要作用，这促使了“双打击”假说的出现。高亲和力 T 细胞引发初始反应，而其低亲和力对应物则使自身免疫持续存在。针对抗原特异性 T 细胞的精准治疗有望避免广泛的免疫抑制。然而，检测这些抗原特异性 T 细胞仍然是一个挑战，已经开发了多种具有不同灵敏度的技术，但仍然存在一些缺点。此外，人类白细胞抗原（HLA）单倍型等因素和通过动物模型进行验证对于推进这些策略至关重要。简而言之，本综述深入探讨了导致 AD 的复杂机制，强调了抗原特异性 T 细胞在引导免疫反应和疾病进展中的关键作用，以及识别抗原特异性细胞的新策略及其在人类中的潜在应用。了解 AD 的机制为靶向治疗干预铺平了道路，可能会增加治疗选择，同时最大限度地降低全身免疫抑制的风险。
