Age-associated-susceptibility to B cell autoimmunity in murine epidermolysis bullosa acquisita

小鼠大疱性表皮松解症中与年龄相关的 B 细胞自身免疫易感性

• 批准号: 497070163
• 负责人: Professor Dr. Rudolf Manz
• 金额: --
• 依托单位: Institut für Systemische Entzündungsforschung (ISEF)
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/497070163?language=en
• 关键词: Age; associated; susceptibility; cell; autoimmunity

B cells/plasma cells are essential for the development and pathogenesis of many autoimmune diseases. They produce autoantibodies, present autoantigens to T cells and modulate inflammation via the production of cytokines. Previous studies brought some insights into molecular mechanisms underlying the development of autoimmune diseases. However, why some individuals develop an autoimmune disease and why they develop it at a certain time is still unknown.For most diseases, the relevant autoantigens are unknown. This limits the investigation of the specific autoimmune B cell response. This is different in epidermolysis bullosa acquisita (EBA), an autoimmune skin disease caused by autoantibodies to type VII collagen (COL7). In our preliminary work, we have used a murine model of this disease to investigate the autoreactive, COL7-specific B cell/plasma cell and T cell responses. This work provides detailed insights on the contribution of B cells and plasma cells in EBA, which might be prototypic for other antibody-mediated autoimmune diseases.Particularly, we provided evidence that depending on the expression of a susceptible MHCII haplotype and the production of the cytokines IL-21 and IFN-gamma by CD4 T cells, autoreactive plasma cells are formed that produce COL7-specific IgG-antibodies with a strong inflammatory potential. We also found that plasma cell derived IL-10 inhibits modulates the cytokine response of COL7-specific T cells and limits EBA skin pathogenesis.We also showed that in healthy mice, IL-10+ plasma cells accumulate with age and that this affects innate immune cells. Accordingly, a recent finding demonstrated that the weaker immune response observed in the elderly is partly mediated through an age-associated increase of systemic IL-10 levels. Generally, aging of the immune system is known to be associated with increased susceptibility to infections and tumors, decreased vaccine efficacy and an increased prevalence of autoimmune diseases. A popular example of age-related changes of an immune response is the increased susceptibility to COVID-19 development seen in older individuals.Based on these results we propose that together with MHCII-haplotype and diet, aging is a crucial factor for controlling the balance between the cytokines IL-10, IL-21 and IFN-gamma, which finally determines the onset of an autoreactive B cell/plasma cell response and disease. In this project, we aim to test this hypothesis using the immune response to COL7 and our established EBA model as an example. We expect the findings to be of general relevance also for other autoimmune diseases.

B细胞/浆细胞对于许多自身免疫性疾病的发展和发病机制是必不可少的。它们产生自身抗体，将自身抗原呈递给T细胞，并通过产生细胞因子来调节炎症。先前的研究为自身免疫性疾病发展的分子机制带来了一些见解。然而，为什么有些人会患上自身免疫性疾病，以及为什么他们会在某个特定的时间患上自身免疫性疾病仍然是未知的。这限制了特异性自身免疫B细胞应答的研究。这在获得性大疱性表皮病（EBA）中是不同的，EBA是一种由VII型胶原（COL 7）自身抗体引起的自身免疫性皮肤病。在我们的初步工作中，我们使用了这种疾病的小鼠模型来研究自身反应性的、COL 7特异性的B细胞/浆细胞和T细胞应答。这项工作提供了关于B细胞和浆细胞在EBA中的作用的详细见解，这可能是其他抗体介导的自身免疫性疾病的原型。特别是，我们提供了证据，表明依赖于易感MHCII单倍型的表达和CD 4 T细胞产生细胞因子IL-21和IFN-γ，形成自身反应性浆细胞，其产生具有强炎症潜能的COL 7特异性IgG抗体。我们还发现，浆细胞来源的IL-10抑制调节COL 7特异性T细胞的细胞因子反应，并限制EBA皮肤pathogenicity.We还表明，在健康小鼠中，IL-10+浆细胞随着年龄的增长而积累，这会影响先天免疫细胞。因此，最近的发现表明，在老年人中观察到的较弱的免疫应答部分是通过年龄相关的全身IL-10水平的增加介导的。通常，已知免疫系统的老化与对感染和肿瘤的易感性增加、疫苗效力降低和自身免疫性疾病的患病率增加有关。年龄相关的免疫反应变化的一个流行的例子是在老年人中观察到的对COVID-19发展的易感性增加。基于这些结果，我们提出，与MHCII单倍型和饮食一起，衰老是控制细胞因子IL-10，IL-21和IFN-γ之间平衡的关键因素，最终决定了自身反应性B细胞/浆细胞反应和疾病的发生。在这个项目中，我们的目标是测试这一假设使用的免疫反应COL 7和我们建立的EBA模型作为一个例子。我们希望这些发现对其他自身免疫性疾病也具有普遍意义。