Anti-inflammatory cell contact-How do regulatory B cells sense and respond to apoptotic cells?

慢性炎症性自身免疫性疾病是全世界健康的重大负担，会导致慢性疼痛、残疾，并显著缩短人的寿命。世界上1%的人口患有自身免疫性风湿病，如类风湿性关节炎和系统性红斑狼疮(SLE)。在后一种情况下，针对凋亡细胞上表达的抗原的抗体与疾病严重程度之间存在很强的相关性。这些疾病和包括多发性硬化症在内的其他疾病可以接受B细胞耗竭疗法(BCDT)的治疗，该疗法与抗肿瘤坏死因子疗法一样有效。然而，大多数患者未能进入缓解期，需要完善和改进BCDT以改善患者的预后。我们发现，在健康中，凋亡细胞向自我反应的B细胞传递耐受信号，这可以保护小鼠免受自身免疫性疾病的影响，如胶原性关节炎和EAE(多发性硬化症的模型)。凋亡细胞是在体内自然死亡的细胞，我们每天产生数百万个这样的细胞。对凋亡细胞的耐受性丧失是自身免疫性疾病的核心。这些细胞在其细胞表面表达来自细胞内的新抗原，人们认为需要非常迅速地吸收凋亡的细胞，以防止它们诱导自身免疫。自身免疫性疾病中分泌的抗体通常是针对细胞死亡时到达细胞表面的新抗原。然而，识别这些凋亡细胞的自身反应性B细胞实际上需要‘看到’这些被称为核小体的核复合体，以便它们在健康中诱导耐受性。因此，似乎正是凋亡细胞上阻止健康自身免疫的抗原，与当耐受性丧失时导致疾病的抗原是相同的。我们希望确切地了解调节性B细胞上的B细胞受体看到的是什么抗原，以及当疾病发展时，这些B细胞是否也是对自身失去耐受性的B细胞。通过研究B细胞受体的特异性，我们将能够在单个细胞水平上研究细胞，这将比后续的整个B细胞亚群提供更多的见解。我们还希望了解人类调节性B细胞的B细胞受体特异性，并确切地知道健康人群中哪些B细胞亚群是调节性的和对凋亡细胞有反应的。我们将把它与类风湿性关节炎和系统性红斑狼疮患者的相同B细胞进行比较，从而建立起这些细胞在健康和疾病中如何发挥作用的图景。由于凋亡细胞是自身免疫耐受崩溃的中心，我们希望对这些细胞进行更详细的研究，询问当核小体表达时与凋亡细胞表面结合的辅助分子，如补体蛋白和天然抗体是否对诱导这些自身反应性B细胞对自身耐受起重要作用。缺乏补体蛋白，特别是第一补体成分C1q的患者发生系统性红斑狼疮的风险非常高，我们认为该分子可能对调节性B细胞中的信号非常重要。我们相信，通过更好地了解这些先天具有自我反应的B细胞，它们通过诱导耐受信号对健康中的凋亡细胞做出反应，我们将能够询问它们是否可以用于诱导耐受或防止移植排斥反应。如果我们能识别出诱导这些调节性B细胞的抗原，我们就能在体内诱导它们，从而增加它们的数量。如果这些与生俱来的B细胞在健康中对诱导对自身凋亡的耐受性非常重要，那么在疾病中分泌致病抗体和促炎细胞因子的细胞被证明是相同的，那么我们将有一个更好的未来治疗的靶点。然后，我们可能最终能够为我们的患者提供长期缓解无菌破坏性炎症的希望。

Chronic inflammatory autoimmune diseases are a significant burden to health worldwide, causing chronic pain, disability and significantly shortening a person's lifespan. 1% of the world's population suffers from autoimmune rheumatic diseases such rheumatoid arthritis and systemic lupus erythematosus (SLE). In the latter condition a strong correlation exists between antibodies to antigens expressed on apoptotic cells and disease severity. These diseases and others including multiple sclerosis are amenable to treatment with B cell depletion therapy (BCDT), which is as efficacious as anti-TNF therapy. However the majority of patients fail to go into remission and refinement and improvement of BCDT is needed to improve patient outcomes. We have discovered that in health, apoptotic cells impart a tolerogenic signal to self-reactive B cells and this protects mice from autoimmune diseases such as collagen induced arthritis and EAE (a model of multiple sclerosis). Apoptotic cells are cells that die naturally in the body and we generate millions of them every day. A loss of tolerance to apoptotic cells is at the heart of autoimmune diseases. These cells express neo-antigens on their cell surface which have come from inside the cell and it is thought that the apoptotic cells need to be taken up very quickly to prevent them inducing autoimmunity. Antibodies that are secreted in autoimmune diseases are generally to these neo- antigens that have come to the cell surface when the cell has died. However the self reactive B cells that recognise these apoptotic cells actually need to 'see' these nuclear complexes called nucleosomes in order for them to induce tolerance in health. Hence it seems that the very antigens on apoptotic cells that prevent autoimmunity in health are the same antigens that result in disease when tolerance breaks down. We wish to understand exactly what antigens the B cell receptor on regulatory B cells is seeing and if these are the same B cells that lose tolerance to self when disease develops. By studying the B cell receptor specificity we will be able to study the cells at a single cell level, which will give greater insights than following whole B cell subsets. We also wish to understand the B cell receptor specificity of human regulatory B cells and to know exactly what subsets of B cells are regulatory and responsive to apoptotic cells in health. We will compare this to the same B cells from patients with rheumatoid arthritis and SLE, thus building up a picture of how these cells function in health and disease. As the apoptotic cell is so central to the breakdown of tolerance in autoimmunity we wish to study these cells in greater detail asking if accessory molecules such as complement proteins and natural antibody that bind to the apoptotic cell surface when the nucleosomes are expressed on them are important to inducing tolerance to self in these self reactive B cells. Patients that lack complement proteins especially the first complement component C1q are at a very high risk of developing SLE and we believe that this molecule may be very important for signalling in the regulatory B cells.We believe that by gaining a better understanding of these self-reactive innate like B cells that respond to apoptotic cells in health by inducing a tolerogenic signal, we will be able to ask if they can be used to induce tolerance or to prevent transplant rejection. If we can identify antigens that induce these regulatory B cells we will be able to induce them in vivo, thus increasing their number. If these innate like B cells that are important for inducing tolerance to apoptotic self in health turn out to be the same cells that secrete pathogenic antibody and secrete pro-inflammatory cytokines in disease, then we will have a much better target for future therapies. We may then finally be able to offer our patients the hope of a long-term remission from sterile destructive inflammation.