Characterisation of autoantigen-specific human B cells in central nervous system autoantibody-mediated diseases

中枢神经系统自身抗体介导疾病中自身抗原特异性人 B 细胞的表征

• 批准号: MR/V007173/1
• 负责人: Sarosh Irani
• 金额: $ 259.39万
• 依托单位: University of Oxford
• 依托单位国家: 英国
• 项目类别: Fellowship
• 财政年份: 2021
• 资助国家: 英国
• 起止时间: 2021 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FV007173%2F1
• 关键词: Characterisation; autoantigen; specific; human; cells

BackgroundOur immune system has evolved to protect us from infections. Often, the most effective protection is via its production of antibodies. Antibodies are made by the immune system's 'B cells'. Antibodies can bind to bacteria and directly clear an infection. However, sometimes, they can - in error - recognise our own body as the invader. These so-called 'autoantibodies' lead to 'autoimmune' diseases which affect ~10% of the population and causes significant disability and sometimes death. So, understanding how the body removes the self-reactive B cells is of major importance to develop better treatments.Autoimmune conditions can affect almost any tissue in the body but, traditionally, the brain has been considered relatively protected. However, over the last decade, we and others have successfully identified 15 brain proteins which are targeted by autoantibodies. This far outweighs the number of similar autoimmune syndromes in any other branch of medicine. Patients with these autoantibodies often have seizures, memory loss and psychiatric symptoms, together called 'encephalitis'. The number of forms of autoimmune encephalitis (AE) continues to grow annually.Oxford is the UK's major referral centre for patients with AE. 95% of our patients consent to research involvement, so my team can directly study patient samples and link findings to their symptoms and treatment responses. Indeed, our patients show some improvements with available medications which suppress their immune system. However, 80% either cannot return to work, have relapses or experience unacceptable side effects from their medications.To improve these outcomes for patients, this project aims to direct the discovery of improved medications. Also, as autoimmune diseases are common and B cells are found in the brain in many neurological conditions, our findings will all inform the biology and care of patients with several other illnesses.Aims of this project:1. To identify which B cells are the first to become self-reactive and which are the most self-reactive. This will highlight cells that are ideal targets for future therapies, lay the foundations for Aims 2 and 3, and offer explanations about causation to our patients.This work will study blood donated by our patients and by healthy people. We will separate blood B cells into populations which represent stages of their development. Then, individual populations can be activated to discover the earliest, and the most potent, producers of the autoreactive antibodies. Comparisons to healthy people will show where the self-reactive B cells are successfully cleared. By repeating these studies after patients are treated, we will understand if current therapies can reset the process to that observed in health. 2. To describe molecules exclusively found on the B cells which make the autoantibodies. Targeting these molecules with medications would simultaneously increase effectiveness and reduce side-effect profiles. Using findings from Aim 1, the most self-reactive B cell populations in blood will be purified. Also, samples from patient spinal fluid will access self-reactive B cells which circulate and contact their ultimate target - the brain. From both sites, we aim to compare the self-reactive to the non self-reactive cells and identify the distinct range of molecules on the former. Work will occur in collaboration with expert cell profilers at Oxford University and Yale University (USA).3. To ask if certain autoantibodies are especially potent at inducing disease. The B cells that make these would be even more precise targets for future therapies.From the B cells purified in Aim 2, we will recover multiple autoantibodies. These will be applied to brain cells 'in a dish' and injected into mice, to identify those which most robustly disrupt these systems. Relating this to data from Aim 2 will reveal the profile of the B cells that made the most potent autoantibodies.

我们的免疫系统已经进化到保护我们免受感染。通常，最有效的保护是通过它产生抗体。抗体是由免疫系统的B细胞产生的。抗体可以与细菌结合，直接清除感染。然而，有时，它们会错误地将我们自己的身体视为入侵者。这些所谓的“自身抗体”会导致“自身免疫性”疾病，影响约10%的人口，并导致严重的残疾，有时甚至死亡。因此，了解身体如何清除自身反应性B细胞对于开发更好的治疗方法至关重要。自身免疫性疾病几乎可以影响身体的任何组织，但传统上，大脑一直被认为是相对受保护的。然而，在过去的十年里，我们和其他人已经成功地鉴定了15种被自身抗体靶向的脑蛋白。这远远超过了其他医学分支中类似自身免疫综合征的数量。患有这些自身抗体的患者通常会出现癫痫发作、记忆丧失和精神症状，这些症状统称为“脑炎”。自身免疫性脑炎（AE）形式的数量每年持续增长。牛津大学是英国AE患者的主要转诊中心。95%的患者同意参与研究，所以我的团队可以直接研究患者样本并将研究结果与他们的症状和治疗反应联系起来。事实上，我们的病人在服用抑制免疫系统的药物后表现出了一些改善。然而，80%的人要么无法重返工作岗位，要么复发，要么经历不可接受的药物副作用。为了改善患者的这些结果，该项目旨在指导改进药物的发现。此外，由于自身免疫性疾病很常见，在许多神经系统疾病中，大脑中都发现了B细胞，我们的发现将为患有其他几种疾病的患者的生物学和护理提供信息。该项目的目的：1.；为了确定哪些B细胞是第一个自我反应的，哪些是最自我反应的。这将突出未来治疗的理想靶点细胞，为目标2和目标3奠定基础，并为我们的患者提供因果关系的解释。这项工作将研究我们的病人和健康人捐献的血液。我们将把血液B细胞分成代表它们发育阶段的群体。然后，个体群体可以被激活，以发现最早的，最有效的，自身反应性抗体的生产者。与健康人的比较将显示自体反应性B细胞被成功清除的位置。通过在患者接受治疗后重复这些研究，我们将了解当前的治疗方法是否可以将这一过程重置为在健康中观察到的过程。2. 描述B细胞中产生自身抗体的分子。针对这些分子进行药物治疗可以同时提高疗效并减少副作用。利用Aim 1的发现，血液中最具自我反应性的B细胞群将被纯化。此外，患者脊髓液的样本将进入自我反应的B细胞，这些B细胞循环并接触它们的最终目标——大脑。从这两个位点，我们的目的是比较自反应性细胞和非自反应性细胞，并确定前者上分子的不同范围。工作将与牛津大学和耶鲁大学（美国）的细胞分析专家合作进行。询问某些自身抗体在诱导疾病方面是否特别有效。制造这些细胞的B细胞将成为未来治疗的更精确的目标。从Aim 2中纯化的B细胞中，我们将恢复多个自身抗体。这些技术将应用于“培养皿”中的脑细胞，并注射到老鼠体内，以识别那些最严重破坏这些系统的细胞。将此与Aim 2的数据联系起来，将揭示产生最有效自身抗体的B细胞的概况。

项目成果

The clinical relevance of serum versus CSF NMDAR autoantibodies associated exclusively with psychiatric features: a systematic review and meta-analysis of individual patient data.

• DOI: 10.1007/s00415-022-11224-6
• 发表时间: 2022-10
• 期刊: JOURNAL OF NEUROLOGY
• 影响因子: 6
• 作者: Blackman, Graham;Lim, Mao Fong;Pollak, Thomas;Al-Diwani, Adam;Symmonds, Mkael;Mazumder, Asif;Carter, Ben;Irani, Sarosh;David, Anthony
• 通讯作者: David, Anthony

Fatigue predicts quality of life after leucine-rich glioma-inactivated 1-antibody encephalitis.

疲劳可预测富含亮氨酸的胶质瘤灭活 1-抗体脑炎后的生活质量。

• DOI: 10.1002/acn3.52006
• 发表时间: 2024
• 期刊: Annals of clinical and translational neurology
• 影响因子: 5.3
• 作者: Binks SNM

Residual Fatigue and Cognitive Deficits in Patients After Leucine-Rich Glioma-Inactivated 1 Antibody Encephalitis.

• DOI: 10.1001/jamaneurol.2021.0477
• 发表时间: 2021-05-01
• 期刊: JAMA neurology
• 影响因子: 29
• 作者: Binks SNM;Veldsman M;Easton A;Leite MI;Okai D;Husain M;Irani SR
• 通讯作者: Irani SR

Autoimmune encephalitis: proposed recommendations for symptomatic and long-term management.

• DOI: 10.1136/jnnp-2020-325302
• 发表时间: 2021-03-01
• 期刊: Journal of neurology, neurosurgery, and psychiatry
• 作者: Abboud H;Probasco J;Irani SR;Ances B;Benavides DR;Bradshaw M;Christo PP;Dale RC;Fernandez-Fournier M;Flanagan EP;Gadoth A;George P;Grebenciucova E;Jammoul A;Lee ST;Li Y;Matiello M;Morse AM;Rae-Grant A;Rojas G;Rossman I;Schmitt S;Venkatesan A;Vernino S;Pittock SJ;Titulaer M;Autoimmune Encephalitis Alliance Clinicians Network
• 通讯作者: Autoimmune Encephalitis Alliance Clinicians Network

Autoimmune encephalitis: proposed best practice recommendations for diagnosis and acute management.

• DOI: 10.1136/jnnp-2020-325300
• 发表时间: 2021-07
• 期刊: Journal of neurology, neurosurgery, and psychiatry
• 作者: Abboud H;Probasco JC;Irani S;Ances B;Benavides DR;Bradshaw M;Christo PP;Dale RC;Fernandez-Fournier M;Flanagan EP;Gadoth A;George P;Grebenciucova E;Jammoul A;Lee ST;Li Y;Matiello M;Morse AM;Rae-Grant A;Rojas G;Rossman I;Schmitt S;Venkatesan A;Vernino S;Pittock SJ;Titulaer MJ;Autoimmune Encephalitis Alliance Clinicians Network
• 通讯作者: Autoimmune Encephalitis Alliance Clinicians Network