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.

背景我们的免疫系统已经进化到可以保护我们免受感染。通常，最有效的保护是通过其产生抗体。抗体是由免疫系统的“B 细胞”产生的。抗体可以与细菌结合并直接清除感染。然而，有时，它们可能会错误地将我们自己的身体识别为入侵者。这些所谓的“自身抗体”会导致“自身免疫”疾病，影响约 10% 的人口，并导致严重残疾，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体内的任何组织，但传统上，大脑被认为相对受到保护。然而，在过去十年中，我们和其他人已经成功鉴定出 15 种自身抗体靶向的大脑蛋白质。这远远超过任何其他医学分支中类似的自身免疫综合征的数量。携带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，统称为“脑炎”。自身免疫性脑炎 (AE) 的种类每年持续增长。牛津是英国 AE 患者的主要转诊中心。我们 95% 的患者同意参与研究，因此我的团队可以直接研究患者样本，并将结果与​​他们的症状和治疗反应联系起来。事实上，我们的患者在使用抑制免疫系统的现有药物后表现出一些改善。然而，80% 的人要么无法重返工作岗位，要么病情复发，要么经历药物带来的不可接受的副作用。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，并且在许多神经系统疾病的大脑中都发现了 B 细胞，因此我们的研究结果将为患有其他几种疾病的患者的生物学和护理提供信息。该项目的目标：1。确定哪些 B 细胞最先产生自身反应，哪些 B 细胞最具自身反应性。这将突出显示作为未来治疗的理想靶标的细胞，为目标 2 和 3 奠定基础，并向我们的患者提供因果关系的解释。这项工作将研究我们的患者和健康人捐献的血液。我们将把血液 B 细胞分成代表其发育阶段的群体。然后，可以激活个体群体来发现最早、最有效的自身反应性抗体的产生者。与健康人的比较将显示自反应 B 细胞在何处被成功清除。通过在患者接受治疗后重复这些研究，我们将了解当前的疗法是否可以将这一过程重置为健康时观察到的情况。 2. 描述仅在 B 细胞上发现的产生自身抗体的分子。用药物靶向这些分子将同时提高疗效并减少副作用。利用目标 1 的发现，血液中最具自身反应性的 B 细胞群将被纯化。此外，来自患者脊髓液的样本将进入自我反应的 B 细胞，这些细胞会循环并接触其最终目标——大脑。我们的目标是从这两个地点比较自反应细胞和非自反应细胞，并识别前者上不同的分子范围。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。3。询问某些自身抗体是否特别有效地诱发疾病。产生这些抗体的 B 细胞将成为未来治疗的更精确靶标。从 Aim 2 中纯化的 B 细胞中，我们将回收多种自身抗体。这些将被应用于“培养皿中”的脑细胞并注射到小鼠体内，以识别那些最能破坏这些系统的细胞。将其与 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

Encephalitis: diagnosis, management and recent advances in the field of encephalitides

• DOI: 10.1136/postgradmedj-2022-141812
• 发表时间: 2022-06-22
• 期刊: POSTGRADUATE MEDICAL JOURNAL
• 影响因子: 5.1
• 作者: Alam, Ali M.;Easton, Ava;Michael, Benedict D.
• 通讯作者: Michael, Benedict D.

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