Origin and Diversity of Pathogenic Human Monoclonal Antibodies and T cells in Tumor-associated Autoimmune Neurological Disorders

在过去的十年中，对自身抗体在神经系统疾病中的作用的日益认识显著地改变了神经病学领域的临床实践。针对NMDAR和其他靶标的病原性自身抗体揭示了不同的疾病机制。单细胞测序技术的进步允许对许多不同疾病状态进行更精细的理解，特别是自身免疫性神经综合征中自身免疫的第一步。在这里，使用已建立的单细胞测序方法，我们将调查肿瘤相关的自身免疫性神经系统综合征，包括NMDAR脑炎的自身抗体的起源和多样性。我们将比较患者不同相关区室（如血清、脑脊液和肿瘤）的B细胞库，并进一步检查患者源性抗体的致病性。我们还将评估这些自身反应性抗体在单克隆水平上的特异性的广度，通过在这些疾病的扩展范围内对潜在的新靶点进行功能鉴定。鉴于T细胞在抗体介导的脑炎中的作用在很大程度上未被探索，并且在第一个资助阶段专注于B细胞之后，我们现在将视角扩展到功能性T细胞受体（TCR）库分析，并探索T细胞在塑造体液自身免疫反应中的作用。了解导致自身免疫性神经综合征发展的潜在免疫机制对于制定有针对性的预防和治疗策略至关重要。

An increasing recognition of the role of autoantibodies in neurological diseases has markedly changed clinical practice in the field of neurology over the last decade. Pathogenic autoantibodies against NMDAR and further targets unraveled distinct disease mechanisms. Advancements in single-cell sequencing technologies allow for a more granular understanding of many different disease states, in particular the first steps of autoimmunity in autoimmune neurological syndromes. Here, using established single-cell sequencing approaches, we will investigate the origin and diversity of autoantibodies in tumor-associated autoimmune neurological syndromes including NMDAR encephalitis. We will compare B cell repertoires of different relevant compartments in patients, such as serum, cerebrospinal fluid and tumor, and further examine the pathogenicity of patient-derived antibodies. We will also assess the breadth of specificities of these autoreactive antibodies at monoclonal level by functional identification of potentially novel targets in an expanded scope of these disorders. Given the largely unexplored role of T cells in antibody-mediated encephalitides and after focusing on B cells in the first funding phase, we now extend the perspective to functional T cell receptor (TCR) repertoire analyses, and explore the role of T cells in shaping the humoral autoimmune response. Understanding the underlying immune mechanisms that lead to the development of autoimmune neurological syndromes will be essential to develop targeted prevention and therapeutic strategies.