Cell Death and Antibody-Mediated Protection from Autoimmunity

描述（由申请人提供）：为了研究自身免疫性疾病可能由死亡/凋亡细胞清除缺陷引起的当前范式的治疗意义，我们进行了初步研究，表明输注来自先天样B细胞的天然抗体可以大大提高狼疮易感小鼠的存活率。我们认为，这些发现反映了一类天然抗体的特性，它们具有共同的免疫生物学特性，这些特性源于它们的自反应性特异性，并且通过影响先天和适应性免疫系统的其他方面，这些抗体可以改善或预防自身免疫发病机制。为了推进这些研究，我们将进一步表征这些抗体的性质，并研究它们在免疫调节中的作用。我们将评估特异性天然抗体的保护特性是否与氧化磷脂上新决定因子的结合特异性有关，氧化磷脂上的新决定因子能够识别凋亡相关的表位，以及这种抗体自身特异性是否会增强垂死细胞的吞噬作用。非自身免疫性和定义明确的狼疮模型也将用于阐明分子和细胞机制，通过这些抗体治疗保护免受自身免疫性发病机制的启动和/或进展，包括狼疮肾炎和自身免疫性细胞减少症。这些研究将剖析这种抗体治疗对单核细胞共刺激特性的影响，并对确定治疗是否可以招募免疫调节树突状细胞特别感兴趣。基于中期研究结果，我们将使用工程抗体变体直接测试机制假设，预测具有增强的保护特性，并测定其体内活性。为了确定这些发现的临床相关性，我们将评估临床人群中自然和病理性自身抗体反应的情况，包括患有狼疮和其他自身免疫性疾病的近亲兄弟姐妹和同卵和异卵双胞胎。这些研究将验证一种假设，即对自身免疫性疾病具有遗传易感性的个体的临床疾病与自身特异性的天然抗体水平直接相关，而天然抗体被认为具有保护作用。总之，这些重要的研究将检验关于先天样B细胞产物的功能作用及其对保护宿主的稳态途径的贡献的范式转换假设。这些研究与该机构的使命相关，因为研究结果将导致开发新的治疗方法，为许多患有不同类型的慢性炎症、退行性和自身免疫性疾病的个体提供益处，这些疾病会影响他们的血细胞、肾脏、血管、关节或其他主要器官。

DESCRIPTION (provided by applicant): To investigate the therapeutic implications of the current paradigm that autoimmune disease can result from defects in the clearance of dying/apoptotic cells, we have conducted preliminary studies that have shown that infusions of a natural antibody derived from innate-like B cells can greatly improve the survival of lupus- prone mice. We believe that these findings reflect the properties of a larger class of natural antibodies with common immunobiologic properties that derive from their self-reactive specificities, and by affecting other facets of the innate and adaptive immune system these antibodies can ameliorate or prevent autoimmune pathogenesis. To advance these studies, we will further characterize the properties of these antibodies, and investigate their roles in immunoregulation. We will assess whether the protective properties of specific natural antibodies are linked to binding specificities for neo-determinants on oxidized phospholipids that enable the recognition of apoptosis-associated epitopes, and whether such antibody autospecificities convey enhanced phagocytosis of dying cells. Non-autoimmune and well-defined lupus models will also be used to elucidate the molecular and cellular mechanisms by which such antibody treatments protect from the initiation and/or progression of autoimmune pathogenesis, which includes lupus nephritis and autoimmune cytopenias. These studies will dissect the effects of such antibody treatments on the co-stimulatory properties of mononuclear cells, with a special interest in determining whether treatments can recruit immunomodulatory dendritic cells. Based on interim findings, we will directly test mechanistic hypotheses using engineered antibody variants predicted to have enhanced protective properties and assay their in vivo activities. To determine the clinical relevance of these findings, we will evaluate the profile of natural and pathologic autoantibody responses in clinical populations, including close siblings and sets of monozygotic and dizygotic twins with lupus and other autoimmune diseases. These studies will test the hypothesis that clinical disease in individuals with inherited genetic susceptibility to autoimmune disease (in)directly correlates with levels of natural antibodies of autospecificities, which are postulated to provide protective properties. Together, these important investigations will test paradigm-shifting hypotheses regarding the functional roles of the products of innate-like B cells and their contributions to homeostatic pathways that protect the host. These studies are relevant to the mission of the agency as the results should lead to the development of new therapeutic approaches that provide benefits to many individuals with diverse types of chronic inflammatory, degenerative and autoimmune diseases, which affect their blood cells, kidneys, blood vessels, joints or other major organs.