Cell Death and Antibody-Mediated Protection from Autoimmunity

描述(由申请者提供)：为了研究当前范式的治疗意义，即自身免疫性疾病可以由死亡/凋亡细胞的清除缺陷引起，我们进行了初步研究，表明注入来自先天类B细胞的天然抗体可以极大地提高狼疮易感小鼠的存活率。我们认为，这些发现反映了一大类天然抗体的特性，这些天然抗体具有共同的免疫生物学特性，这些特性源于它们的自我反应特异性，并且通过影响先天性和获得性免疫系统的其他方面，这些抗体可以改善或防止自身免疫的发病。为了推进这些研究，我们将进一步确定这些抗体的特性，并研究它们在免疫调节中的作用。我们将评估特定天然抗体的保护特性是否与氧化磷脂上新决定簇的结合特异性有关，从而能够识别与凋亡相关的表位，以及这种抗体自身特异性是否传递了死亡细胞的增强吞噬能力。非自身免疫性狼疮模型和明确定义的狼疮模型也将被用来阐明这种抗体治疗防止自身免疫发病机制的分子和细胞机制，包括狼疮性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，特别是确定治疗是否可以招募免疫调节树突状细胞。在中期发现的基础上，我们将使用工程抗体变体直接测试机械假说，并分析它们在体内的活性。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自身抗体反应的概况，包括近亲以及患有狼疮和其他自身免疫性疾病的同卵和异卵双胞胎。这些研究将检验这样一个假设，即具有自身免疫性疾病遗传易感性的个人的临床疾病与自身特异的天然抗体水平直接相关，这些抗体被认为具有保护性特性。总之，这些重要的研究将检验关于先天类B细胞产物的功能作用及其对保护宿主的动态平衡途径的贡献的范式转换假说。这些研究与该机构的使命相关，因为这些结果应该导致开发新的治疗方法，为许多患有不同类型的慢性炎症性、退行性和自身免疫性疾病的人带来好处，这些疾病影响到他们的血细胞、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.