Viral Pathogenesis of Idiopathic Bone Marrow Failure and Immune Cytopenias

描述(申请人提供)：许多疾病在没有明显原因的情况下袭击人类，尽管进行了密集的研究，但它们的病因仍然是特发性的。因此，针对这种情况对现有的发病机制理论进行争论可能会导致意想不到的进展和新的科学探索路线。例如，一些特发性或自身免疫性疾病甚至癌症很可能是由感染性病原体引起的，即使传统的研究途径倾向于其他机制。免疫介导的骨髓衰竭综合征(BMFS)和免疫细胞减少症，包括再生障碍性贫血(AA)、某些形式的骨髓发育不良、红细胞再生障碍性贫血等，都是以各种免疫效应机制对血液或造血细胞的免疫破坏为特征的，靶点的特异性决定了个体的临床表现。各种致病机制被假设为触发免疫反应，但还没有确定具体的触发因素。澄清这些看似特发性疾病的致病事件的性质构成了一个重大的医学挑战。虽然乍一看，这些疾病的零星发生、它们看似非传染性的性质以及其他感染过程的迹象可能会证明其他病因，但我们认为，感染性因素是触发随后的免疫病理生理级联的责任。我们的假设认为，病毒病原体构成了再生障碍性贫血或其他免疫介导性细胞减少症的激发事件，这一假说挑战了对这些特定情况下自身免疫的传统理解，但如果能够识别感染性病原体，可能是病毒，这样的发现不仅将改变这些疾病的范式，也将改变许多其他自身免疫性疾病的范式。最重要的是，这将使它们变得可预防。最近对感染发病机制的描述表明，我们的应用程序是可行的。我们建议应用高密度病毒阵列作为工具来筛选和识别致病病毒。我们规定，即使由于持续、低产量或潜伏的感染，即使数量很少，违规病原体也将存在于血细胞或受影响的组织中。我们将应用11k病毒芯片在每个疾病实体的组织中建立DNA和RNA杂交模式，在出现时和复发期间的最早样本中，并将通过设计包含最有希望的探针的多个副本的定制阵列来缩小搜索范围。如果结果表明是一种新的病原体，我们将克隆并鉴定其基因组。如果检测到以前发现的病毒，我们将应用血清学和聚合酶链式反应检测，以确定病毒核酸在不同组织中的发生率、血清阳性率和滴度。我们认为，挑战这些疾病的特发性、主要是自身免疫性是生物医学研究的一项重要任务，因为识别病毒病原体将使这些疾病是可以避免的，并受到预防和改进诊断的影响。

DESCRIPTION (provided by applicant): Many diseases strike humans without obvious cause and, despite intense research, their etiology remains idiopathic. Thus, contesting current theories of pathogenesis for such conditions may result in unexpected progress and new lines of scientific inquiry. For example, it is likely that some idiopathic or autoimmune conditions or even cancers may be attributable to infectious agents even if conventional research avenues favor other mechanisms. Immune-mediated bone marrow failure syndromes (BMFS) and immune cytopenias, including aplastic anemia (AA), some forms of myelodysplasia, red cell aplasia and others, are all characterized by immune destruction of blood or blood-forming cells by various immunologic effector mechanisms, the target specificity determining the individual clinical presentations. Various pathogenetic mechanisms have been hypothesized to trigger an immune reaction, but no specific triggers have been identified. Clarification of the nature of causative events in these seemingly idiopathic diseases constitutes a major medical challenge. While at first glance the sporadic occurrence of these conditions, their seeming non-contagious nature and other signs of an infectious process may argue for other etiologies, we propose that infectious agents are responsible for triggering the subsequent immune pathophysiologic cascade. Our hypothesis that viral pathogens constitute the inciting events in AA or other immune-mediated cytopenias challenges the traditional understanding of autoimmunity in these specific conditions but if infectious agents, likely viruses, can be identified, such a discovery would change the paradigm not only for these diseases but also for many other autoimmune diseases. Most importantly, it would render them preventable. Recent descriptions of infectious pathogenesis in conditions not otherwise though to be caused by a virus demonstrate the viability of our application. We propose to apply high-density viral arrays as tools to screen and identify causative viruses. We stipulate that the offending pathogen will be present in blood cells or affected tissues even if in low quantities due to the persistent low productive or latent infection. We will apply 11k viral chip to establish DNA and RNA hybridization patterns in tissues for each disease entity in the earliest samples at presentation and during relapse and will narrow our search by design of custom arrays containing multiple copies of the most promising probes. Should results suggest a novel pathogen, we will clone and characterize its genome. Should a previously identified virus be detected we will apply serologic and PCR testing to establish incidence of viral nucleic acid detection in various tissues, seropositivity and titers. We believe that is a an important task of biomedical research to challenge the idiopathic primarily autoimmune nature of these disease as recognition of viral pathogen would render these disease avoidable and subject to prevention and improved diagnosis.