Viral Pathogenesis of Idiopathic Bone Marrow Failure and Immune Cytopenias

描述（由申请人提供）：许多疾病袭击人类没有明显的原因，尽管深入研究，其病因仍然是特发性的。因此，对这些疾病的发病机制的现有理论的质疑可能会导致意想不到的进展和新的科学探索。例如，一些特发性或自身免疫性疾病甚至癌症可能归因于感染因子，即使传统的研究途径有利于其他机制。免疫介导的骨髓衰竭综合征（BMFS）和免疫性血细胞减少症（包括再生障碍性贫血（AA）、某些形式的骨髓增生异常、红细胞再生障碍等）均以通过各种免疫效应机制对血液或造血细胞的免疫破坏为特征，靶特异性决定个体临床表现。各种发病机制已被假设为触发免疫反应，但没有具体的触发器已被确定。澄清这些看似特发性疾病的病因事件的性质构成了一个重大的医学挑战。虽然乍一看，这些条件的零星发生，他们似乎非传染性的性质和感染过程的其他迹象可能会争论其他病因，我们提出，感染因子负责触发随后的免疫病理生理级联反应。我们的假设，即病毒病原体构成AA或其他免疫介导的血细胞减少症的煽动事件挑战了传统的理解，在这些特定的条件下，自身免疫性，但如果感染性病原体，可能是病毒，可以确定，这样的发现将改变范式不仅为这些疾病，而且为许多其他自身免疫性疾病。最重要的是，这将使它们可以预防。最近描述的感染性发病机制的条件下，否则虽然是由病毒引起的证明了我们的应用程序的可行性。我们建议应用高密度病毒芯片作为工具来筛选和鉴定致病病毒。我们规定，致病病原体将存在于血细胞或受影响的组织中，即使由于持续的低生产力或潜伏感染而数量很少。我们将应用11k病毒芯片在最早的样本中和复发期间为每个疾病实体建立组织中的DNA和RNA杂交模式，并将通过设计包含多个拷贝的最有希望的探针的定制阵列来缩小我们的搜索范围。如果结果表明一种新的病原体，我们将克隆并描述其基因组。如果检测到先前鉴定的病毒，我们将应用血清学和PCR检测，以确定各种组织中病毒核酸检测的发生率、血清阳性率和滴度。我们认为，生物医学研究的一个重要任务是挑战这些疾病的特发性主要是自身免疫性，因为识别病毒病原体将使这些疾病可以避免，并受到预防和改善诊断。 公共卫生相关性：确定人类疾病的未知传染原因是生物医学研究的一个重要目标，因为它为预防、诊断和有效治疗开辟了途径。骨髓衰竭综合征是与血细胞产生缺陷相关的造血组织的严重疾病，其被认为是由自身免疫介导的，类似于类风湿性关节炎或糖尿病。因此，对引起免疫系统异常反应的病毒病原体的鉴定，不仅对骨髓衰竭综合征的治疗，而且对其他自身免疫性疾病的治疗和未来的研究方向都将产生重大影响。

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. PUBLIC HEALTH RELEVANCE: Identification of unknown infectious causes for human diseases is an important goal of biomedical research as it opens avenues to prevention, diagnostics and effective treatments. Bone marrow failure syndromes are serious diseases of blood-forming tissues associated with deficient blood cell production that are thought to be mediated by autoimmunity, similar to rheumatoid arthritis or diabetes mellitus. Identification of viral pathogens that trigger aberrant reaction of immune system would have a major impact on the management and future research direction for not only bone marrow failure syndromes but also other autoimmune conditions.