The Role of Humoral Autoimmunity in Idiopathic Pulmonary Fibrosis

描述（由申请人提供）：特发性肺纤维化（IPF）是一种可怕的纤维化肺病，常规药物治疗难以治愈，预后不良。我们研究小组的最新发现以及其他研究结果，包括IPF患者适应性免疫过程的证据，这些证据符合传统的自身免疫标准。在其他观察结果中，一组IPF患者具有针对热休克蛋白70的自身抗体，沿着有致病性证据，并且这种自身免疫应答的存在与患病患者的更差的后续结果相关。自身免疫反应往往是自我延续的，并且通常对非特异性免疫抑制剂治疗反应不佳。致病性自身免疫反应的存在可能导致IPF对既往治疗的持续性和难治性。这些和其他相关发现使我们证实了本申请的中心假设：抗体介导的自身免疫在IPF进展中起重要作用。 本文提出的研究将通过体外试验阐明IPF自身抗体的致病机制，这些试验测量患者来源的IgG对原代人肺细胞的影响（具体目标1），通过使用高通量抗原阵列发现其他临床重要的IPF自身抗体（具体目标2），并通过克隆IPF患者的IgG基因为后续详细研究提供材料（具体目标3）。 这些研究的结果将使人们更好地理解和评价导致IPF进展的自身免疫过程，从而挑战当前疾病发病机制的范式，并确定可用于个体IPF患者诊断的免疫学生物测定。最重要的是，这里的发现将导致对IPF患者的机制性聚焦和潜在更有效的免疫调节的临床试验的进一步兴趣和理由（例如，特异性抗B细胞剂），以在随后的增量延续建议中遵循。相关性（见说明）：特发性肺纤维化（IPF）是一种可怕的，通常是老年人致命的肺部疾病。目前尚无已知对IPF有效的药物治疗。我们已经发现自身免疫似乎参与IPF的证据，其中患者自身的免疫系统攻击肺部。这些发现提高了靶向这些自身免疫过程的治疗可能对IPF更有效的可能性。 此外，有一种感觉，即所提供的自身抗体数据可能很容易被误解，并且在基于这种方法的治疗之前必须进行大量工作。

DESCRIPTION (provided by applicant): Idiopathic pulmonary fibrosis (IPF) is a dreaded fibrotic lung disease that is refractory to usual medical treatments and has a dismal prognosis. Recent findings of our research group, as well as others, include evidence of adaptive immunologic processes in IPF patients that fulfill conventional criteria of autoimmunity. Among other observations, a cohort of IPF patients have autoantibodies against heat shock protein 70, along with evidence of pathogenecity, and the presence of this autoimmune response is associated with worse subsequent outcomes of the afflicted patients. Autoimmune responses tend to be self-perpetuating, and often respond poorly to nonspecific immunosuppressant treatments. The presence of pathogenic autoimmune responses could contribute to the unremitting nature and refractoriness of IPF to previous treatments. These and other, related findings lead us to posit the central hypothesis of this application: Antibody-mediated autoimmunity can play an important role in IPF progression. The research proposed here will elucidate pathogenic mechanisms of IPF autoantibodies by in vitro assays that measure effects of patient-derived IgG on primary human lung cells (Specific Aim 1), discover other clinically-important IPF autoantibodies by use of high-throughput antigen arrays (Specific Aim 2), and provide materials for later detailed investigations by cloning IgG genes of IPF patients (Specific Aim 3). The findings of these studies will result in greater understanding and appreciation of autoimmune processes that contribute to IPF progression, thereby challenging current paradigms of disease pathogenesis, and identify immunologic bioassays that could be useful for prognostications of individual IPF patients. Most importantly, the findings here will result in further interest and justification for a clinical trial of mechanistically-focused, and potentially more efficacious, immune modulation of IPF patients (e.g., specific anti-B-cell agents), to follow in subsequent incremental continuation proposals. RELEVANCE (See instructions): Idiopathic pulmonary fibrosis (IPF) is a dreaded, and usually fatal lung disease of older adults. No medical treatments are known to be effective for IPF. We have found evidence that autoimmunity appears to be involved in IPF, in which the patient's own immune system attacks the lung. These findings raise the possibility that treatments that target these autoimmune process may be more effective for IPF. Also, there was a sense that the autoantibody data provided may be easily misinterpreted and that much work must precede a therapy based on this approach.