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）是一种可怕的肺纤维化疾病，常规药物治疗难治性，预后差。我们的研究小组以及其他研究小组最近的发现包括IPF患者的适应性免疫过程的证据，这些过程符合传统的自身免疫标准。在其他观察结果中，一组IPF患者有针对热休克蛋白70的自身抗体，并有致病性的证据，这种自身免疫反应的存在与患者的后续预后恶化有关。自身免疫反应往往是自我延续的，通常对非特异性免疫抑制剂治疗反应不佳。病原性自身免疫反应的存在可能有助于IPF对既往治疗的持久性和难治性。这些和其他相关的发现使我们提出了这项应用的中心假设：抗体介导的自身免疫在IPF的进展中发挥重要作用。本文的研究将通过体外检测患者源性IgG对人原代肺细胞的作用来阐明IPF自身抗体的致病机制（Specific Aim 1），利用高通量抗原阵列发现其他临床重要的IPF自身抗体（Specific Aim 2），并通过克隆IPF患者IgG基因为后续的详细研究提供材料（Specific Aim 3）。这些研究的发现将导致对促进IPF进展的自身免疫过程的更好理解和认识，从而挑战当前疾病发病机制的范式，并确定可能对个体IPF患者预后有用的免疫生物测定。最重要的是，这里的发现将进一步引起人们的兴趣，并证明对IPF患者进行机械聚焦的、可能更有效的免疫调节（例如，特异性抗b细胞药物）的临床试验是合理的，以遵循随后的渐进继续建议。相关性（见说明）：特发性肺纤维化（IPF）是一种可怕的老年人肺部疾病，通常是致命的。没有已知的药物治疗对指间纤维症有效。我们已经发现证据表明，自身免疫似乎与IPF有关，在IPF中，患者自身免疫系统攻击肺部。这些发现提出了一种可能性，即针对这些自身免疫过程的治疗可能对IPF更有效。此外，有一种感觉，即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.