Use of Microarrays to Understand Systemic Arthritis

使用微阵列了解系统性关节炎

• 批准号: 8294457
• 负责人: Maria Virginia Pascual
• 金额: $ 32.66万
• 依托单位: BAYLOR RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-22 至 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8294457
• 关键词: Acute; Address; Anemia; Antigens; Arthritis; Biology; Blood; Blood Cells; Candidate Disease Gene; Cells; Child; Childhood; Chronic; Chronic Childhood Arthritis; Clinical; Collaborations; Communicable Diseases; Complication; Data; Development; Diagnosis; Diagnostic; Diagnostic tests; Differential Diagnosis; Disease; Erythroid; Exposure to; Fever; Flare; Future; Gene Mutation; Genes; Genetic; Genomics; Hemophagocytic Syndrome; Hospitalization; Immune response; Immune system; Immunology; Infection; Infectious Agent; Inflammatory; Inflammatory Response; Interleukin-1; Lead; Leukocytosis; Light; Malignant Neoplasms; Mediator of activation protein; Mutation; Pathogenesis; Patients; Peripheral; Phase; Play; Polyarthritides; Positioning Attribute; Preventive; Production; Regulation; Resolution; Rheumatism; Risk; Role; Screening procedure; Secondary to; Secure; Series; Signs and Symptoms; Source; Staging; Staphylococcus aureus; Susceptibility Gene; Symptoms; TFRC gene; TNF gene; Testing; Transcript; Vasculitis; Work; base; cell type; conventional therapy; cytokine; disability; environmental agent; genetic analysis; improved; in vitro Assay; microbial; neutrophil; new therapeutic target; novel; novel therapeutics; outcome forecast; public health relevance; research study; response; tool

DESCRIPTION (provided by applicant): Juvenile idiopathic arthritis (JIA) is the most common rheumatic disease in childhood and an important cause of short and long-term disability. Systemic Onset Juvenile Idiopathic Arthritis (SoJIA) represents up to 20percent of all the cases of JIA. This disease does not respond to conventional therapies or anti-TNF agents and it leads to serious disabilities in a large proportion of patients. During the past 4 years we have addressed most of the aims that were included in our original application. This has resulted in the following advances: 1) identification of Interleukin-1 as a major mediator of the systemic phase of the disease, 2) resolution of clinical symptoms upon initiation of IL-1 blockade, 3) identification of a signature specific to the initial, systemic phase of the disease that permits to establish the diagnosis against a panel of other febrile illnesses, 4) identification of the cell type that gives rise to this SoJIA-specific signature, 5) identification of environmental agents that trigger a dysregulated IL-1B production by SoJIA blood cells, 6) identification of the neutrophil as a potential major source of IL-1B in SoJIA, 7) identification of transcripts that are differentially regulated in SoJIA versus healthy controls in response to environmental agents. These transcripts represent candidates for genetic analysis. Our hypothesis is that SoJIA arises as the result of an inappropriate response of the innate immune system to an environmental insult. This inappropriate response very likely has a genetic basis. Having identified one of the potential triggers of IL-1 overproduction, and counting on an in vitro assay to test the effect of these and novel triggers on cells from patients and controls, we are now in a good position to select candidate genes for genetic and functional analyses. The specific aims of our current application are: 1. To confirm and extend our observations that candidate blood gene signatures are SoJIA-specific and can be used as diagnostic tools. 2. To further characterize the cell type(s) giving rise to the unique SoJIA gene signature. 3. To characterize the role of infectious agents in the initial stage and acute exacerbations/flare-ups of patients with SoJIA. Completion of these studies will set the stage for future experiments aimed at characterizing candidate genes at the genetic level and at ascertaining their contribution to IL-1B dysregulation. To perform these studies, we have secured collaborations with infectious disease experts, statisticians, geneticists and experts in the biology and regulation of IL-1 activation. The results of these studies will have immediate clinical and basic immunology applications and should contribute to improve the outlook of children suffering from this often devastating disease. PUBLIC HEALTH RELEVANCE: The successful accomplishment of this project would have significant consequences on SoJIA patients, including the availability of a simple diagnostic test and the identification of potential environmental triggers that may lead to novel therapeutic and/or preventive approaches. These studies will also set the stage for future discovery of susceptibility genes that could be used for screening and diagnostic purposes as well. Understanding the basis of IL-1 dysregulation might shed light on very basic aspects of cytokine biology and help finding novel therapeutic targets for this disease.

描述（由申请人提供）：少年特发性关节炎（JIA）是儿童时期最常见的风湿病，也是短期和长期残疾的重要原因。系统性发作少年特发性关节炎（Sojia）代表所有JIA病例的20％。该疾病对常规疗法或抗TNF药物没有反应，并且会导致大部分患者严重残疾。在过去的四年中，我们已经解决了我们原始申请中包含的大多数目标。这导致了以下进展：1）鉴定白介素1是该疾病全身阶段的主要中介者，2）启动IL-1阻塞后解决临床症状的解决方案，3）鉴定特定于初始，全身性疾病的特定签名，该疾病的初始阶段，允许识别其他febrile疾病诊断的诊断，以识别该疾病的诊断，4）识别该疾病的诊断，4）4）引发sojia血细胞产生失调的IL-1B产生的环境药物，6）中粒细胞鉴定为sojia中IL-1b的潜在主要来源，7）鉴定在索吉亚州与健康对照中受差异调节的转录本在响应环境药物的响应中受到差异调节。这些转录本代表用于遗传分析的候选者。我们的假设是，苏吉亚是由于先天免疫系统对环境侮辱的不当反应而产生的。这种不适当的反应很可能具有遗传基础。在确定了IL-1过量生产的潜在触发因素之一，并计算出体外测定，以测试这些和新型触发因素对患者和对照组的细胞的影响，我们现在处于一个很好的位置，可以为遗传和功能分析选择候选基因。我们当前应用的具体目的是：1。确认和扩展我们的观察结果，即候选血液基因特异性是特异性的，可以用作诊断工具。 2。进一步表征细胞类型，从而产生独特的sojia基因特征。 3。表征传染剂在初始阶段的作用，以及患有sojia的患者的急性加重/爆发。这些研究的完成将为未来的实验奠定阶段，旨在表征遗传水平上的候选基因并确定其对IL-1B失调的贡献。为了进行这些研究，我们已经与IL-1激活生物学和调节方面的传染病专家，统计学家，遗传学家和专家确保了合作。这些研究的结果将立即具有临床和基本免疫学应用，并应有助于改善这种经常遭受这种毁灭性疾病的儿童的前景。 公共卫生相关性：该项目的成功完成将对Sojia患者产生重大影响，包括简单的诊断测试的可用性以及可能导致新型治疗和/或预防方法的潜在环境触发器的识别。这些研究还将为未来发现易感基因的阶段奠定基础，这些基因也可以用于筛查和诊断目的。了解IL-1失调的基础可能会阐明细胞因子生物学的非常基本的方面，并有助于为该疾病寻找新的治疗靶点。

项目成果

The interferon-alpha signature of systemic lupus erythematosus.

• DOI: 10.1177/0961203310371161
• 发表时间: 2010-08
• 期刊: Lupus
• 影响因子: 2.6
• 作者: Obermoser G;Pascual V
• 通讯作者: Pascual V

A multidimensional blood stimulation assay reveals immune alterations underlying systemic juvenile idiopathic arthritis.

• DOI: 10.1084/jem.20170412
• 发表时间: 2017-11-06
• 期刊: The Journal of experimental medicine
• 作者: Cepika AM;Banchereau R;Segura E;Ohouo M;Cantarel B;Goller K;Cantrell V;Ruchaud E;Gatewood E;Nguyen P;Gu J;Anguiano E;Zurawski S;Baisch JM;Punaro M;Baldwin N;Obermoser G;Palucka K;Banchereau J;Amigorena S;Pascual V
• 通讯作者: Pascual V

From IL-2 to IL-37: the expanding spectrum of anti-inflammatory cytokines.

• DOI: 10.1038/ni.2406
• 发表时间: 2012-10
• 期刊: Nature immunology
• 影响因子: 30.5

Clinical and transcriptional response to the long-acting interleukin-1 blocker canakinumab in Blau syndrome-related uveitis.

• DOI: 10.1002/art.37776
• 发表时间: 2013-02
• 期刊: ARTHRITIS AND RHEUMATISM
• 作者: Simonini, Gabriele;Xu, Zhaohui;Caputo, Roberto;De Libero, Cinzia;Pagnini, Ilaria;Pascual, Virginia;Cimaz, Rolando
• 通讯作者: Cimaz, Rolando