Normal And Pathologic Mechanisms Of Inflammation, Innate And Acquired Immunity

炎症、先天性和获得性免疫的正常和病理机制

基本信息

批准号：
7733893
负责人：
Sharon M Wahl
金额：
$ 181.5万
依托单位：
NATIONAL INSTITUTE OF DENTAL & CRANIOFACIAL RESEARCH
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/7733893
关键词：
ANXA2 gene Adult Adverse event Alteplase Animal Model Anti-Tumor Necrosis Factor Therapy Antigen-Presenting Cells Asthma Autoantibodies Autoimmune Diseases Autoimmune Process Autoimmune Responses Autoimmunity Automobile Driving Bacteria Basic Science Binding Proteins Biochemical Biological Markers Biopsy Biopsy Specimen Blood Circulation CD209 gene Cardiovascular Diseases Cell Lineage Cell surface Cells Chronic Clinical Coagulation Process Collaborations Complement Activation Complex Condition Coronary Arteriosclerosis DNA Microarray Chip DNA Microarray format Data Dendritic Cells Dentition Development Diagnostic Neoplasm Staging Disease Docking Endopeptidases Etanercept Etiology Event Exocrine Glands Experimental Animal Model Expressed Sequence Tags Failure Fibrinolysis Gene Expression Gene Expression Profile Generations Genes Genetic Gingiva Head and Neck Squamous Cell Carcinoma Healed Host Defense Human Immune Immune response Immunity Immunosuppressive Agents Impaired wound healing In Situ Infection Infiltration Inflammation Inflammatory Inflammatory Response Injury Interferons Interleukin-17 Interleukin-4 Invasive Knockout Mice Lesion Life Link Lipopolysaccharides Low Birth Weight Infant Lymphocyte Lymphoid Cell Malignant - descriptor Malignant Neoplasms Mediating Modeling Molecular Molecular Profiling Monitor Mononuclear Mouth Diseases Mus Myelogenous Myeloid Cells Nature Neoplasms Oral Oral mucous membrane structure Organism Pathogenesis Pathologic Pathway interactions Patients Pattern Peptide Hydrolases Periodontal Diseases Periodontitis Peripheral Phagocytes Pharmaceutical Preparations Physiological Plasma Plasmin Plasminogen Population Porphyromonas gingivalis Predisposition Premature Birth Process Production Protective Agents Proteomics Regulation Regulation of Proteolysis Relative (related person)Research Personnel Role SLPI gene Salivary Glands Sampling Score Seminal Series Signal Transduction Sjogren&apos s Syndrome Squamous cell carcinoma Syndrome System T-Lymphocyte T-Lymphocyte Subsets TALL-1 protein TGF-Beta-Null Mice TNF gene Therapeutic Intervention Tissues Transforming Growth Factor beta Tumor Immunity Virus Wound Healing acquired immunity base chemokine cytokine functional genomics healing immune function immunopathology inhibitor/antagonist insight interest laser capture microdissection macrophage malignant mouth neoplasm microbial microorganism monocyte mouth squamous cell carcinoma neoplastic novel strategies oral pathogen osteoclastogenesis outcome forecast pathogen periodontopathogen prevent programs repaired research study response tumor tumor progression

项目摘要

Infectious inflammation and injury in oral mucosa(35%) Chronic periodontal diseases, which are complex, inflammatory oral diseases involving gram-negative microorganisms such as P. gingivalis, are characterized by destruction of supporting tissues surrounding the dentition. However, it is becoming increasingly clear that while the presence of these organisms is central to pathogenesis, the destructive process is largely host-derived. To define underlying parameters involved in this disfiguring pathogenesis, gene expression profiles of human gingival biopsy samples from patients with adult periodontitis were compared to healthy gingiva. Based on our initial data, genes involved in tissue turnover/inflammatory processes were over-represented in disease relative to non-disease samples. Of significant interest was the fact that many of the identified genes were those associated with activated mononuclear phagocytic cell populations, consistent with in situ analysis of inflamed gingival tissues revealing infiltrates of CD68+ macrophages and DC-SIGN+ dendritic cells in association with lymphocytes. Given the seminal role of antigen presenting cells in innate and adaptive immunity, and the common lineage of monocytes, macrophages and dendritic cells, we hypothesized that these cells would express both convergent and divergent functional genomic profiles when exposed to periodontopathogens, and that these transcriptional signatures may provide insight into the complex, initial inflammatory response to microbial challenge. Because P. gingivalis (Pg) is considered a primary etiologic agent in oral mucosal disease, we focused on defining the response of myeloid cells to lipopolysaccharide derived from this pathogen and the immediate early transcriptional response monitored using the Affymetrix system. We identify a Pg LPS-inducible convergent, transcriptional core response of >500 annotated genes/ESTs among these populations, reflected by a shared, but quantitatively distinct proteomic response. Nonetheless, despite these similarities, clear differences emerged between the monocytes, DC and macrophages. The finding that long-lived myeloid inflammatory cells, particularly DC, rapidly and aggressively respond to Pg LPS with generation of chemokines, proteases and cytokines capable of driving T helper cell lineage (Th17) polarization without evidence of corresponding immunosuppressive pathways highlights their prominent role in host defense and progressive tissue pathogenesis. The shared, unique and/or complementary transcriptional and proteomic profiles may frame the context of the host response to P. gingivalis, contributing to the destructive nature of periodontal inflammation, including osteoclastogenesis. These studies are of additional importance since P. gingivalis, once considered to be primarily an oral pathogen, has more recently been linked to several systemic conditions, such as coronary artery disease and preterm delivery of low birth weight infants. SLPI regulation of proteolytic cascade in inflammation and cancer (35%) Enhanced inflammation, delayed healing and susceptibility to infection have suggested a link between SLPI deficiency and regulation of inflammatory responses. How SLPI mediates these disparate activities, particularly those related to cell regulation, has remained a mystery. In our search for a cell surface molecule, we identified annexin II as a SLPI-binding protein. Among other activities, annexin II serves as a docking station for tissue-type plasminogen activator and plasminogen, facilitating plasminogen activation and generation of the protease, plasmin, prompting us to hypothesize that SLPI might influence plasmin generation. Based on a series of experiments, we demonstrated that the SLPI-annexin II interaction interrupts the proteolytic cascade responsible for plasmin generation. Moreover, we have shown that in SLPI null mice, macrophages process unregulated levels of plasmin, which contributes to excess tissue degradation, increased inflammation and failed healing following tissue injury. By inhibiting plasmin, which has a myriad of downstream consequences relative to complement activation, fibrinolysis, cytokine regulation, TGF-beta activation and other inflammatory sequelae, SLPI can exert control over proteolytic and inflammatory activation networks. Because fibrinolytic processes are fundamental not only to inflammation, coagulation and tissue repair, but growing evidence highlights their dysregulation in the pathogenesis of multiple chronic inflammatory disorders, cardiovascular disease and malignancy, further defining and regulating these pathways is of major significance. Relevant to these findings, we have been exploring the role of SLPI as a protective agent in metastic head and neck squamous cell carcinoma (HNSCC), which remains one of the 10 most frequently occurring cancers worldwide with a very poor prognosis, in collaboration with investigators at UMD. Building on newly identified genetic links in the biochemical signals that influence neoplasia, we surmised that SLPI might influence tumor progression by multiple mechanisms. Based on immunohistochemical analysis of human oral squamous carcinoma tissues, SLPI expression was higher in noninvolved than in malignant tissue, and levels significantly inversely correlated with oral squamous cancer stage, pattern of invasion and NFkB activation. Thus, our data imply that SLPI may have anti-tumor activities, suggesting a strategy to predict (biomarker) and prevent (therapy) tumor invasive potential in oral cancer. Our continuing studies include exploring these pathways in a model of squamous cell carcinoma in SLPI null and WT mice and we have obtained initial data that the absence of SLPI is associated with more rapid and extensive development of tumors. Autoimmunity and Sjogrens syndrome (30%) An important objective of our studies is to explore underlying mechanisms by which inflammatory and immune responses go awry, resulting in autoimmune pathogenesis, as exemplified by Sjogrens syndrome (SS). The autoimmune hallmarks of SS are attested by the focal lymphoid cell infiltration of the exocrine glands (focus score) and the production of autoantibodies. The etiology of SS remains largely unknown and a conundrum is presented by the failure of many drugs that are effective in other autoimmune disorders, particularly TNF antagonists, such as etanercept. Importantly, plasma type 1 IFN was elevated in SS patients at baseline and not diminished by etanercept and paradoxically, TNF increased in the treated primary (p)SS patient group. Significantly increased levels of IFN and IFN-inducible genes, including B cell activating factor (BAFF), are consistent with failure of etanercept to suppress disease, and may explain some anti-TNF related adverse events. Another likely clue to the lack of efficacy of TNF inhibitors is the elevated IL-17 in Sjogrens patients peripheral circulation, which is also unmodulated by anti-TNF therapy. Collectively, these data indicated that TNF is not a pivotal cytokine in the pathogenesis of SS, driving our studies to define the underlying immunopathogenic mechanisms responsible for exocrinopathy and thereby, to define potential new target molecules for treatment. In salivary gland biopsies, we are performing gene profiling to correlate specific gene expression with T cell subsets and/or their products within the inflamed tissues. We will continue to explore the clinical aspects of SS along with our animal model studies, including the TGF- beta null mice in which the salivary glands are a target of autoimmune lymphocytic infiltration, sharing histopathologic features with those typical of SS in humans.

口腔粘膜的感染性炎症和损伤（35％）复杂的慢性牙周疾病，涉及革兰氏阴性微生物（如牙龈疟原虫）的炎性口腔疾病的特征是破坏了牙列周围的支撑组织。但是，越来越清楚的是，尽管这些生物的存在对于发病机理至关重要，但破坏性过程在很大程度上是宿主衍生的。为了定义涉及这种毁容发病机理的潜在参数，将来自成人牙周炎患者的人牙龈活检样品的基因表达谱与健康的牙龈进行了比较。根据我们的初始数据，相对于非疾病样本，疾病中涉及组织更新/炎症过程的基因过多。引人注目的事实是，许多已鉴定的基因都是与活化的单核吞噬细胞群体相关的基因，与对发炎的牙龈组织的原位分析一致，揭示了CD68+巨噬细胞的浸润和DC-SIGN+树突状细胞与淋巴细胞的融合。鉴于抗原呈现细胞在先天和适应性免疫中的精彩作用，以及单核细胞，巨噬细胞和树突状细胞的共同谱系，我们假设这些细胞表达会融合和不同的功能基因组谱时，当暴露于牙周病患者时，这些细胞可能会带来这些转录式信号，并且这些转录式构成了良好的响应，最初的变形型，最初的变形型，最初的变形型。由于牙龈疟原虫（PG）被认为是口服粘膜疾病中的主要病因学剂，因此我们重点是定义髓样细胞对源自该病原体的脂多糖的反应，并使用Affymetrix系统监测了髓样细胞对脂多糖的反应。我们在这些种群中识别> 500个注释基因/EST的PG LPS诱导的转录核心响应，反映出共享但定量不同的蛋白质组学反应。尽管如此，尽管有这些相似之处，但单核细胞，直流和巨噬细胞之间仍然存在明显的差异。长期寿命的髓样炎性细胞，尤其是DC，迅速而积极地对PG LPS产生产生的趋化因子，蛋白酶和细胞因子的产生，能够驱动T辅助细胞谱系（TH17）极化，而没有证据表明其免疫抑制途径在宿主防御和渐进式组织和渐进式组织中的重要作用。共享，独特和/或互补的转录和蛋白质组学特征可能会构建宿主对牙龈疟原虫的反应的背景，从而有助于牙周炎症的破坏性，包括骨质粒细胞生成。这些研究更为重要，因为牙龈疟原虫曾经被认为主要是一种口腔病原体，最近与几种系统性疾病有关，例如冠状动脉疾病和低出生体重婴儿的早产。炎症和癌症中蛋白水解级联反应的SLPI调节（35％）增强的炎症，延迟的愈合和对感染的敏感性表明SLPI缺乏症与炎症反应的调节之间存在联系。 SLPI如何介导这些不同的活动，特别是与细胞调节有关的活动，仍然是一个谜。在寻找细胞表面分子时，我们将膜联蛋白II鉴定为SLPI结合蛋白。在其他活动中，膜联蛋白II是组织型纤溶酶原激活剂和纤溶酶原的对接站，促进纤溶酶原激活和蛋白酶的产生，纤溶酶，促使我们促使我们假设SLPI可能会影响纤溶酶的产生。基于一系列实验，我们证明了SLPI-Annexin II相互作用中断负责纤溶酶产生的蛋白水解级联反应。此外，我们已经表明，在SLPI无效小鼠中，巨噬细胞过程不受管制的纤溶酶水平，这会导致组织损伤后炎症过多，炎症增加和愈合失败。通过抑制纤溶酶（相对于补体激活，纤维蛋白溶解，细胞因子调节，TGF-β激活和其他炎症后遗症）的纤溶酶，SLPI可以对蛋白水解和炎性激活网络施加控制。因为纤维蛋白水解过程不仅对炎症，凝结和组织修复是基本的，而且越来越多的证据突出了它们在多种慢性炎性疾病，心血管疾病和恶性肿瘤的发病机理中的失调，进一步定义和调节这些途径具有重要意义。与这些发现相关，我们一直在探索SLPI在转移头和颈部鳞状细胞癌（HNSCC）中作为保护剂的作用，该癌仍然是与UMD的研究人员合作的全球10种最常见的癌症之一。在影响肿瘤的生化信号中新鉴定的遗传联系的基础上，我们推测SLPI可能会通过多种机制影响肿瘤进展。基于人口腔鳞状癌组织的免疫组织化学分析，无侵染的SLPI表达高于恶性组织，并且水平与口服鳞状癌期，入侵模式和NFKB活化的水平显着崩溃。因此，我们的数据表明SLPI可能具有抗肿瘤活性，这表明了预测（生物标志物）和预防（治疗）肿瘤在口腔癌中的策略。我们的持续研究包括在SLPI NULL和WT小鼠中的鳞状细胞癌模型中探索这些途径，并且我们获得了初始数据，即缺乏SLPI与肿瘤的更快，更广泛的发展有关。自身免疫性和Sjogrens综合征（30％）我们研究的一个重要目的是探索炎症和免疫反应出现问题的潜在机制，导致自身免疫发病机理，如Sjogrens综合征（SS）的例证。 SS的自身免疫性标志是通过外分泌腺的局灶性淋巴样细胞浸润（焦点评分）和自身抗体的产生来证明的。 SS的病因仍然在很大程度上未知，并且由许多在其他自身免疫性疾病（尤其是TNF拮抗剂）（例如Etanercept）中有效的药物的失败提出了难题。重要的是，在基线时SS患者的血浆1型IFN升高，并且不会因eTanercept而降低，并且矛盾的是，治疗的原发性（P）SS患者组中TNF增加。包括B细胞激活因子（BAFF）在内的IFN和IFN诱导基因的水平显着增加与依那耐抑制抑制疾病的失败一致，并且可以解释一些抗TNF相关的不良事件。 TNF抑制剂缺乏疗效的另一个可能的线索是，IL-17升高在临时患者外周循环中，这也未受抗TNF治疗的调整。总的来说，这些数据表明，TNF不是SS发病机理中的关键细胞因子，它推动了我们的研究来定义负责外分泌病的潜在免疫发育机制，从而定义了潜在的新靶标分子的治疗方法。在唾液腺活检中，我们正在进行基因分析，以将特定基因表达与T细胞亚群和/或其产物在发炎的组织中相关联。我们将继续探索SS的临床方面以及我们的动物模型研究，包括唾液腺是自身免疫性淋巴细胞浸润的靶标的TGF-beta Null小鼠，与人类典型的SS共享组织病理学特征。

项目成果

期刊论文数量（35）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Rofecoxib modulates multiple gene expression pathways in a clinical model of acute inflammatory pain.

罗非考昔在急性炎性疼痛的临床模型中调节多种基因表达途径。

DOI：
10.1016/j.pain.2006.09.011
发表时间：
2007
期刊：
Pain
影响因子：
7.4
作者：
Wang,Xiao-Min;Wu,Tian-Xia;Hamza,May;Ramsay,EdwardS;Wahl,SharonM;Dionne,RaymondA
通讯作者：
Dionne,RaymondA

Conversion of peripheral CD4+CD25- naive T cells to CD4+CD25+ regulatory T cells by TGF-beta induction of transcription factor Foxp3.