Normal And Pathologic Mechanisms Of Inflammation, Innate And Acquired Immunity

自身免疫与干燥综合征(SS)(55%) 我们研究的一个重要目标是确定炎症和免疫反应出错的潜在机制，导致自身免疫发病机制，如干燥综合征。SS的自身免疫特征包括局灶性淋巴样细胞外分泌腺的浸润(病灶积分)和自身抗体的产生。SS的病因在很大程度上仍不清楚，许多治疗其他自身免疫性疾病的有效药物失败，特别是肿瘤坏死因子拮抗剂，这是一个难题。在细胞水平上，我们发现IL-17和TGFβ的表达随着活检病灶评分的增加而逐渐增加，将IL-17与SS组织病理联系起来。局部参与的天然免疫防御群体包括巨噬细胞，在我们的SS组织微阵列分析中，我们专注于与疾病相关的过表达基因。其中表达最高的基因是哺乳动物几丁质酶家族的成员。几丁质酶-3-样-1(CHI3L1/YKL-40)和几丁质酶1(CHIT1)是哺乳动物几丁质酶样糖蛋白家族中高度保守的成员，在转录水平上很明显，在炎症的唾液腺中也以糖蛋白的形式存在。由于这些和其他巨噬细胞衍生的分子，包括纤溶途径的组成部分的表达升高，与SS的更严重的疾病相对应，这些观察结果暗示了潜在的免疫病理巨噬细胞参与，此外，几丁质酶和/或其他巨噬细胞产物可能提供诊断工具。 SLPI对炎症和癌症中蛋白水解级联反应的调节(30%) 在缺乏SLPI的情况下，炎症增加、愈合延迟和对感染的易感性表明SLPI与炎症反应的调节之间存在联系。在SLPI缺失的小鼠中，巨噬细胞处理不受调节的纤溶酶水平，导致组织过度降解，增加炎症，并在组织损伤后无法愈合。通过抑制纤溶酶，纤溶酶在补体激活、纤溶、细胞因子调节、转化生长因子-β激活和其他炎症后遗症方面具有无数下游后果，SLPI可以对蛋白分解和炎症激活网络施加控制。由于纤溶过程不仅是炎症、凝血和组织修复的基础，而且越来越多的证据表明纤溶过程在多种慢性炎症性疾病、心血管疾病和恶性肿瘤的发病机制中的失调，进一步定义和调控这些途径具有重要意义。与这些发现相关的是，我们与UMD的研究人员一起探索了SLPI在转移性头颈部鳞状细胞癌(HNSCC)中的作用，HNSCC是世界上最常见的10种癌症之一，预后非常差。SLPI在未受累组织中的表达高于恶性组织，其表达水平与HNSCC分期和侵袭方式呈显著负相关。此外，我们的数据显示了细胞因子对这些侵袭途径的调节，提示了一种在口腔癌中调节肿瘤侵袭潜力的策略。 将肿瘤坏死因子α作为皮肤异常创面愈合的治疗靶点(15%) 创伤愈合状态受损会导致相当大的发病率和治疗费用，在美国每年导致数十亿美元的支出。慢性创面和受损的急性创面均以过度炎症、蛋白分解增强和基质沉积减少为特征。这些混杂因素在老年人中加剧，部分原因与局部和全身肿瘤坏死因子水平升高有关。此外，我们使用了SLPI缺失的创伤愈合受损小鼠模型，与年龄相关的人类愈合延迟相当，以证明局部应用抗肿瘤坏死因子中和抗体可以钝化白细胞募集和NFkB激活，改变M1和M2巨噬细胞之间的平衡，并加速伤口愈合。我们的数据表明，抑制肿瘤坏死因子是逆转与缺乏SLPI相关的严重受损的愈合反应的关键事件，并可能适用于预防和/或治疗人类受损的伤口愈合状态。

Autoimmunity and Sjogren's syndrome (SS) (55%) An important objective of our studies is to define the underlying mechanisms by which inflammatory and immune responses go awry, resulting in autoimmune pathogenesis, as exemplified by Sjogren's syndrome. The autoimmune hallmarks of SS include focal lymphoid cell infiltration of exocrine glands (focus score) and 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. At the cellular level, we showed that expression of IL-17 and also TGFbeta progressively increases with higher biopsy focus scores, connecting IL-17 to SS tissue pathology. Locally involved innate immune defense populations include macrophages, and in our microarray analysis of SS tissues, we focused on disease related overexpressed genes. Among the most highly expressed genes were members of the mammalian chitinase family. Both chitinase-3-like-1 (CHI3L1/YKL-40) and chitinase 1 (CHIT1), highly conserved members of the mammalian chitinase-like glycoprotein family were evident at the transcriptome levels, as well as detected as glycoproteins within inflamed salivary glands. Since the elevated expression of these and other macrophage-derived molecules, including components of the fibrinolytic pathway, corresponded with more severe disease in SS, these observations implicate a potential immunopathologic macrophage involvement and furthermore, that chitinases and/or other macrophage products may provide a diagnostic tool. SLPI regulation of proteolytic cascade in inflammation and cancer (30%) Enhanced inflammation, delayed healing and susceptibility to infection in the absence of SLPI suggested a link between SLPI and regulation of inflammatory responses. 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 explored the role of SLPI in metastatic head and neck squamous cell carcinoma (HNSCC), one of the 10 most frequently occurring cancers worldwide with a very poor prognosis, with investigators at UMD. SLPI expression was higher in noninvolved than in malignant tissue, and levels significantly inversely correlated with HNSCC stage and pattern of invasion. Moreover, our data demonstrate cytokine regulation of these invasive pathways suggesting a strategy to modulate tumor invasive potential in oral cancer. TNFalpha as a therapeutic target for aberrant cutaneous wound healing (15%) Impaired wound healing states lead to substantial morbidity and cost with treatment resulting in an expenditure of billions of dollars per annum in the USA. Both chronic and impaired acute wounds are characterized by excessive inflammation, enhanced proteolysis, and reduced matrix deposition. These confounding factors are exacerbated in the elderly, in part, related to increased local and systemic TNF levels. Moreover, we used the SLPI null mouse model of impaired wound healing, comparable to age-related delayed human healing, to demonstrate that topical application of anti-TNF neutralizing antibodies blunts leukocyte recruitment and NFkB activation, alters the balance between M1 and M2 macrophages, and accelerates wound healing. Our data suggest that inhibiting TNF is a critical event in reversing the severely impaired healing response associated with the absence of SLPI, and may be applicable to prophylaxis and/or treatment of impaired wound healing states in humans.