Normal And Pathologic Mechanisms Of Inflammation, Innate And Acquired Immunity

转化生长因子-β、Th17和调节性T细胞在控制感染、免疫和肿瘤疾病中的作用 自然产生和诱导的调节性T细胞(Treg)，除了可诱导/适应性的TR1和Th3细胞外，在控制自身和非自身抗原的免疫应答中也是基本的。Treg特异性表达转录因子Foxp3，其主要特征是膜上表达的CD4、CD25、GITR、CTLA-4、转化生长因子-β和转化生长因子-β2型受体，所有这些都是其独特的功能谱系。我们之前已经证明，这些细胞的体外生成和过继转移到免疫介导的粘膜病理的实验动物中可以缓解疾病的症状。最近的证据还表明Treg参与控制先天性免疫反应，包括抑制自然杀伤(NK)细胞。同样明显的是，尽管Treg的增加在自身免疫和抗原驱动的病理中是有益的，但这些细胞的过度表达也可能是有害的，特别是在传染病和肿瘤疾病中。在这一点上，我们已经确定在肿瘤组织的浸润性细胞中有高水平的转化生长因子-β的表达，此外还有大量与这些肿瘤相关的Foxp3细胞。这些Treg可能导致免疫监测未能发现和/或消除此类肿瘤，并成为促进免疫介导的肿瘤治疗的潜在靶点。新的证据表明，转化生长因子-β为T辅助淋巴细胞17(Th17)的谱系承诺提供了一个独特和必要的触发。Th17生成细胞有助于美化先天途径和自身免疫性疾病的进化，将转化生长因子-β与免疫反应的诱导和抑制联系起来。 分泌性白细胞蛋白酶抑制物--一种天然的免疫调节分子： 针对细胞内病原体的有效宿主防御依赖于天然免疫反应和获得性免疫反应的激活，以遏制或消除感染微生物。同样重要的是终止旺盛反应的调节机制，以恢复免疫系统的动态平衡。SLPI是一种有效的丝氨酸蛋白酶抑制剂，具有抗微生物和抗炎功能，存在于口腔、鼻腔、呼吸道和生殖道的粘膜表面的液体中。此外，SLPI是由小鼠巨噬细胞产生的，但也通过抑制NFkB依赖的信号通路来抑制巨噬细胞的激活。SLPI的杀菌活性和对病原体介导的免疫反应的抑制活性相结合，表明该分子参与了固有的宿主防御，而SLPI缺失的小鼠提供了一个模型来探索SLPI在体内的炎症反应和宿主防御中的作用。在黏膜哮喘模型中，SLPI被发现对过敏原诱导的呼吸道高反应性的发展具有保护作用，并且在SLPI消融后疾病加剧。为了确定SLPI如何参与防御感染病原体，在皮肤利什曼病模型中，SLPI缺失型和野生型小鼠被感染细菌(肺炎链球菌、金黄色葡萄球菌)或细胞内寄生虫主要利什曼原虫。与C57BL/6SLPI野生型仔鼠不同，SLPI野生型小鼠在接种主要乳杆菌的地方会出现自我修复的皮肤病变，而SLPI缺失的小鼠则会随着病变大小和寄生虫数量的增加而加剧慢性感染，从而导致寄生虫的全身传播。尽管SLPI野生型小鼠的损伤自发愈合涉及Th1主导的细胞因子反应，但SLPI缺失小鼠中抑制性Th2细胞因子IL-4、IL-10和转化生长因子-β的升高可能是导致宿主反应失败的原因，尽管干扰素-γ水平持续升高。同样，在细菌感染中，切除SLPI与夸大但无效的免疫反应有关。这些研究强调了SLPI在传染病中的保护作用，并揭示了其作为治疗炎症和传染病的治疗剂的潜力。

TGF-beta, Th17 and regulatory T cells in the control of infectious, immune and neoplastic diseases: Naturally occurring and inducible regulatory T cells (Treg), in addition to inducible/adaptive Tr1 and Th3 cells, are fundamental in the control of immune responsiveness to self and nonself antigens. Characterized by membrane expression of CD4, CD25, GITR, CTLA-4, TGF-beta and TGF-beta receptor type II, all of which contribute to their unique functional repertoire, Treg specifically express the transcription factor Foxp3. We have previously shown that generation of these cells in vitro and adoptive transfer into experimental animals with immune-mediated mucosal pathology alleviates the symptoms of disease. Recent evidence also implicates Treg in control of innate immune responses, including suppression of natural killer (NK) cells. It is also evident that whereas an increase in Treg is beneficial in autoimmune and antigen-driven pathologies where insufficient numbers are contributory, an over-representation of these cells can also be detrimental, especially evident in infectious and neoplastic diseases. In this regard, we have identified a high level of expression of TGF-beta in cells infiltrating tumor tissues, in addition to an abundance of Foxp3+ cells in association with these tumors. These Treg may contribute to the failure of immune surveillance to detect and/or eliminate such tumors and be a potential target in promoting immune-mediated tumor therapy. New evidence reveals that TGF-beta provides a unique and essential trigger for T helper lymphocyte 17 (Th17) lineage commitment. Th17 generating cells are instrumental in embellishing innate pathways and in the evolution of autoimmune disease, linking TGF-beta with both induction and suppression of an immune response. Secretory Leukocyte Protease Inhibitor - an Innate Immunomodulatory Molecule: Effective host defense against intracellular pathogens relies upon activation of both innate and adaptive immune responses to contain or eliminate the infectious microbe. Equally important are regulatory mechanisms to terminate exuberant responses to restore homeostasis in the immune system. SLPI is a potent serine protease inhibitor with both anti-microbial and anti-inflammatory functions and is found in fluids associated with mucosal surfaces of the oral, nasal, respiratory, and reproductive tracts. Furthermore, SLPI is produced by mouse macrophages but also inhibits macrophage activation by suppressing NFkB-dependent signaling pathways. The combination of SLPIs microbicidal activity and suppressive activity on pathogen-mediated immune responses implicate this molecule in innate host defense and the SLPI null mouse provides a model to explore the in vivo role for SLPI in inflammatory responses and host defense. Using a model of mucosal asthma, SLPI was found to be protective from development of allergen-induced airway hyperreactivity and disease was exacerbated following ablation of SLPI. To determine how SLPI participates in defense against infectious pathogens, SLPI null and wildtype mice were infected with bacteria (Streptococcus pneumoniae, Staphylococcus aureus) or an intracellular parasite Leishmania major in a model of cutaneous leishmaniasis. In contrast to C57Bl/6 SLPI wildtype littermates which develop self-healing skin lesions at the site of L. major inoculation, SLPI null mice develop an exacerbated chronic infection with increased lesion size and parasite numbers that results in systemic spread of parasites. Whereas spontaneous healing of lesions in SLPI wildtype mice involves a Th1-dominant cytokine response, elevated suppressive Th2 cytokines IL-4, IL-10 and TGF-beta in SLPI null mice likely contribute to the failed host response, despite persistently elevated levels of IFN-gamma. Similarly, in bacterial infections, ablation of SLPI is associated with exaggerated, but ineffective immune responses. These studies highlight a protective role for SLPI in infectious diseases and reveal its potential as a therapeutic agent for the treatment of inflammatory and infectious diseases.