免疫系统主要分为先天免疫系统和获得性免疫系统(后天免疫系统)两种类型。美国加州大学圣地亚哥分校医学院的一项新研究则首次发现了一种器官独有的先天免疫系统。该研究勾勒出了肺脏制定其对微生物入侵的抵抗策略的一种独特机制的轮廓。这些研究结果发表在4月18日的《免疫》(Immunity)杂志上。研究人员指出,这种肺脏特有的先天免疫应答可能将肺部因过度炎症反应导致的损伤最小化。
众所周知,身体的呼吸道长期被暴露在吸入的颗粒或微生物中。肺脏中微小的空气囊泡alveola是呼吸系统和循环系统进行气体交换的场所,它们受到alveolar巨噬细胞的保护,从而避免入侵微生物的侵害。
巨噬细胞是身体炎性反应有关的白细胞,它时刻警惕入侵者并将其杀死。Alveolar巨噬细胞是身体中独特的一种巨噬细胞,这是因为它们的活动会受到由肺脏上皮细胞表达的化合物TGFβ的抑制。
由于alveola所处的微环境非常独特(长期被微生物等包围),如果巨噬细胞免疫系统持续地处于战备状态就可能使它遭到破坏,很容易导致自身免疫疾病中常见到的炎症。因此,alveola具有一种复杂的免疫系统以抑制巨噬细胞处于稳定状态,并在需要抵抗入侵微生物时被活化,然后再次被抑制——这种循环是alveola微环境特有的。
剖析这种免疫机制能够使研究人员了解到如何能人为延长alveolar巨噬细胞的活化状态的信息,而这些信息将在抵御任何新的能够影响下呼吸道的生物恐怖制剂中具有重要意义。
研究数据揭示出了alveolar巨噬细胞如何避过TGFb的抑制作用一段时间以完成免疫任务的一个复杂环路。这个过程通过一套细胞表面受体(integrins,粘合素或整合素)调节TGFβ活动来完成。
这种调节使得alveolar巨噬细胞只在非常有限的时间里展现“杀手”的冷酷面。粘合素使TGFβ短时间失活,之后肺中的一种叫做MMP9的酶再将其功能恢复。也就是说,巨噬细胞醒来一会,该系统自己的酶就又会活化抑制因子使它们再次沉睡。
补充:
integrin,国内将译为粘合素、整合素等,本书暂命名为粘合素。integrin是最初在1986年提出的概念,描述一个膜受体家族,此家族的粘附分子主要介导细胞与细胞外基质的粘附,使细胞得以附着而形成整体(integration),故得名。此外,粘合素家族的粘附分子还介导白细胞与血管内皮细胞的粘附。
粘合素家族的粘附分子都是由α、β两条链由非共价键连接组成的异源双体(heterodimer),α、β链均为Ⅰ类穿膜蛋白。目前已知至少有14种α亚单位和8种β亚单位,除α7和αIEL外,其它粘合素分子亚单位均已基因克隆成功。粘合素分子在体内分布很广泛,多数粘合素分子可以表达于多种组织细胞,如VLA组的粘合素分子在体内广泛分布于各种组织细胞;而多数细胞可同时表达数种不同的粘合素分子。对体外哺乳动物来源的细胞系粘合素分子表达研究发现,每一种细胞系可同时表达2~10种不同的粘合素分子,但不同类型的细胞表达粘合素分子的种类是不同的。
Researchers reveal lung's unique innate immune system
For the first time, scientists have documented an organ-specific innate immune system. In research published in the April 18 edition of the journal Immunity, scientists at the University of California, San Diego (UCSD) School of Medicine outline the unique mechanism by which the lung shapes its defensive strategies against microbial invasion.
“This innate immune response is specific to the lung, and was probably designed to minimize collateral damage to lung tissue caused by unchecked inflammation,” said Eyal Raz, M.D., Professor of Medicine at UCSD School of Medicine.
The body’s respiratory tract is constantly exposed to inhaled particles or microorganisms. The alveola – tiny air sacs in the lung where exchanges of gases between the respiratory and circulatory systems takes place – are protected from invading microbes by the alveolar macrophage.
Macrophages are white blood cells involved in the inflammatory response throughout the body, cells normally on the alert for invaders to kill. Alveolar macrophages are unique among macrophages in the body, because their activation is inhibited by TGFb, a compound expressed in the lung by epithelial cells.
“Because the microenvironment of the alveola is a delicate one, it would be damaged if the macrophage immune system was in a constant battle-ready status,” said Raz. “This could readily lead to the type of inflammation we see in autoimmune diseases of the lung such as asthma.”
Therefore, the alveola possess a complex immune system in which the macrophage is repressed in its steady state, activated when called upon to fight invading microorganisms, and then re-repressed, in a circuit that is unique to this microenvironment.
“Dissecting this immune mechanism provides us with the knowledge of how we might prolong the activation status of alveolar macrophages. This knowledge could prove to be essential in combating any novel microbial agents that could infect the lower airways, such as a new flu strain or bioterrorist agents,” said Raz.
The researchers’ data outlines a complex circuit in which the alveolar macrophages circumvent the inhibition by TGFb for brief period of time, in order perform their immune task. This is accomplished through regulation of TGFb activity by a set of cell surface receptors, proteins called integrins.
This regulation allows the alveolar macrophages to take on their “killer” function – the ability of macrophages to engulf invading microorganisms – but only for a very limited period of time. The mediating role of TGFb, briefly inactivated by the integrin, is then restored by one of the lung’s own enzymes, the MMP9.
“Basically, the macrophages wake up for a while, but the system’s own enzymes activate the inhibitor that puts them back to sleep,” said Kenji Takabayshi, Ph.D., first author of the study.
Other contributors to this paper include Maripat Corr, Tomoko Hayashi, Vanessa Redecke, Lucinda Beck, and Donald Guiney of the Department of Medicine at UCSD School of Medicine; and Dean Sheppard, Lung Biology Center, University of California, San Francisco.
University of California–San Diego