The role of interleukin-4 in IgE and IgG subclass formation.
The role of interleukin-4 in IgE and IgG subclass formation.
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IL-4 在 IgE 和 IgG 亚类形成中的作用。
DOI：
10.1007/bf00225324
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发表时间：
1990
期刊：
影响因子：
--
通讯作者：
Spiegelberg,HL
中科院分区：
文献类型：
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作者：
Spiegelberg,HL
结论在过去5年中，关于IgE和IgG亚类抗体形成的调节机制有三个主要的新发现。首先，显示IL-4诱导B细胞分泌IgE、鼠IgG 1和人IgG 4，并且IFN-γ和IL-2抑制该作用。其次，发现克隆的小鼠T辅助细胞可分为两种类型：Th 1，分泌IL-2和IFN-γ;和Th 2，分泌IL-4和IL-5。第三，鼠肥大细胞，如Th 2，分泌IL-4和IL-5，但不分泌IL-2和IFN-γ。在获得这些体外数据后不久，获得了直接和间接的证据，证明IL-4和IFN-γ在体内也对IgE形成起拮抗作用。总的来说，这一新的信息是一个重大突破，并证明了淋巴因子在决定B细胞分泌的IG同种型，特别是IgE和某些IgG亚类中的重要作用。然而，IgE和IgG亚类调节的许多方面还没有解决，特别是，它是不清楚什么是异常的淋巴因子调节IgE抗体形成的过敏性patients.The问题，目前在许多实验室广泛研究的同种型调节如下：什么是确切的分子机制的开关从IgM到IgE或IgG亚类。特别是，IL-4在诱导转换机制中的作用是什么？此外，IL-4是否仅影响IgM向IgE的转换，或者如某些体外实验所示，它在IgE分泌细胞的分化中也很重要？在小鼠中，许多实验表明IgG 1可以在体内独立于IL-4形成，这也可能是IgG 4在人中的情况。IL-4诱导的IgE和IgG 1在体外的严格连接似乎并不总是发生在体内。一个非常重要的问题：过敏原或蠕虫寄生虫如何选择性地诱导明显的T辅助细胞和IL-4依赖的IgE和IgG 4抗体在人中形成？不太可能存在两种T辅助细胞谱系，并且过敏原和蠕虫寄生虫仅与产生IL-4的Th 2细胞相互作用。相反，似乎过敏原和寄生虫通过与辅助细胞的相互作用或可能通过对B细胞的直接作用来影响Th 0至Th 2的分化。后者是由以下事实提出的：并非所有多克隆B细胞活化剂都能使B细胞对IL-4产生应答并分泌IgE。在小鼠中，对于IL-4诱导的IgE分泌，LPS是比PRP好得多的B细胞激活剂，而对于IL-4诱导的IgG 1形成，PRP与LPS相同。过敏原和蠕虫寄生虫可诱导IgE形成的另一种机制是通过肥大细胞活化。如果这些抗原“非特异性地”激活肥大细胞分泌IL-4，则该IL-4可诱导IgM向IgE转换，并且还可诱导Th 0向Th 2分化。过敏原可能通过皮肤、呼吸道和胃肠道（富含肥大细胞的解剖部位）的渗透来免疫宿主。蠕虫感染在肠道中诱导大的肥大细胞增多症，并且GVHD也诱导多克隆IgE形成，引起皮肤肥大细胞的脱粒。这些观察结果支持肥大细胞可能在IgE形成中起作用的观点。尽管目前尚处于高度推测阶段，但对这一有趣的假设进行检验是可能的，也是值得的。另一个尚未解决的问题是：特应性患者IgE抗体产生的调节是什么异常？患者的辅助性T细胞是否产生过多的IL-4或不足的IFN-γ？IL-4是否优先诱导IgM转换为IgE，而不是IgM转换为IgG 4？这些问题目前正在实验中解决，然而，没有明确的答案。
ConclusionsOver the last 5 years, three major new findings were made regarding the mechanism of regulation of IgE and IgG subclass antibody formation. First, it was shown that IL-4 induces B cells to secrete IgE, murine IgG1 and human IgG4 and that IFN-γ and IL-2 inhibit this effect. Second, it was found that cloned murine T helper cells can be divided into two types: Th1, secreting IL-2 and IFN-γ; and Th2, secreting IL-4 and IL-5. Third, murine mast cells, like Th2, secrete IL-4 and IL-5 but not IL-2 and IFN-γ. Soon after these in vitro data were obtained, direct and indirect evidence was obtained demonstrating that IL-4 and IFN-γ also act antagonistically on IgE formation in vivo. Collectively, this new information is a major breakthrough and demonstrates the important role of lymphokines in determining the Ig isotype secreted by B cells, particularly IgE and certain IgG subclasses. However, many aspects of IgE and IgG subclass regulation are not yet resolved and in particular, it is not clear what is abnormal in the lymphokine-regulated IgE antibody formation in atopic patients.The questions regarding isotype regulation which are presently studied extensively in many laboratories are the following: what is the precise molecular mechanism of the switch from IgM to IgE or IgG subclass. In particular, what is the effect of IL-4 in the induction of the switch mechanism? Also, is IL-4 only affecting the IgM to IgE switch or is it also important in the differentiation of IgE-secreting cells as some in vitro experiments suggest? In the mouse, many experiments indicate that IgGl can be formed in vivo independently of IL-4 and this may also be the case for IgG4 in man. The strict linkage of IL-4-induced IgE and IgG1 in vitro does not always seem to occur in vivo.A very important question: how do allergens or helminthic parasites selectively induce the apparent T helper cell and IL-4-dependent IgE and IgG4 antibody formation in man? It is unlikely that two lineages of T helper cells exist and that allergens and helminthic parasites interact only with the IL-4 producing Th2 cells. Instead, it appears that allergens and parasites affect the Th0 to Th2 differentiation through interaction with accessory cells or perhaps by a direct effect on B cells. The latter is suggested by the fact that not all polyclonal B cell activators prepare B cells to respond to IL-4 with IgE secretion. In the mouse, LPS is a far better B cell activator than PRP for IL-4-induced IgE secretion, whereas PRP is equal to LPS in IL-4-induced IgG1 formation. Another mechanism by which allergens and helminthic parasites could induce IgE formation is via mast cell activation. If these antigens “nonspecifically” activate mast cells to secrete IL-4, this IL-4 could induce the IgM to IgE switch and may also induce the Th0 to Th2 differentiation. Allergens presumably immunize the host via penetration of the skin and respiratory and gastrointestinal tract, anatomic sites which are rich in mast cells. Helminthic infections induce a large mastocytosis in the intestinal tract and GVHD which also induces polyclonal IgE formation, causes degranulation of the skin mast cells. These observations support the notion that mast cells may play a role in the IgE formation. Although highly speculative at this time, it is possible and worthwhile to test this interesting hypothesis.Another unresolved question is: what is abnormal in the regulation of IgE antibody production in atopic patients? Do the patient's T helper cell produce too much IL-4 or not enough IFN-γ? Does IL-4 preferentially induce the IgM to IgE rather than IgM to IgG4 switch? These questions are being addressed experimentally at this time, however, no clear cut …