King C L, Nutman T B
Division of Geographic Medicine, Case Western Reserve University, Cleveland, OH 44106-4983.
J Immunol. 1993 Jul 1;151(1):458-65.
Helminth infections, like atopic disorders, show characteristic elevations of serum IgE and IgG4. To examine the mechanisms underlying the regulation of these two isotypes and of the other IgG subclasses, the frequency (Fo) of isotype-specific B lymphocytes (Bc) from 11 patients with helminth infections was compared by filter-spot ELISA using fresh peripheral blood-derived lymphocytes after 14-day Ag stimulation in vitro. The role of IL-4 and IFN-gamma in the generation and regulation of Ag-driven isotype responses was determined. The Fo of freshly obtained lymphocytes (expressed/10(5) Bc) secreting polyclonal Ig for the following isotypes was: IgE (geometric mean = 0.72; range, 0 to 17.7); IgG4 (geometric mean = 4.9; range, 1.8 to 24.4); IgG1 (geometric mean = 134.3; range, 16.7 to 318). The Fo of IgE correlated with IgG4-secreting Bc among study subjects (r = 0.8, p < 0.01), however there was no association with the other isotypes. Parasite Ag added to cultured lymphocytes induced significant expansion in the number of Ig-secreting Bc for IgE and all IgG subclasses. In contrast, addition of a nonparasite Ag, tetanus toxoid, generated increased Fo of Ig-secreting Bc for IgG1, IgG2, and IgG3, and no expansion of IgG4 or IgE. The essential role of IL-4 in the expansion of IgE- and IgG4-secreting B cells in response to filarial Ag was demonstrated when simultaneous addition of neutralizing anti-IL-4 antibodies completely inhibited this response in all 11 patients studied. Neutralizing anti-IL-4 had no effect on either filarial or tetanus toxoid-driven expansion of IgG1-, IgG2-, or IgG3-secreting Bc. An inhibitory role of endogenously produced IFN-gamma was also shown when addition of neutralizing anti-IFN-gamma to cultures significantly augmented Ag-driven expansion of Bc-secreting IgE and all IgG subclasses; IgE, 0.4- to 9-fold; IgG4, 1.4- to 12-fold; IgG1, 1.6- to 13-fold; IgG2, 1.9- to 5-fold; and IgG3, 2.7- to 6-fold. This study demonstrates that parasite Ag stimulates Bc expansion in helminth-infected patients. Although this response for all five isotypes studied is down-regulated by IFN-gamma, the generation of only the IgE and IgG4 responses appears to be mediated selectively by IL-4. These findings support the concept that IgE and IgG4 production are linked and related to the quantities of IL-4 and IFN-gamma induced by Ag-specific T cells.
蠕虫感染与特应性疾病一样，血清IgE和IgG4会出现特征性升高。为了研究这两种免疫球蛋白亚型以及其他IgG亚类调节的潜在机制，采用滤膜斑点ELISA法，比较了11例蠕虫感染患者经体外14天抗原刺激后，新鲜外周血来源淋巴细胞中各亚型特异性B淋巴细胞（Bc）的频率（Fo）。确定了IL-4和IFN-γ在抗原驱动的免疫球蛋白亚型反应的产生和调节中的作用。新鲜获取的淋巴细胞分泌以下各亚型多克隆Ig的Fo（以/10⁵ Bc表示）为：IgE（几何平均值 = 0.72；范围，0至17.7）；IgG4（几何平均值 = 4.9；范围，1.8至24.4）；IgG1（几何平均值 = 134.3；范围，16.7至318）。在研究对象中，IgE的Fo与分泌IgG4的Bc相关（r = 0.8，p < 0.01），但与其他亚型无关。添加到培养淋巴细胞中的寄生虫抗原可诱导分泌IgE和所有IgG亚类的Ig分泌Bc数量显著增加。相比之下，添加非寄生虫抗原破伤风类毒素可使分泌IgG1、IgG2和IgG3的Ig分泌Bc的Fo增加，而IgG4或IgE无增加。当同时添加中和性抗IL-4抗体完全抑制了所有11例研究患者的这种反应时，证明了IL-4在丝虫抗原刺激下分泌IgE和IgG4的B细胞扩增中起关键作用。中和性抗IL-4对丝虫或破伤风类毒素驱动的分泌IgG1、IgG2或IgG3的Bc扩增均无影响。当向培养物中添加中和性抗IFN-γ显著增强了抗原驱动的分泌IgE和所有IgG亚类的Bc扩增时，也显示了内源性产生的IFN-γ的抑制作用；IgE增加0.4至9倍；IgG4增加1.4至12倍；IgG1增加1.6至13倍；IgG2增加1.9至5倍；IgG3增加2.7至6倍。本研究表明，寄生虫抗原可刺激蠕虫感染患者的Bc扩增。尽管所研究的所有五种亚型的这种反应均受到IFN-γ的下调，但似乎只有IgE和IgG4反应的产生是由IL-4选择性介导的。这些发现支持了IgE和IgG4的产生相关且与抗原特异性T细胞诱导的IL-4和IFN-γ量有关的概念。
