Ballow M, Wang W, Xiang S
Department of Pediatrics, Children's Hospital of Buffalo, State University of New York at Buffalo 14214, USA.
Clin Immunol Immunopathol. 1996 Sep;80(3 Pt 2):S73-81. doi: 10.1006/clin.1996.0144.
Retinoic acid (RA) and its parent compound retinol (ROH, vitamin A) have been recognized as important immunopotentiating agents since the early 1900s. We have focused our studies on the effects of retinoids on B-cell immune function in the newborn infant. The response of cord blood mononuclear cells (CBMC) to formalinized Cowan I strain Staphylococcus aureus (SAC), a T-cell-dependent factor for inducing the differentiation of B cells into immunoglobulin (Ig)-secreting cells, was used as a model system for studying whether RA could alter the immunoglobulin synthesis of newborn B lymphocytes. The addition of RA to SAC-stimulated CBMC cultures produced a 2- to 47-fold increase in IgM synthesis. An ELISA-spot assay showed that the RA-induced enhancement in Ig synthesis was due to the recruitment of more B cells to differentiate into Ig-secreting cells. Whereas RA enhanced IgM production of CBMC stimulated with SAC, RA augmented only IgG production of SAC-stimulated adult peripheral blood mononuclear cells (PBMC). To determine if the differences in dose-response characteristics between CBMC and adult PBMC resided within the target cell, i.e., the B cell, T-cell-enriched and T-cell-depleted (B-cell) fractions from CBMC and adult PBMC were cocultured in various combinations. The isotype, i.e., IgM vs IgG, and the dose-response curve characteristics were intrinsic to the responding B-cell source, i.e., newborn vs adult. Highly purified T cells from CBMC, when preincubated for 36 hr with RA, enhanced IgM synthesis of cord blood B cells. Supernatants from purified T cells generated a factor which could enhance B-cell synthesis. Although interleukin (IL)-2, IL-4, and IL-6 could not be detected by ELISA in the T-cell-derived supernatants, RA probably generates a cytokine/interleukin from T cells which modulates B-cell Ig secretion. RA can also act directly on B cells as evidenced by the augmentation in Ig synthesis of Epstein-Barr virus (EBV)-transformed B-cell lines. These data suggest that RA can have a direct effect on B cells. Since increased proliferation (numbers) of lymphoblastoid B cells was not responsible for the increased amounts of Ig in the supernatant fluids, we examined whether cytokines secreted by EBV-transformed B cells could be acting as an autocrine factor in increasing Ig synthesis. EBV-transformed B-cell clones incubated with RA for 6 days produced a 20- to 45-fold increase in IL-6. An understanding of the mechanisms by which RA enhances B-cell immune function may lead to the use of RA or its derivatives in patients with immune deficiencies and in preterm infants with immature immune systems.
自20世纪初以来，视黄酸（RA）及其母体化合物视黄醇（ROH，维生素A）就被认为是重要的免疫增强剂。我们专注于研究类视黄醇对新生儿B细胞免疫功能的影响。脐血单个核细胞（CBMC）对福尔马林化的考恩I株金黄色葡萄球菌（SAC）的反应，SAC是诱导B细胞分化为免疫球蛋白（Ig）分泌细胞的T细胞依赖性因子，被用作研究RA是否能改变新生B淋巴细胞免疫球蛋白合成的模型系统。在SAC刺激的CBMC培养物中添加RA可使IgM合成增加2至47倍。酶联免疫斑点试验表明，RA诱导的Ig合成增强是由于更多B细胞被募集分化为Ig分泌细胞。虽然RA增强了SAC刺激的CBMC的IgM产生，但RA仅增强了SAC刺激的成人外周血单个核细胞（PBMC）的IgG产生。为了确定CBMC和成人PBMC之间剂量反应特征的差异是否存在于靶细胞即B细胞内，将来自CBMC和成人PBMC的富含T细胞和去除T细胞（B细胞）的组分以各种组合进行共培养。同种型，即IgM与IgG，以及剂量反应曲线特征对于反应性B细胞来源即新生儿与成人来说是内在的。来自CBMC的高度纯化的T细胞，当与RA预孵育36小时时，增强了脐血B细胞的IgM合成。纯化T细胞的上清液产生了一种可增强B细胞合成的因子。虽然通过酶联免疫吸附测定在T细胞来源的上清液中未检测到白细胞介素（IL）-2、IL-4和IL-6，但RA可能从T细胞产生一种调节B细胞Ig分泌的细胞因子/白细胞介素。RA也可直接作用于B细胞，这可由爱泼斯坦-巴尔病毒（EBV）转化的B细胞系Ig合成的增加得到证明。这些数据表明RA可对B细胞产生直接影响。由于淋巴母细胞样B细胞增殖（数量）增加并非上清液中Ig量增加的原因，我们研究了EBV转化的B细胞分泌的细胞因子是否可作为自分泌因子增加Ig合成。用RA孵育6天的EBV转化的B细胞克隆使IL-6增加了20至45倍。了解RA增强B细胞免疫功能的机制可能会导致在免疫缺陷患者和免疫系统不成熟的早产儿中使用RA或其衍生物。
