Singer S M, Umetsu D T, McDevitt H O
Department of Microbiology and Immunology, Standford University Medical Center, CA 94305, USA.
Proc Natl Acad Sci U S A. 1996 Apr 2;93(7):2947-52. doi: 10.1073/pnas.93.7.2947.
To better understand the role of class II major histocompatibility complex molecules in both normal and autoimmune responses, we have produced a series of I-Ab transgenic mice. One of these transgenic constructs, designated NOD.PD, has the sequence of the NOD beta chain (Abeta(g7)) except at positions 56 and 57, where Pro-Asp replaces His-Ser. Several NOD.PD transgenic lines have been produced. One line of these mice carried a very high number of copies (>50) of the NOD.PD transgene. As has been described in other mice carrying high copy numbers of I-Ab transgenes, B-cell development was abnormal. The steady state numbers of mature B cells (IgM+/IgD(hi)) in the periphery were greatly reduced in transgenic mice compared to nontransgenic littermates. Surprisingly, rather than being accompanied by a generalized hypogammaglobulinemia, this B-cell deficiency was accompanied by elevated concentrations of IgG1 and IgE in the serum. Conversely, the levels of IgG2a were reduced in transgenic mice compared to nontransgenic littermates. Because this isotype pattern was characteristic of interleukin (IL)-4-induced class-switching, we then investigated the role of IL-4 in causing the observed phenotype. We crossed the high copy number transgenic mice with an IL-4-deficient strain of mice. As expected, the elevated levels of IgE in high copy number transgenic mice were eliminated when the IL-4 gene was inactivated. However, the reduction in the number of B cells was not ameliorated. These data indicate that the primary defect caused by the transgene was to reduce the number of B cells in these mice. This reduction was accompanied by a secondary increase in IL-4 production, which drove the remaining B cells toward the production of IgGl and IgE.
为了更好地理解Ⅱ类主要组织相容性复合体分子在正常和自身免疫反应中的作用，我们培育了一系列I-Ab转基因小鼠。其中一种转基因构建体，命名为NOD.PD，除了第56和57位氨基酸外，具有NODβ链（Abeta(g7)）的序列，在这两个位置脯氨酸-天冬氨酸取代了组氨酸-丝氨酸。已经培育出了几个NOD.PD转基因品系。其中一个品系的小鼠携带了非常高拷贝数（>50）的NOD.PD转基因。正如在其他携带高拷贝数I-Ab转基因的小鼠中所描述的那样，B细胞发育异常。与非转基因同窝小鼠相比，转基因小鼠外周成熟B细胞（IgM+/IgD(hi)）的稳态数量大大减少。令人惊讶的是，这种B细胞缺陷并非伴随着全身性低丙种球蛋白血症，而是伴随着血清中IgG1和IgE浓度的升高。相反，与非转基因同窝小鼠相比，转基因小鼠中IgG2a的水平降低。因为这种同种型模式是白细胞介素（IL）-4诱导的类别转换的特征，所以我们随后研究了IL-4在导致观察到的表型中的作用。我们将高拷贝数转基因小鼠与IL-4缺陷型小鼠品系进行杂交。正如预期的那样，当IL-4基因失活时，高拷贝数转基因小鼠中升高的IgE水平消失了。然而，B细胞数量的减少并未得到改善。这些数据表明，转基因导致的主要缺陷是减少了这些小鼠中的B细胞数量。这种减少伴随着IL-4产生的继发性增加，这促使剩余的B细胞产生IgG1和IgE。
