B LYMPHOCYTE TOLERANCE IN HEALTH AND AUTOIMMUNITY

该项目的长期目标是了解自体特异的B细胞 控制，以确定是否有自身免疫倾向的菌株 小鼠具有固有的B细胞耐受性缺陷，如果是这样的话，将 基因参与其中。 作为本研究的基础，转基因小鼠可获得功能重排的反义 已产生H-2KkDk IgM抗体基因。在这些小鼠中，B细胞 在适当的H-2 I类抗原存在的情况下克隆删除。 这项建议的具体目标如下。 1.自体特异型B细胞的命运与(1) 他们遇到自身抗原的发展，(Ii)他们的IGD表达， 以及(Iii)它们的细胞谱系将被确定。不成熟，成熟 来自抗H-2k转基因的未刺激和记忆CD5+和CD-B细胞 然后在体内和体外用自身抗原对小鼠进行攻击 分析以评估自身反应细胞是否被删除或 功能上是可以容忍的。 2.T细胞在B细胞阳性和阴性选择中的作用 将在抗H-2k转基因小鼠中进行分析。正常和T细胞耗尽 转基因小鼠将被分析为B细胞克隆多样化和 抗原介导的耐受。 3.两种明显显性自身免疫对B细胞耐受性的影响 BXSB和NZB小鼠品系的基因座将与 抗H-2k转基因小鼠。如果观察到明显的缺陷，则遗传基础 将通过经典和分子遗传学方法进行研究。 4.现有的IgM抗H-2转基因株系和新的抗H-2转基因株系 同时含有Mu和Delta恒定区重链基因 正在制作中的将被描述为。其水平和组织特异性 转基因表达与内源抑制程度 将分析免疫球蛋白基因重排。IgM+IGD抗-H- 2KkDk小鼠将用于特定目的1，部分(II)。

The long term goal of the project is to understand how autospecific B cells are controlled, to determine whether or not autoimmune-prone strains of mice have intrinsic B cell tolerance defects and, if so, to localize the genes involved. As a basic for this study mice transgenic for functionally rearranged anti- H-2KkDk IgM antibody genes have been generated. In these mice B cells are clonally deleted in the presence of the appropriate H-2 class I antigens. The Specific Aims of this proposal are as follows. 1. The fate of autospecific B cells with respect to (i) the stage of development at which they encounter autoantigen, (ii) their IgD expression, and (iii) their cell lineage will be determined. Immature, mature unstimulated, and memory CD5+ and CD- B cells from anti-H-2k transgenic mice will be challenged in vivo and in vitro with self antigen then analyzed to assess whether or not autoreactive cells are deleted or functionally tolerized. 2. The role of T cells in the positive and negative selection of B cells will be analyzed in anti-H-2k transgenic mice. Normal and T cell depleted transgenic mice will be analyzed for B cell clonal diversification and antigen mediated-tolerance. 3. The impact on B cell tolerance of two apparently dominant autoimmune loci of the BXSB and NZB mouse strains will be analyzed in crosses with anti-H-2k transgenic mice. If a clear defect is observed the genetic basis will be sought through classical and molecular genetic approaches. 4. The existing IgM anti-H-2 transgenic lines and new anti-H-2 lines containing both mu and delta constant region heavy chain genes that are now being produced will be characterized. The level and tissue specificity of transgene expression and the extent of suppression endogenous immunoglobulin gene rearrangement will be analyzed. The IgM + IgD anti-H- 2KkDk mice will be used in Specific Aim 1, part (ii).