Melchers F, Rolink A, Grawunder U, Winkler T H, Karasuyama H, Ghia P, Andersson J
Basel Institute for Immunology, Switzerland.
Curr Opin Immunol. 1995 Apr;7(2):214-27. doi: 10.1016/0952-7915(95)80006-9.
Early in B-cell development, large numbers of cells have to be generated, each of which expresses only one type of B-cell receptor (i.e. Ig) on its surface. This is achieved by the surface expression of a pre-B cell receptor containing a mu heavy chain/surrogate light chain which differentially provides signals for two responses of precursor B cells at this stage of development. On the one hand, it signals inhibition of further rearrangements of variable heavy chain to diverse-joining heavy chain loci to achieve allelic exclusion at the heavy-chain locus. On the other hand, it signals proliferative expansion by factors between 20 and 100. Later in B-cell development, tolerance to autoantigens must be established and maintained. Tolerance is achieved by developmental arrest and induction of secondary light-chain gene rearrangements in those IgM+ immature B cells that are reactive to autoantigens presented in the primary B-cell generating organs. Even later in development, when mature surface (s)IgM+/sIgD+ B cells encounter autoantigens presented to them in the periphery, either deletion or anergy of the autoantigen-reactive cells occurs. Anergic cells have a sIg-dependent, sIg-proximal defect in signaling and are short-lived. Anergy can be broken in vitro by polyclonal activation via ligation of CD40 in the presence of IL-4. A small part of the remaining immature B cells not reactive to autoantigens are selected to become mature, antigen-reactive sIgM+/sIgD+ B cells. Molecules which might guide such positive selection of B cells still remain to be identified.
在B细胞发育早期，必须产生大量细胞，每个细胞在其表面仅表达一种类型的B细胞受体（即Ig）。这是通过前B细胞受体的表面表达来实现的，该受体包含μ重链/替代轻链，在发育的这个阶段为前体B细胞的两种反应差异地提供信号。一方面，它发出信号抑制可变重链与多样连接重链基因座的进一步重排，以在重链基因座实现等位基因排斥。另一方面，它发出信号通过20到100之间的因子进行增殖性扩增。在B细胞发育后期，必须建立并维持对自身抗原的耐受性。耐受性是通过发育停滞以及在初级B细胞生成器官中对自身抗原具有反应性的那些IgM+未成熟B细胞中诱导二次轻链基因重排来实现的。在发育的更后期，当成熟的表面（s）IgM+/sIgD+ B细胞在外周遇到呈递给它们的自身抗原时，自身抗原反应性细胞会发生缺失或失能。失能细胞在信号传导中具有sIg依赖性、sIg近端缺陷且寿命短暂。在IL-4存在的情况下，通过CD40的连接进行多克隆激活可在体外打破失能状态。一小部分对自身抗原无反应的剩余未成熟B细胞被选择成为成熟的、对抗原具有反应性的sIgM+/sIgD+ B细胞。可能指导B细胞这种阳性选择的分子仍有待确定。
