Mongini P K, Blessinger C A, Highet P F, Inman J K
Department of Rheumatic Diseases, Hospital for Joint Diseases, New York, NY 10003.
J Immunol. 1992 Jun 15;148(12):3892-901.
The potential for ligand-initiated signal transduction through B cell membrane IgM is assessed in terms of ligand concentration, binding site valency, and binding site affinity for membrane Ig. Estimates of the physicochemical requirements for achieving G0* enhancement of class II MHC expression, G1 entry, and S phase entry in human B cells were made by comparing the stimulatory effects of three affinity-diverse anti-Cmu2 mAb when in bivalent (unconjugated) form, or as mAb-dextran conjugates with low binding site valency (oligovalent ligands) or high binding site valency (multivalent ligands). An increase in binding site number (and concomitant molecular mass) caused a profound reduction in both the minimal concentration and affinity requisites for B cell activation. The enhancing effect of increased binding site valency was most evident for the signaling of those most distal stages in B cell activation, i.e., G1 and S phase, which were difficult to induce with bivalent ligands. The results suggest that highly multimeric TI-2 Ag may be good immunogens because they are able to elicit a full activation response not only from infrequent high affinity B cells, but also from a substantial proportion of the many lower affinity Ag-specific B cells in virgin B cell populations. Interestingly, the activation of B cells by ligands with binding sites of high intrinsic affinity (Ka = 5 x 10(8) M-1) was less influenced by increases in binding site valency than was B cell activation by ligands with intermediate binding site affinity (Ka = 2 x 10(7) M-1). This suggests that the minimal epitope valency requirement for T cell-independent B cell activation by mIg cross-linking Ag may be dependent on the intrinsic affinity with which membrane Ig molecules on a given B cell interact with the redundantly expressed epitopes.
通过B细胞膜IgM进行配体启动信号转导的潜力，是根据配体浓度、结合位点价态以及结合位点对膜Ig的亲和力来评估的。通过比较三种具有不同亲和力的抗Cμ2单克隆抗体在二价（未偶联）形式下，或作为具有低结合位点价态（寡价配体）或高结合位点价态（多价配体）的单克隆抗体-葡聚糖偶联物的刺激作用，对人B细胞中实现II类MHC表达增强、进入G1期和进入S期的物理化学要求进行了估计。结合位点数目的增加（以及随之而来的分子量增加）导致B细胞激活的最低浓度和亲和力要求大幅降低。结合位点价态增加的增强作用在B细胞激活最远端阶段的信号传导中最为明显，即G1期和S期，而二价配体很难诱导这些阶段。结果表明，高度多聚的TI-2抗原可能是良好的免疫原，因为它们不仅能够从不常见的高亲和力B细胞引发完全激活反应，而且还能从原始B细胞群体中大量较低亲和力的抗原特异性B细胞引发反应。有趣的是，与具有中等结合位点亲和力（Ka = 2 x 10(7) M-1）的配体相比，具有高内在亲和力（Ka = 5 x 10(8) M-1）结合位点的配体对B细胞的激活受结合位点价态增加的影响较小。这表明，通过mIg交联抗原实现非T细胞依赖性B细胞激活的最小表位价态要求可能取决于给定B细胞上的膜Ig分子与冗余表达表位相互作用的内在亲和力。
