Jabara H H, Vercelli D, Schneider L C, Williams D P, Genbauffe F S, Poisson L R, Waters C A, Geha R S
Division of Immunology, Children's Hospital, Boston, MA 02115, USA.
J Allergy Clin Immunol. 1995 Apr;95(4):893-900. doi: 10.1016/s0091-6749(95)70134-6.
Studies of human IgE-secreting B cells have proven difficult because of the small size of this population. We have used an interleukin-4 (IL-4) fusion toxin to detect functionally IL-4 receptor (IL-4R) expression on B cells involved in IgE synthesis.
In diphtheria toxin IL-4 (DAB389IL-4) the receptor-binding domain of diphtheria toxin has been replaced with human IL-4. DAB389IL-4 cytotoxicity depends on IL-4R binding and internalization.
Addition of DAB389IL-4 inhibited IgE synthesis induced by IL-4+ anti-CD40 monoclonal antibody or hydrocortisone. IgE inhibition resulted from DAB389IL-4 B-cell cytotoxicity because DAB389IL-4 inhibited IL-4-independent B-cell proliferation. Thus induction of human IgE synthesis involves IL-4R+ cells. In contrast, terminally differentiated, IgE-producing B cells no longer express functional IL-4R because DAB389IL-4 only modestly inhibited ongoing IgE synthesis by B cells from patients with hyper-IgE states and only minimally affected IL-4-induced IgE synthesis in normal B cells when the toxin was added at day 7. Pokeweed mitogen-induced IgM synthesis was sensitive to early but not to late addition of DAB389IL-4. Thus the loss of functional IL-4R immunoglobulin-secreting B cells is independent of isotype switching.
IgE-secreting B cells no longer express functional IL-4R. Therapies for allergic disease that target the IL-4R would not affect IgE-secreting B cells but may block the recruitment of B cells into the IgE-secreting pool. For optimal benefits this approach may be combined with therapies that target IL-4R-, IgE-secreting B cells.
由于人类分泌IgE的B细胞数量较少，对其进行研究颇具难度。我们使用了一种白细胞介素4（IL-4）融合毒素来检测参与IgE合成的B细胞上功能性白细胞介素4受体（IL-4R）的表达。
在白喉毒素IL-4（DAB389IL-4）中，白喉毒素的受体结合结构域已被人IL-4取代。DAB389IL-4的细胞毒性取决于IL-4R的结合和内化。
添加DAB389IL-4可抑制由IL-4+抗CD40单克隆抗体或氢化可的松诱导的IgE合成。IgE的抑制是由DAB389IL-4对B细胞的细胞毒性所致，因为DAB389IL-4可抑制不依赖IL-4的B细胞增殖。因此，人类IgE合成的诱导涉及IL-4R+细胞。相比之下，终末分化的、产生IgE的B细胞不再表达功能性IL-4R，因为DAB389IL-4仅适度抑制高IgE状态患者B细胞持续进行的IgE合成，且在第7天添加毒素时，对正常B细胞中IL-4诱导的IgE合成影响极小。美洲商陆有丝分裂原诱导的IgM合成对早期添加DAB389IL-4敏感，但对晚期添加不敏感。因此，功能性IL-4R在分泌免疫球蛋白的B细胞中的丧失与同种型转换无关。
分泌IgE的B细胞不再表达功能性IL-4R。针对IL-4R的过敏性疾病治疗方法不会影响分泌IgE的B细胞，但可能会阻止B细胞进入分泌IgE的细胞池。为获得最佳疗效，这种方法可与针对分泌IgE的IL-4R- B细胞的治疗方法相结合。
