Waldmann T A, Broder S, Goldman C K, Frost K, Korsmeyer S J, Medici M A
J Clin Invest. 1983 Feb;71(2):282-95. doi: 10.1172/jci110768.
The pathogenesis of the immunoglobulin deficiency of 20 patients with ataxia telangiectasia was studied using an in vitro immunoglobulin biosynthesis system. 10 patients had no detectable IgA in their serum as assessed by radial diffusion in agar and 3 had a reduced serum IgA concentration. The peripheral blood mononuclear cells of 17 of the patients and 17 normal controls were cultured with pokeweed mitogen for 12 d and the immunoglobulin in the supernatants measured. The immunoglobulin synthesis was below the lower limit of the normal 95% confidence interval for IgM in 5 patients, for IgG in 8, and for IgA in 14. The mononuclear cells from 9 of the 10 patients with a serum IgA concentration less than 0.1 mg/ml failed to synthesize IgA in vitro. None of the patients manifested excessive suppressor cell activity. All patients had reduced but measurable helper T cell activity for immunoglobulin synthesis by co-cultured normal pokeweed mitogen-stimulated B cells (geometric mean 22% of normal). Furthermore, the addition of normal irradiated T cells to patient peripheral blood mononuclear cells led to an augmentation of IgM synthesis in 15 of 17 and to increased IgG synthesis in 9 of the 17 patients studied, including 9 of the 12 patients who had synthesized IgG before the addition of the irradiated T cells. In addition, IgA synthesis was increased in all eight patients examined that had serum IgA concentrations greater than 0.1 mg/ml. These studies suggest that a helper T cell defect contributes to the diminished immunoglobulin synthesis. However, a helper T cell defect does not appear to be the sole cause since there was no IgA synthesis by the peripheral blood mononuclear cells of 9 of the 10 patients with a profoundly reduced serum IgA even when co-cultured with normal T cells. Furthermore, the cells of the nine patients with profoundly reduced IgA levels examined also failed to produce IgA when stimulated with the relatively helper T cell-independent polyclonal activators, Nocardia water soluble mitogen or Epstein-Barr virus. Taken together these data support the view that the reduced immunoglobulin synthesis of these patients is due to defects of both B cells and helper T cells. Such a broad defect in lymphocyte maturation taken in conjunction with our demonstration of persistent alpha fetoprotein production by ataxia telangiectasia patients provides support for the proposal that these patients exhibit a generalized defect in tissue differentiation.
利用体外免疫球蛋白生物合成系统研究了20例共济失调毛细血管扩张症患者免疫球蛋白缺乏的发病机制。通过琼脂放射扩散法评估，10例患者血清中未检测到IgA，3例患者血清IgA浓度降低。将17例患者及17名正常对照者的外周血单个核细胞与商陆有丝分裂原共培养12天，检测上清液中的免疫球蛋白。5例患者的免疫球蛋白合成低于正常IgM 95%置信区间下限，8例低于正常IgG 95%置信区间下限，14例低于正常IgA 95%置信区间下限。10例血清IgA浓度低于0.1mg/ml的患者中，有9例的单个核细胞在体外不能合成IgA。所有患者均未表现出过度的抑制细胞活性。对于共培养的经商陆有丝分裂原刺激的正常B细胞的免疫球蛋白合成，所有患者的辅助性T细胞活性均降低但仍可检测到（几何平均值为正常的22%）。此外，将正常照射的T细胞添加到患者外周血单个核细胞中，17例患者中有15例IgM合成增加，17例患者中有9例IgG合成增加，包括添加照射T细胞前能合成IgG的12例患者中的9例。另外，在检测的所有8例血清IgA浓度大于0.1mg/ml的患者中，IgA合成均增加。这些研究提示辅助性T细胞缺陷导致免疫球蛋白合成减少。然而，辅助性T细胞缺陷似乎并非唯一原因，因为10例血清IgA严重降低的患者中，有9例的外周血单个核细胞即使与正常T细胞共培养也不能合成IgA。此外，检测的9例IgA水平严重降低的患者的细胞在用相对不依赖辅助性T细胞的多克隆激活剂——诺卡氏菌水溶性有丝分裂原或爱泼斯坦-巴尔病毒刺激时，也不能产生IgA。综合这些数据支持这样一种观点，即这些患者免疫球蛋白合成减少是由于B细胞和辅助性T细胞均存在缺陷。淋巴细胞成熟过程中如此广泛的缺陷，再结合我们所证明的共济失调毛细血管扩张症患者持续产生甲胎蛋白的现象，为这些患者存在组织分化普遍缺陷的观点提供了支持。
