Noordzij Jeroen G, de Bruin-Versteeg Sandra, Comans-Bitter W Marieke, Hartwig Nico G, Hendriks Rudolf W, de Groot Ronald, van Dongen Jacques J M
Department of Immunology, Erasmus University Rotterdam/University Hospital Rotterdam-Dijkzigt, 3000 DR, Rotterdam, The Netherlands.
Pediatr Res. 2002 Feb;51(2):159-68. doi: 10.1203/00006450-200202000-00007.
X-linked agammaglobulinemia (XLA) is characterized by a severe B-cell deficiency, resulting from a differentiation arrest in the bone marrow (BM). Because XLA is clinically and immunologically heterogeneous, we investigated whether the B-cell differentiation arrest in BM of XLA patients is heterogeneous as well. First, we analyzed BM samples from 19 healthy children by flow cytometry. This resulted in a normal B-cell differentiation model with eight consecutive stages. Subsequently, we analyzed BM samples from nine XLA patients. Eight patients had amino acid substitutions in the Bruton's tyrosine kinase (BTK) domain or premature stop codons, resulting in the absence of functional BTK proteins. In seven of these eight patients a major differentiation arrest was observed at the transition between cytoplasmic Ig(mu-) pre-B-I cells and cytoplasmic Ig(mu+) pre-B-II cells, consistent with a role for BTK in pre-B-cell receptor signaling. However, one patient exhibited a very early arrest at the transition between pro-B cells and pre-B-I cells, which could not be explained by a different nature of the BTK mutation. We conclude that the absence of functional BTK proteins generally leads to an almost complete arrest of B-cell development at the pre-B-I to pre-B-II transition. The ninth XLA patient had a splice site mutation associated with the presence of low levels of wild-type BTK mRNA. His BM showed an almost normal composition of the precursor B-cell compartment, suggesting that low levels of BTK can rescue the pre-B-cell receptor signaling defect, but do not lead to sufficient numbers of mature B lymphocytes in the peripheral blood.
X连锁无丙种球蛋白血症（XLA）的特征是严重的B细胞缺陷，这是由骨髓（BM）中的分化停滞引起的。由于XLA在临床和免疫学上具有异质性，我们研究了XLA患者骨髓中B细胞分化停滞是否也具有异质性。首先，我们通过流式细胞术分析了19名健康儿童的骨髓样本。这产生了一个具有八个连续阶段的正常B细胞分化模型。随后，我们分析了9名XLA患者的骨髓样本。8名患者在布鲁顿酪氨酸激酶（BTK）结构域有氨基酸替代或提前终止密码子，导致功能性BTK蛋白缺失。在这8名患者中的7名中，在细胞质Ig（μ-）前B-I细胞和细胞质Ig（μ+）前B-II细胞之间的转变处观察到主要的分化停滞，这与BTK在前B细胞受体信号传导中的作用一致。然而，一名患者在原B细胞和前B-I细胞之间的转变处表现出非常早期的停滞，这无法用BTK突变的不同性质来解释。我们得出结论，功能性BTK蛋白的缺失通常会导致B细胞发育在从前B-I到前B-II转变时几乎完全停滞。第九名XLA患者有一个剪接位点突变，与低水平野生型BTK mRNA的存在有关。他的骨髓显示前体B细胞区室的组成几乎正常，这表明低水平的BTK可以挽救前B细胞受体信号传导缺陷，但不会导致外周血中足够数量的成熟B淋巴细胞。
