Ochs H D, Smith C I
Department of Pediatrics, University of Washington, Seattle 98195-6320, USA.
Medicine (Baltimore). 1996 Nov;75(6):287-99. doi: 10.1097/00005792-199611000-00001.
X-linked agammaglobulinemia (XLA), characterized by a profound deficiency of B lymphocytes due to an arrest in B lymphocyte development, is caused by mutations in the gene encoding Btk (Bruton tyrosine kinase). The BTK gene has been cloned and the genomic organization determined. BTK codes for 19 exons and is expressed in all hematopoietic cell lineages but is selectively down-regulated in T lymphocytes and plasma cells. The different Btk domains include PH, TH, SH3, SH2, and the kinase (SH1) domains. Btk, a cytoplasmic protein tyrosine kinase, is involved in cell signaling, although the precise pathway remains elusive. Mutation analysis has been performed in 236 families representing 282 patients. Mutations are scattered throughout the gene and consist of missense, nonsense, and splice site mutations as well as deletions and insertions. The major consequence of nonfunctional Btk appears to be a delay or block of the development of pro-B cells to pre-B cells and then to mature lymphocytes. Because IgG is actively transported across the placenta, affected newborns have normal levels of serum IgG at birth followed by gradually decreasing IgG levels and development of hypogammaglobulinemia and increased susceptibility to infections. Bacterial infections are the most common clinical manifestation. Resistance to viral infection is intact, except for an unusual susceptibility to infections with enteroviruses that may result in vaccine-related paralytic poliomyelitis or a dermatomyositis-meningoencephalitis syndrome. The diagnosis of XLA is based on the presence of lymphoid hypoplasia, markedly reduced serum levels of all 3 major classes of immunoglobulins, failure to make antibody to antigenic stimulation, and almost complete absence of B lymphocytes in the peripheral blood. Carrier detection and prenatal diagnosis are possible. The prophylactic infusion of high-dose intravenous immunoglobulin (IVIG) and the use of antibiotics have markedly improved the long-term prognosis of patients with XLA.
X连锁无丙种球蛋白血症（XLA）的特征是由于B淋巴细胞发育停滞导致B淋巴细胞严重缺乏，它由编码布鲁顿酪氨酸激酶（Btk）的基因突变引起。BTK基因已被克隆并确定了基因组结构。BTK由19个外显子编码，在所有造血细胞谱系中均有表达，但在T淋巴细胞和浆细胞中选择性下调。不同的Btk结构域包括PH、TH、SH3、SH2和激酶（SH1）结构域。Btk是一种细胞质蛋白酪氨酸激酶，参与细胞信号传导，尽管确切途径仍不清楚。已对代表282例患者的236个家庭进行了突变分析。突变分散在整个基因中，包括错义突变、无义突变、剪接位点突变以及缺失和插入。无功能Btk的主要后果似乎是前B细胞发育为前B细胞，进而发育为成熟淋巴细胞的过程延迟或受阻。由于IgG可主动穿过胎盘，受影响的新生儿出生时血清IgG水平正常，随后IgG水平逐渐下降，出现低丙种球蛋白血症，且感染易感性增加。细菌感染是最常见的临床表现。除了对肠道病毒感染异常易感，可能导致疫苗相关的麻痹性脊髓灰质炎或皮肌炎-脑膜脑炎综合征外，对病毒感染的抵抗力正常。XLA的诊断基于淋巴组织发育不全、所有3种主要免疫球蛋白的血清水平显著降低、对抗抗原刺激无抗体产生以及外周血中几乎完全没有B淋巴细胞。携带者检测和产前诊断是可行的。大剂量静脉注射免疫球蛋白（IVIG）的预防性输注和抗生素的使用显著改善了XLA患者的长期预后。
