Agematsu Kazunaga, Futatani Takeshi, Hokibara Sho, Kobayashi Norimoto, Takamoto Masaya, Tsukada Satoshi, Suzuki Harumi, Koyasu Shigeo, Miyawaki Toshio, Sugane Kazuo, Komiyama Atsushi, Ochs Hans D
Department of Infectious Immunology, Graduate School of Medicine, Matsumoto, Shinshu University, Japan.
Clin Immunol. 2002 Apr;103(1):34-42. doi: 10.1006/clim.2001.5197.
The molecular basis of common variable immunodeficiency (CVID) is unknown. To assess humoral immunity in CVID, we selected 24 patients with early or late onset of disease. X-linked agammaglobulinemia (XLA), X-linked hyper-IgM syndrome (XHIM), and non-XHIM were excluded based on clinical phenotype, assessment of the immune response, presence of Bruton's tyrosine kinase (Btk) in monocytes or platelets, and normal expression of CD40 ligand by activated T cells. The number of circulating B cells was within the normal range or reduced. IgD(-) CD27(+) memory B cells were markedly reduced or absent in all 24 patients and IgD(+) CD27(+) B cells were diminished in 8 patients. Circulating B cells from all 6 patients examined, including CVID patients with IgD(+) CD27(+) cells, failed to undergo somatic hypermutation in immunoglobulin-variable (V)-region genes, similar to cord blood B cells. B cells from CVID patients produced IgM and IgG, but not IgA upon the engagement of Ig receptor and CD40 in the presence of IL-2 and IL-10. B cells from all but 5 patients secreted IgE when stimulated by CD40 crosslinking in the presence of IL-4. The observation of defective memory B cells with abnormal cell marker expression and function demonstrates that naive CVID B cells including those expressing IgD(+) CD27(+), in analogy to cord blood and hyper-IgM syndrome B cells, may be responsible for their failure to differentiate into plasma cells and to produce high-affinity antibodies of different isotypes.
常见变异型免疫缺陷（CVID）的分子基础尚不清楚。为评估CVID患者的体液免疫，我们选取了24例疾病早发或晚发的患者。基于临床表型、免疫反应评估、单核细胞或血小板中布鲁顿酪氨酸激酶（Btk）的存在情况以及活化T细胞中CD40配体的正常表达，排除了X连锁无丙种球蛋白血症（XLA）、X连锁高IgM综合征（XHIM）和非XHIM患者。循环B细胞数量在正常范围内或减少。所有24例患者中IgD(-) CD27(+)记忆B细胞明显减少或缺失，8例患者中IgD(+) CD27(+) B细胞减少。包括有IgD(+) CD27(+)细胞的CVID患者在内的所有6例接受检测的患者的循环B细胞，在免疫球蛋白可变（V）区基因中均未发生体细胞超突变，这与脐血B细胞相似。在存在白细胞介素-2（IL-2）和白细胞介素-10（IL-10）的情况下，CVID患者的B细胞在Ig受体和CD40结合后产生IgM和IgG，但不产生IgA。除5例患者外，所有患者的B细胞在存在IL-4的情况下受到CD40交联刺激时均分泌IgE。对具有异常细胞标志物表达和功能的缺陷记忆B细胞的观察表明，与脐血和高IgM综合征B细胞类似，包括那些表达IgD(+) CD27(+)的幼稚CVID B细胞可能是其无法分化为浆细胞并产生不同同种型高亲和力抗体的原因。
