Centre of Chronic Immunodeficiency, University Medical Centre Freiburg, Faculty of Biology, Albert-Ludwigs-Universität, Freiburg, Germany.
J Allergy Clin Immunol. 2013 Apr;131(4):959-71. doi: 10.1016/j.jaci.2013.01.046. Epub 2013 Mar 5.
B cells develop from hematopoietic precursor cells in an ordered maturation and selection process. Extensive studies with many different mouse mutants provided fundamental insights into this process. However, the characterization of genetic defects causing primary immunodeficiencies was essential in understanding human B-cell biology. Defects in pre-B-cell receptor components or in downstream signaling proteins, such as Bruton tyrosine kinase and B-cell linker protein, arrest development at the pre-B-cell stage. Defects in survival-regulating proteins, such as B-cell activator of the TNF-α family receptor (BAFF-R) or caspase recruitment domain-containing protein 11 (CARD11), interrupt maturation and prevent differentiation of transitional B cells into marginal zone and follicular B cells. Mature B-cell subsets, immune responses, and memory B-cell and plasma cell development are disturbed by mutations affecting Toll-like receptor signaling, B-cell antigen receptor coreceptors (eg, CD19), or enzymes responsible for immunoglobulin class-switch recombination. Transgenic mouse models helped to identify key regulatory mechanisms, such as receptor editing and clonal anergy, preventing the activation of B cells expressing antibodies recognizing autoantigens. Nevertheless, the combination of susceptible genetic backgrounds with the rescue of self-reactive B cells by T cells allows the generation of autoreactive clones found in patients with many autoimmune diseases and even in those with primary immunodeficiencies. The rapid progress of functional genomic research is expected to foster the development of new tools that specifically target dysfunctional B lymphocytes to treat autoimmunity, B-cell malignancies, and immunodeficiency.
B 细胞在有序的成熟和选择过程中从造血前体细胞发育而来。利用许多不同的小鼠突变体进行的广泛研究为这一过程提供了基本的见解。然而，对导致原发性免疫缺陷的遗传缺陷的特征描述对于理解人类 B 细胞生物学至关重要。前 B 细胞受体成分或下游信号蛋白（如布鲁顿酪氨酸激酶和 B 细胞接头蛋白）的缺陷会在前 B 细胞阶段阻止发育。存活调节蛋白（如 TNF-α 家族受体的 B 细胞激活剂（BAFF-R）或衔接蛋白 CARD11）的缺陷中断成熟并阻止过渡 B 细胞分化为边缘区和滤泡 B 细胞。影响 Toll 样受体信号、B 细胞抗原受体共受体（如 CD19）或负责免疫球蛋白类别转换重组的酶的突变会干扰成熟 B 细胞亚群、免疫反应以及记忆 B 细胞和浆细胞的发育。转基因小鼠模型有助于确定关键的调节机制，如受体编辑和克隆无能，防止表达识别自身抗原的抗体的 B 细胞的激活。尽管如此，易感遗传背景与 T 细胞拯救自身反应性 B 细胞的结合允许在许多自身免疫性疾病患者甚至在原发性免疫缺陷患者中产生自身反应性克隆。功能基因组学研究的快速进展有望促进开发新的工具，这些工具可特异性靶向功能失调的 B 淋巴细胞以治疗自身免疫、B 细胞恶性肿瘤和免疫缺陷。
