Notarangelo L D, Giliani S, Mella P, Schumacher R F, Mazza C, Savoldi G, Rodriguez-Pérez C, Badolato R, Mazzolari E, Porta F, Candotti F, Ugazio A G
Istituto di Medicina Molecolare Angelo Nocivelli, Clinica Pediatrica Università di Brescia, Italy.
Immunobiology. 2000 Aug;202(2):106-19. doi: 10.1016/s0171-2985(00)80058-3.
Combined immune deficiencies comprise a spectrum of genetic disorders characterized by developmental or functional defects of both T and B lymphocytes. Recent progress in cell biology and molecular genetics has unraveled the pathophysiology of most of these defects. In particular, the most common form of severe combined immune deficiency in humans, with lack of circulating T cells, a normal or increased number of B lymphocytes, and an X-linked pattern of inheritance (SCIDXI) has been shown to be due to defects of the IL2RG gene, encoding for the common gamma chain (gammac), shared by several cytokine receptors. Furthermore, defects of the JAK3 gene, encoding for an intracellular tyrosine kinase required for signal transduction through gammac-containing cytokine receptors, have been identified in patients with autosomal recessive T-B+ SCID. Characterization of the functional properties of cytokines that signal through the gammac-JAK3 signaling pathway has been favored by the detailed analysis of SCID patients. Specifically, the key role of IL-7 in promoting T cell development has been substantiated by the identification of rare patients with T-B+ SCID who have a defect in the alpha subunit of the IL-7 receptor (IL7Ralpha). The heterogeneity of genetic defects along the same signaling pathway that may lead to combined immune deficiency is paralleled by the heterogeneity of immunological phenotypes that may associate with defects in the same gene, thus creating a need for detailed immunological and molecular investigations in order to dissect the spectrum of combined immune deficiencies in humans.
联合免疫缺陷包括一系列遗传性疾病，其特征为T淋巴细胞和B淋巴细胞均存在发育或功能缺陷。细胞生物学和分子遗传学的最新进展已揭示了这些缺陷中大多数的病理生理学机制。特别是，人类最常见的严重联合免疫缺陷形式，即缺乏循环T细胞、B淋巴细胞数量正常或增加且呈X连锁遗传模式（X连锁严重联合免疫缺陷，SCID-XI），已被证明是由于编码共同γ链（γc）的IL2RG基因存在缺陷所致，该γ链为几种细胞因子受体所共有。此外，在常染色体隐性遗传的T⁺B⁻ SCID患者中已鉴定出JAK3基因存在缺陷，JAK3基因编码一种通过含γc的细胞因子受体进行信号转导所需的细胞内酪氨酸激酶。对SCID患者的详细分析有助于对通过γc-JAK3信号通路进行信号传导的细胞因子的功能特性进行表征。具体而言，通过鉴定罕见的T⁺B⁻ SCID患者（其白细胞介素7受体α亚基（IL7Rα）存在缺陷），证实了IL-7在促进T细胞发育中的关键作用。沿着可能导致联合免疫缺陷的同一信号通路，遗传缺陷的异质性与可能与同一基因缺陷相关的免疫表型的异质性相平行，因此需要进行详细的免疫学和分子研究，以剖析人类联合免疫缺陷的谱系。
