Research Center for Immunodeficiencies, Pediatrics Center of Excellence, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran; Iranian Primary Immunodeficiencies Network (IPIN), Tehran University of Medical Sciences, Tehran, Iran.
Research Center for Immunodeficiencies, Pediatrics Center of Excellence, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran; Iranian Primary Immunodeficiencies Network (IPIN), Tehran University of Medical Sciences, Tehran, Iran; Division of Clinical Immunology, Department of Laboratory Medicine, Karolinska Institute at Karolinska University Hospital Huddinge, Stockholm, Sweden.
J Allergy Clin Immunol Pract. 2019 Mar;7(3):864-878.e9. doi: 10.1016/j.jaip.2018.09.004. Epub 2018 Sep 19.
Predominantly antibody deficiencies (PADs) are the most common primary immunodeficiencies, characterized by hypogammaglobulinemia and inability to generate effective antibody responses.
We intended to report most common monogenic PADs and to investigate how patients with PAD who were primarily diagnosed as suffering from agammaglobulinemia, hyper-IgM (HIgM) syndrome, and common variable immunodeficiency (CVID) have different clinical and immunological findings.
Stepwise next-generation sequencing and Sanger sequencing were performed for confirmation of the mutations in the patients clinically diagnosed as suffering from agammaglobulinemia, HIgM syndrome, and CVID.
Among 550 registered patients, the predominant genetic defects associated with agammaglobulinemia (48 Bruton's tyrosine kinase [BTK] and 6 μ heavy chain deficiencies), HIgM syndrome (21 CD40 ligand and 7 activation-induced cytidine deaminase deficiencies), and CVID (17 lipopolysaccharides-responsive beige-like anchor deficiency and 12 atypical Immunodeficiency, Centromeric instability, and Facial dysmorphism syndromes) were identified. Clinical disease severity was significantly higher in patients with μ heavy chain and CD40 ligand mutations compared with patients with BTK (P = .003) and activation-induced cytidine deaminase (P = .009) mutations. Paralysis following live polio vaccination was considerably higher in patients with μ heavy chain deficiency compared with BTK deficiency (P < .001). We found a genotype-phenotype correlation among patients with BTK mutations regarding clinical manifestation of meningitis and chronic diarrhea. Surprisingly, we noticed that first presentations in most patients with Immunodeficiency, Centromeric instability, and Facial dysmorphism were respiratory complications (P = .008), whereas first presentations in patients with lipopolysaccharides-responsive beige-like anchor deficiency were nonrespiratory complications (P = .008).
This study highlights similarities and differences in the clinical and genetic spectrum of the most common PAD-associated gene defects. This comprehensive comparison will facilitate clinical decision making, and improve prognosis and targeted treatment.
主要抗体缺陷症（PAD）是最常见的原发性免疫缺陷症，其特征是低丙种球蛋白血症和无法产生有效的抗体反应。
我们旨在报告最常见的单基因 PAD，并研究主要诊断为丙种球蛋白缺乏症、高免疫球蛋白 M（HIgM）综合征和普通可变免疫缺陷症（CVID）的 PAD 患者的临床和免疫学发现有何不同。
对临床诊断为丙种球蛋白缺乏症、高免疫球蛋白 M 综合征和 CVID 的患者进行逐步下一代测序和 Sanger 测序，以确认突变。
在 550 名登记患者中，与丙种球蛋白缺乏症（48 例布鲁顿酪氨酸激酶 [BTK]和 6 例μ重链缺乏症）、高免疫球蛋白 M 综合征（21 例 CD40 配体和 7 例激活诱导胞苷脱氨酶缺乏症）和 CVID（17 例脂多糖反应性 beige 样锚定缺陷和 12 例非典型免疫缺陷、着丝粒不稳定、面畸形综合征）相关的主要遗传缺陷被确定。与 BTK（P=0.003）和激活诱导胞苷脱氨酶（P=0.009）突变患者相比，μ重链和 CD40 配体突变患者的临床疾病严重程度显著更高。与 BTK 缺乏症相比，μ重链缺乏症患者接种脊髓灰质炎活疫苗后瘫痪的发生率明显更高（P<0.001）。我们在 BTK 突变患者中发现了基因型-表型相关性，涉及脑膜炎和慢性腹泻的临床表现。令人惊讶的是，我们注意到大多数免疫缺陷、着丝粒不稳定和面畸形患者的首发表现是呼吸道并发症（P=0.008），而脂多糖反应性 beige 样锚定缺陷患者的首发表现是非呼吸道并发症（P=0.008）。
本研究强调了最常见的 PAD 相关基因缺陷的临床和遗传谱的异同。这种全面的比较将有助于临床决策，并改善预后和靶向治疗。
