Assistance Publique - Hôpitaux de Paris (AP-HP), Laboratoire d'Immunologie, Hôpital Européen Georges-Pompidou, Paris, France.
Pediatrics Department, Jean Verdier Hospital, Assistance Publique des Hôpitaux de Paris, Paris 13 University, Bondy, France.
Front Immunol. 2019 Aug 8;10:1936. doi: 10.3389/fimmu.2019.01936. eCollection 2019.
The complement system is crucial for defense against pathogens and the removal of dying cells or immune complexes. Thus, clinical indications for possible complete complement deficiencies include, among others, recurrent mild or serious bacterial infections as well as autoimmune diseases (AID). The diagnostic approach includes functional activity measurements of the classical (CH50) and alternative pathway (AP50) and the determination of the C3 and C4 levels, followed by the quantitative analysis of individual components or regulators. When biochemical analysis reveals the causal abnormality of the complement deficiency (CD), molecular mechanisms remains frequently undetermined. Here, using direct sequencing analysis of the coding region we report the pathogenic variants spectrum that underlie the total or subtotal complement deficiency in 212 patients. We identified 107 different hemizygous, homozygous, or compound heterozygous pathogenic variants in 14 complement genes [β ( = 1), ( = 3), ( = 2), ( = 12), ( = 5), C5 ( = 12), ( = 9), ( = 17), β ( = 7), ( = 3), ( = 7), ( = 18), ( = 10), ( = 2)]. Molecular analysis identified 17 recurrent pathogenic variants in 6 genes (, and ). More than half of the pathogenic variants identified in unrelated patients were also found in healthy controls from the same geographic area. Our study confirms the strong association of meningococcal infections with terminal pathway deficiency and highlights the risk of pneumococcal and auto-immune diseases in the classical and alternative pathways. Results from this large genetic investigation provide evidence of a restricted number of molecular mechanisms leading to complement deficiency and describe the clinical potential adverse events of anti-complement therapy.
补体系统对于防御病原体、清除死亡细胞或免疫复合物至关重要。因此，可能存在完全补体缺陷的临床指征包括，反复发生轻度或严重细菌感染以及自身免疫性疾病（AID）等。诊断方法包括经典途径（CH50）和替代途径（AP50）的功能活性测量以及 C3 和 C4 水平的测定，然后进行单个成分或调节剂的定量分析。当生化分析揭示出补体缺陷（CD）的因果异常时，分子机制通常仍未确定。在这里，我们通过对编码区的直接测序分析，报告了在 212 名患者中导致总或部分补体缺陷的致病变异谱。我们在 14 个补体基因中鉴定出 107 种不同的半合子、纯合子或复合杂合致病变异[β（= 1），（= 3），（= 2），（= 12），（= 5），C5（= 12），（= 9），（= 17），（= 7），（= 3），（= 7），（= 18），（= 10），（= 2）]。分子分析在 6 个基因（、和）中鉴定出 17 种常见的致病变异。在无关联患者中鉴定出的致病变异中有一半以上也存在于来自同一地理区域的健康对照者中。我们的研究证实了脑膜炎球菌感染与末端途径缺陷之间的强关联，并强调了经典途径和替代途径中肺炎球菌感染和自身免疫性疾病的风险。这项大规模遗传研究的结果提供了证据，证明了导致补体缺陷的分子机制数量有限，并描述了抗补体治疗的临床潜在不良事件。
