Clinical and Genetic Spectrum of a Large Cohort With Total and Sub-total Complement Deficiencies

Frontiers in Immunology

Paula Vieira-Martins¹  Pauline Bordereau¹  Carine El Sissy¹  Aurélia Gruber¹  Magali Devriese¹  Jérémie Rosain¹  Véronique Frémeaux-Bacchi²  Claire Fieschi⁴  Muhamed-Kheir Taha⁵  Loïc de Pontual⁷  Capucine Picard⁸ 

[1] Assistance Publique – Hôpitaux de Paris (AP-HP), Laboratoire d'Immunologie, Hôpital Européen Georges-Pompidou, Paris, France;Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, USPC, Université Paris Descartes, Complement and Diseases Team, Paris, France;Department of Clinical Immunology, Hôpital Saint-Louis, Assistance Publique – Hôpitaux de Paris (AP-HP), Paris, France;Inserm U1126, Centre Hayem, Hôpital Saint-Louis, Paris, France;Invasive Bacterial Infection and National Reference Center for Meningococci, Pasteur Institut, Paris, France;Paris University, INSERM UMR1163, Imagine Institute, Paris, France;Pediatrics Department, Jean Verdier Hospital, Assistance Publique des Hôpitaux de Paris, Paris 13 University, Bondy, France;Study Center for Primary Immunodeficiencies (AP-HP), Hôpital Necker-Enfants maladies Hospital, Paris, France;

关键词: complement;    genetic variants;    meningococcal infections;    deficiency;    auto immune diseases;   

DOI  :  10.3389/fimmu.2019.01936

来源: DOAJ

【 摘 要 】

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 [C1Qβ (n = 1), C1r (n = 3), C1s (n = 2), C2 (n = 12), C3 (n = 5), C5 (n = 12), C6 (n = 9), C7 (n = 17), C8 β (n = 7), C9 (n = 3), CFH (n = 7), CFI (n = 18), CFP (n = 10), CFD (n = 2)]. Molecular analysis identified 17 recurrent pathogenic variants in 6 genes (C2, CFH, C5, C6, C7, and C8). 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.

【 授权许可】

Unknown