Primary complement C5 deficiencies – Molecular characterization and clinical review of two families
Introduction
The complement system is an important part of innate immunity. It is involved in the defense against microorganisms and in removal of waste material such as dying host cells and immune complexes (Walport, 2001, Ricklin et al., 2010). It is activated via three different pathways; the classical, the lectin and the alternative activation pathways. All activation pathways lead to generation of a C3 convertase, and subsequently to formation of a complement C5 convertase which cleaves C5 into C5a (residues 678–751) and C5b. C5a is a potent anaphylatoxin and chemoattractant, while C5b is a part of the terminal C5b-9 complement complex (TCC). TCC exists in two forms, the membrane attack complex (C5b-9), which might lyse microbes and cells or in sublytic doses activate cells, and the soluble sC5b-9 complex which is formed in the fluid phase (Bossi et al., 2004, Walport, 2001). The host is protected against collateral activity mediated by the complement system by several fluid-phase regulators as well as surface regulators on host cells (Mollnes et al. 2002).
Deficiencies of the different complement components are associated with a broad range of diseases (reviewed by Skattum et al. (2011) and Blom (2010)). Deficiencies of the components in the classical activation pathway are associated with increased tendency to acquire bacterial infections and autoimmunity syndromes like systemic lupus erythematosus. Likewise, deficiency states in the lectin pathway are associated with increased risk of infections, but the role in autoimmunity is less clear. However, recently is has been shown that deficiency states in some of the lectin pathway components leads to embryonic development defects (Rooryck et al. 2011). Concerning deficiencies of the components of the alternative pathway these patients have an increased risk of contracting severe Neisseria infections. This is also the case for patients deficient of components in the terminal pathway, who, however, display a higher rate of recurrent disease but a lower mortality rate than patients without complement deficiency or patients with properdin deficiency (Fiigueroa and Densen 1991). Deficiencies of fluid phase complement regulators lead to increased spontaneous turnover of complement components and thus secondary increased risk of infection. Furthermore, variations in the genes encoding complement regulators and gain of function mutations in the complement components are also associated with increased susceptibility to disease such as atypical uremic syndrome (aHUS), membranoproliferative glomerulonephritis type II, age related macular degeneration and paroxysmal nocturnal hemoglobinuria (PNH).
Besides genetically determined deficiencies of the terminal complement components an increasing number of patients are now experiencing secondary C5 deficiency due to C5 inhibition treatment. Eculizumab (Soliris®) is a monoclonal antibody blocking cleavage of C5, thereby inhibiting the release of biologically active C5a as well C5b, which is a prerequisite for the formation of TCC (Alachkar et al., 2012, Bauters et al., 2012, Daina et al., 2012, Keating et al., 2012, Ohanian et al., 2011, Vivarelli et al., 2012). This drug is now approved for treatment of PNH and aHUS, and is under investigation for treatment of other conditions where activation of the terminal pathway contributes to the pathogenesis. Since the number of therapeutically induced functional C5 deficiency patients most likely will increase in the future, it is particularly important to investigate if lack of C5 is associated with other adverse conditions than the reported association with Neisseria infections. Information about this could come directly from studies of eculizumab-treated patients, but the primary disease may interfere and blur the results. Therefore, clinical review of congenital C5 deficiency is an important contribution to this knowledge. In previous case reports invasive meningococcal infections is the major clinical symptom, but pneumonia (Fijen et al., 1999, Delgado-Cervino et al., 2005, Rosenfeld et al., 1976), otitis media (Fijen et al., 1999, Aguilar-Ramirez et al., 2009, Rosenfeld et al., 1976, Sanal et al., 1992) and discoid or systemic lupus erythematosus (Asghar et al., 1991, Rosenfeld et al., 1976), have been reported in some patients. Complement C5 deficiency has been reported in more than 50 individuals, but the molecular basis has only been reported in 8 families previously.
Here we present the molecular diagnosis of two C5 deficient families, review the history of infections and compare the infection rate with the healthy relatives.
Section snippets
Family A
The proband in family A was previously included in a functional study of the role of C5 in bacterial killing (Lappegard et al. 2009). She is now 49 years old and was diagnosed with C5 deficiency after her second episode of invasive Neisserial meningococcal infection 12 years old. Both of her parents originated from Norway and are not known to be related. She has three brothers, three sisters and two sons. One sister died at the age of three years from bacterial meningitis. One of the brothers
Complement activation and protein determination
In the probands an absence of complement deposition in all three pathways was found, leading to the suspicion of a terminal complement factor deficiency. The diagnosis of C5 deficiency was subsequently confirmed by undetectable levels of C5 and normal levels of other terminal complement factors (Table 1).
Family A
Analysis of cDNA fragments in family A (the Norwegian family) showed no amplification of the fragment F4 spanning exons 20–27 and lack of exon 27 sequence in fragment F5 spanning exons 26–36 To
Discussion
Pre-mRNA miss-splicing has been described as the molecular basis of many different monogenic diseases and may even have been overlooked as the cause of disease in studies focusing only on DNA sequencing (Novoyatleva et al. 2006). With the data presented here, the molecular basis of hereditary complement C5 deficiency has been described in 11 families (Aguilar-Ramirez et al., 2009, Arnaout et al., 2013, Cheng et al., 2012, Delgado-Cervino et al., 2005, Lopez-Lera et al., 2009, Pfarr et al., 2005
Acknowledgements
This study was supported by the Odd Fellow Foundation, Novo Nordisk Research Foundation, The Capital Region of Denmark, The Svend Andersen Research Foundation and Rigshospitalet.
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