Activation of the ficolin-lectin pathway during attacks of hereditary angioedema

J Allergy Clin Immunol. 2014 Dec;134(6):1388-1393.e1. doi: 10.1016/j.jaci.2014.05.030. Epub 2014 Jul 16.

Abstract

Background: The activation of plasma enzyme systems is insufficiently controlled in hereditary angioedema due to the deficiency of C1-inhibitor (C1-INH) (HAE-C1-INH). Recently, it was suggested that the ficolin-lectin pathway (ficolin-LP) might play a more dominant role than the mannose-binding lectin-lectin pathway in the pathomechanism of HAE-C1-INH.

Objective: Because the role of the ficolin-LP during edematous attacks is still enigmatic, we analyzed its activity during such episodes.

Methods: Thirty-five patients with HAE-C1-INH, who have experienced severe attacks on 106 occasions, were enrolled. We analyzed blood samples drawn during attacks, and obtained 35 samples from the same patients during symptom-free periods. The serum levels of ficolin-2, ficolin-3, MASP-2, ficolin-3/MASP-2 complex, C1-INH, and C4, as well as the extent of ficolin-3-mediated terminal complement complex (FCN3-TCC) deposition, were measured using ELISA-based methods.

Results: Levels of MASP-2 and of the ficolin-3/MASP-2 complex were elevated (P < .0001 and .033, respectively), whereas that of FCN3-TCC was lower (P < .0001) during attacks than during the symptom-free period. During symptom-free periods, FCN3-TCC deposition was significantly related to concentrations of ficolin-3 (R = 0.2778; P = .0022), antigenic C1-INH (R = 0.3152; P = .0006), and C4 (R = 0.5307; P < .0001). Both ficolin-3 and MASP-2 levels correlated inversely with the time from the onset of the attack until blood sampling.

Conclusions: There is a marked heterogeneity of the pathomechanism and development of hereditary angioedema attacks in different patients. Our results suggest that the activation of the ficolin-LP may deplete the innately low level of C1-INH and thus, it may contribute to the uncontrolled activation of plasma cascade systems, and thereby to edema formation.

Keywords: C1-inhibitor; Hereditary angioedema; MASPs; edematous attack; ficolins; lectin pathway.

MeSH terms

  • Adult
  • Angioedemas, Hereditary / blood*
  • Complement C1 Inhibitor Protein / metabolism
  • Complement C4 / metabolism
  • Female
  • Ficolins
  • Glycoproteins / blood*
  • Humans
  • Lectins / blood*
  • Male
  • Mannose-Binding Protein-Associated Serine Proteases / metabolism*
  • Middle Aged
  • Signal Transduction
  • Young Adult

Substances

  • Complement C1 Inhibitor Protein
  • Complement C4
  • FCN3 protein, human
  • Glycoproteins
  • Lectins
  • MASP2 protein, human
  • Mannose-Binding Protein-Associated Serine Proteases