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

Dorottya Csuka; Lea Munthe-Fog; Estrid Hein; Zsuzsanna Zotter; Zoltán Prohászka; Henriette Farkas; Lilian Varga; Peter Garred

doi:10.1016/j.jaci.2014.05.030

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

Dorottya Csuka, Lea Munthe-Fog, Estrid Hein, Zsuzsanna Zotter, Zoltán Prohászka, Henriette Farkas, Lilian Varga, Peter Garred

Department of Clinical Medicine

13 Citations (Scopus)

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.

Original language	English
Journal	The Journal of allergy and clinical immunology
Volume	134
Issue number	6
Pages (from-to)	1388–1393.e1
ISSN	0091-6749
DOIs	https://doi.org/10.1016/j.jaci.2014.05.030
Publication status	Published - 1 Dec 2014

Keywords

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

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10.1016/j.jaci.2014.05.030

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@article{f7523c19a8ee475398e79bd4368f0b9b,

title = "Activation of the ficolin-lectin pathway during attacks of hereditary angioedema",

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 = "Adult, Angioedemas, Hereditary, Complement C1 Inhibitor Protein, Complement C4, Female, Glycoproteins, Humans, Lectins, Male, Mannose-Binding Protein-Associated Serine Proteases, Middle Aged, Signal Transduction, Young Adult",

author = "Dorottya Csuka and Lea Munthe-Fog and Estrid Hein and Zsuzsanna Zotter and Zolt{\'a}n Proh{\'a}szka and Henriette Farkas and Lilian Varga and Peter Garred",

year = "2014",

month = dec,

day = "1",

doi = "10.1016/j.jaci.2014.05.030",

language = "English",

volume = "134",

pages = "1388–1393.e1",

journal = "Journal of Allergy and Clinical Immunology",

issn = "0091-6749",

publisher = "Mosby Inc.",

number = "6",

}

TY - JOUR

T1 - Activation of the ficolin-lectin pathway during attacks of hereditary angioedema

AU - Csuka, Dorottya

AU - Munthe-Fog, Lea

AU - Hein, Estrid

AU - Zotter, Zsuzsanna

AU - Prohászka, Zoltán

AU - Farkas, Henriette

AU - Varga, Lilian

AU - Garred, Peter

PY - 2014/12/1

Y1 - 2014/12/1

N2 - 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.

AB - 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.

KW - Adult

KW - Angioedemas, Hereditary

KW - Complement C1 Inhibitor Protein

KW - Complement C4

KW - Female

KW - Glycoproteins

KW - Humans

KW - Lectins

KW - Male

KW - Mannose-Binding Protein-Associated Serine Proteases

KW - Middle Aged

KW - Signal Transduction

KW - Young Adult

U2 - 10.1016/j.jaci.2014.05.030

DO - 10.1016/j.jaci.2014.05.030

M3 - Journal article

C2 - 25042985

SN - 0091-6749

VL - 134

SP - 1388–1393.e1

JO - Journal of Allergy and Clinical Immunology

JF - Journal of Allergy and Clinical Immunology

IS - 6

ER -

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

Abstract

Keywords

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