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

Institut for Klinisk Medicin

13 Citationer (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.

Originalsprog	Engelsk
Tidsskrift	The Journal of allergy and clinical immunology
Vol/bind	134
Udgave nummer	6
Sider (fra-til)	1388–1393.e1
ISSN	0091-6749
DOI	https://doi.org/10.1016/j.jaci.2014.05.030
Status	Udgivet - 1 dec. 2014

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10.1016/j.jaci.2014.05.030

Citationsformater

@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

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