Human genetic deficiencies reveal the roles of complement in the inflammatory network: lessons from nature

Knut Tore Lappegård; Dorte Christiansen; Anne Pharo; Ebbe Billmann Thorgersen; Bernt Christian Hellerud; Julie Lindstad; Erik Waage Nielsen; Grethe Bergseth; Dag Fadnes; Tore G Abrahamsen; E Arne Høiby; Lone Schejbel; Peter Garred; John D Lambris; Morten Harboe; Tom Eirik Mollnes

doi:10.1073/pnas.0903613106

Human genetic deficiencies reveal the roles of complement in the inflammatory network: lessons from nature

Knut Tore Lappegård, Dorte Christiansen, Anne Pharo, Ebbe Billmann Thorgersen, Bernt Christian Hellerud, Julie Lindstad, Erik Waage Nielsen, Grethe Bergseth, Dag Fadnes, Tore G Abrahamsen, E Arne Høiby, Lone Schejbel, Peter Garred, John D Lambris, Morten Harboe, Tom Eirik Mollnes

98 Citations (Scopus)

Abstract

Complement component C5 is crucial for experimental animal inflammatory tissue damage; however, its involvement in human inflammation is incompletely understood. The responses to gram-negative bacteria were here studied taking advantage of human genetic complement-deficiencies--nature's own knockouts--including a previously undescribed C5 defect. Such deficiencies provide a unique tool for investigating the biological role of proteins. The experimental conditions allowed cross-talk between the different inflammatory pathways using a whole blood model based on the anticoagulant lepirudin, which does not interfere with the complement system. Expression of tissue factor, cell adhesion molecules, and oxidative burst depended highly on C5, mediated through the activation product C5a, whereas granulocyte enzyme release relied mainly on C3 and was C5a-independent. Release of cytokines and chemokines was mediated to varying degrees by complement and CD14; for example, interleukin (IL)-1beta and IL-8 were more dependent on complement than IFN-gamma and IL-6, which were highly dependent on CD14. IL-1 receptor antagonist (IL-1ra) and IFN-gamma inducible protein 10 (IP-10) were fully dependent on CD14 and inversely regulated by complement, that is, complement deficiency and complement inhibition enhanced their release. Granulocyte responses were mainly complement-dependent, whereas monocyte responses were more dependent on CD14. Notably, all responses were abolished by combined neutralization of complement and CD14. The present study provides important insight into the comprehensive role of complement in human inflammatory responses to gram-negative bacteria.

Original language	English
Journal	Proceedings of the National Academy of Science of the United States of America
Volume	106
Issue number	37
Pages (from-to)	15861-6
Number of pages	6
ISSN	0027-8424
DOIs	https://doi.org/10.1073/pnas.0903613106
Publication status	Published - 2009

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10.1073/pnas.0903613106

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Lappegård, K. T., Christiansen, D., Pharo, A., Thorgersen, E. B., Hellerud, B. C., Lindstad, J., Nielsen, E. W., Bergseth, G., Fadnes, D., Abrahamsen, T. G., Høiby, E. A., Schejbel, L., Garred, P., Lambris, J. D., Harboe, M., & Mollnes, T. E. (2009). Human genetic deficiencies reveal the roles of complement in the inflammatory network: lessons from nature. Proceedings of the National Academy of Science of the United States of America, 106(37), 15861-6. https://doi.org/10.1073/pnas.0903613106

Human genetic deficiencies reveal the roles of complement in the inflammatory network: lessons from nature. / Lappegård, Knut Tore; Christiansen, Dorte; Pharo, Anne et al.

In: Proceedings of the National Academy of Science of the United States of America, Vol. 106, No. 37, 2009, p. 15861-6.

Research output: Contribution to journal › Journal article › Research › peer-review

Lappegård, KT, Christiansen, D, Pharo, A, Thorgersen, EB, Hellerud, BC, Lindstad, J, Nielsen, EW, Bergseth, G, Fadnes, D, Abrahamsen, TG, Høiby, EA, Schejbel, L, Garred, P, Lambris, JD, Harboe, M & Mollnes, TE 2009, 'Human genetic deficiencies reveal the roles of complement in the inflammatory network: lessons from nature', Proceedings of the National Academy of Science of the United States of America, vol. 106, no. 37, pp. 15861-6. https://doi.org/10.1073/pnas.0903613106

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title = "Human genetic deficiencies reveal the roles of complement in the inflammatory network: lessons from nature",

abstract = "Complement component C5 is crucial for experimental animal inflammatory tissue damage; however, its involvement in human inflammation is incompletely understood. The responses to gram-negative bacteria were here studied taking advantage of human genetic complement-deficiencies--nature's own knockouts--including a previously undescribed C5 defect. Such deficiencies provide a unique tool for investigating the biological role of proteins. The experimental conditions allowed cross-talk between the different inflammatory pathways using a whole blood model based on the anticoagulant lepirudin, which does not interfere with the complement system. Expression of tissue factor, cell adhesion molecules, and oxidative burst depended highly on C5, mediated through the activation product C5a, whereas granulocyte enzyme release relied mainly on C3 and was C5a-independent. Release of cytokines and chemokines was mediated to varying degrees by complement and CD14; for example, interleukin (IL)-1beta and IL-8 were more dependent on complement than IFN-gamma and IL-6, which were highly dependent on CD14. IL-1 receptor antagonist (IL-1ra) and IFN-gamma inducible protein 10 (IP-10) were fully dependent on CD14 and inversely regulated by complement, that is, complement deficiency and complement inhibition enhanced their release. Granulocyte responses were mainly complement-dependent, whereas monocyte responses were more dependent on CD14. Notably, all responses were abolished by combined neutralization of complement and CD14. The present study provides important insight into the comprehensive role of complement in human inflammatory responses to gram-negative bacteria.",

author = "Lappeg{\aa}rd, {Knut Tore} and Dorte Christiansen and Anne Pharo and Thorgersen, {Ebbe Billmann} and Hellerud, {Bernt Christian} and Julie Lindstad and Nielsen, {Erik Waage} and Grethe Bergseth and Dag Fadnes and Abrahamsen, {Tore G} and H{\o}iby, {E Arne} and Lone Schejbel and Peter Garred and Lambris, {John D} and Morten Harboe and Mollnes, {Tom Eirik}",

note = "Keywords: Adolescent; Adult; Antigens, CD14; Case-Control Studies; Cell Adhesion; Complement Activation; Complement C2; Complement C5; Complement System Proteins; Escherichia coli; Female; Gram-Negative Bacteria; Humans; Immunity, Innate; Inflammation; Male; Models, Immunological; Monocytes; Neisseria meningitidis; Phagocytosis; Respiratory Burst; Thromboplastin",

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T1 - Human genetic deficiencies reveal the roles of complement in the inflammatory network: lessons from nature

AU - Lappegård, Knut Tore

AU - Christiansen, Dorte

AU - Pharo, Anne

AU - Thorgersen, Ebbe Billmann

AU - Hellerud, Bernt Christian

AU - Lindstad, Julie

AU - Nielsen, Erik Waage

AU - Bergseth, Grethe

AU - Fadnes, Dag

AU - Abrahamsen, Tore G

AU - Høiby, E Arne

AU - Schejbel, Lone

AU - Garred, Peter

AU - Lambris, John D

AU - Harboe, Morten

AU - Mollnes, Tom Eirik

N1 - Keywords: Adolescent; Adult; Antigens, CD14; Case-Control Studies; Cell Adhesion; Complement Activation; Complement C2; Complement C5; Complement System Proteins; Escherichia coli; Female; Gram-Negative Bacteria; Humans; Immunity, Innate; Inflammation; Male; Models, Immunological; Monocytes; Neisseria meningitidis; Phagocytosis; Respiratory Burst; Thromboplastin

PY - 2009

Y1 - 2009

N2 - Complement component C5 is crucial for experimental animal inflammatory tissue damage; however, its involvement in human inflammation is incompletely understood. The responses to gram-negative bacteria were here studied taking advantage of human genetic complement-deficiencies--nature's own knockouts--including a previously undescribed C5 defect. Such deficiencies provide a unique tool for investigating the biological role of proteins. The experimental conditions allowed cross-talk between the different inflammatory pathways using a whole blood model based on the anticoagulant lepirudin, which does not interfere with the complement system. Expression of tissue factor, cell adhesion molecules, and oxidative burst depended highly on C5, mediated through the activation product C5a, whereas granulocyte enzyme release relied mainly on C3 and was C5a-independent. Release of cytokines and chemokines was mediated to varying degrees by complement and CD14; for example, interleukin (IL)-1beta and IL-8 were more dependent on complement than IFN-gamma and IL-6, which were highly dependent on CD14. IL-1 receptor antagonist (IL-1ra) and IFN-gamma inducible protein 10 (IP-10) were fully dependent on CD14 and inversely regulated by complement, that is, complement deficiency and complement inhibition enhanced their release. Granulocyte responses were mainly complement-dependent, whereas monocyte responses were more dependent on CD14. Notably, all responses were abolished by combined neutralization of complement and CD14. The present study provides important insight into the comprehensive role of complement in human inflammatory responses to gram-negative bacteria.

AB - Complement component C5 is crucial for experimental animal inflammatory tissue damage; however, its involvement in human inflammation is incompletely understood. The responses to gram-negative bacteria were here studied taking advantage of human genetic complement-deficiencies--nature's own knockouts--including a previously undescribed C5 defect. Such deficiencies provide a unique tool for investigating the biological role of proteins. The experimental conditions allowed cross-talk between the different inflammatory pathways using a whole blood model based on the anticoagulant lepirudin, which does not interfere with the complement system. Expression of tissue factor, cell adhesion molecules, and oxidative burst depended highly on C5, mediated through the activation product C5a, whereas granulocyte enzyme release relied mainly on C3 and was C5a-independent. Release of cytokines and chemokines was mediated to varying degrees by complement and CD14; for example, interleukin (IL)-1beta and IL-8 were more dependent on complement than IFN-gamma and IL-6, which were highly dependent on CD14. IL-1 receptor antagonist (IL-1ra) and IFN-gamma inducible protein 10 (IP-10) were fully dependent on CD14 and inversely regulated by complement, that is, complement deficiency and complement inhibition enhanced their release. Granulocyte responses were mainly complement-dependent, whereas monocyte responses were more dependent on CD14. Notably, all responses were abolished by combined neutralization of complement and CD14. The present study provides important insight into the comprehensive role of complement in human inflammatory responses to gram-negative bacteria.

U2 - 10.1073/pnas.0903613106

DO - 10.1073/pnas.0903613106

M3 - Journal article

C2 - 19717455

SN - 0027-8424

VL - 106

SP - 15861

EP - 15866

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

IS - 37

ER -

Human genetic deficiencies reveal the roles of complement in the inflammatory network: lessons from nature

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