The down-stream effects of mannan-induced lectin complement pathway activation depend quantitatively on alternative pathway amplification
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The down-stream effects of mannan-induced lectin complement pathway activation depend quantitatively on alternative pathway amplification. / Harboe, Morten; Garred, Peter; Karlstrøm, Ellen; Lindstad, Julie K; Stahl, Gregory L; Mollnes, Tom Eirik.
I: Molecular Immunology, Bind 47, Nr. 2-3, 2009, s. 373-80.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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TY - JOUR
T1 - The down-stream effects of mannan-induced lectin complement pathway activation depend quantitatively on alternative pathway amplification
AU - Harboe, Morten
AU - Garred, Peter
AU - Karlstrøm, Ellen
AU - Lindstad, Julie K
AU - Stahl, Gregory L
AU - Mollnes, Tom Eirik
N1 - Keywords: Adolescent; Adult; Antibodies, Monoclonal; Complement C2; Complement C4b; Complement Factor D; Complement Membrane Attack Complex; Complement Pathway, Alternative; Humans; Male; Mannans; Mannose-Binding Lectin; Serum
PY - 2009
Y1 - 2009
N2 - Complement activation plays an important role in human pathophysiology. The effect of classical pathway activation is largely dependent on alternative pathway (AP) amplification, whereas the role of AP for the down-stream effect of mannan-induced lectin pathway (LP) activation is poorly understood. In normal human serum specific activation of LP was obtained after exposure to a wide concentration range of mannan on the solid phase. Reaction mechanisms in this system were delineated in inhibition experiments with monoclonal antibodies. Direct mannose-binding lectin (MBL) independent activation of AP was not observed even at high mannan concentrations since addition of the inhibiting anti-MBL mAb 3F8 completely abolished generation of the terminal C5b-9 complex (TCC). However, selective blockade of AP by anti-factor D inhibited more than 80% of TCC release into the fluid phase after LP activation showing that AP amplification is quantitatively responsible for the final effect of initial specific LP activation. TCC generation on the solid phase was distinctly but less inhibited by anti-fD. C2 bypass of the LP pathway could be demonstrated, and AP amplification was also essential during C2 bypass in LP as shown by complete inhibition of TCC generation in C2-deficient serum by anti-fD and anti-properdin antibodies. In conclusion, the down-stream effect of LP activation depends strongly on AP amplification in normal human serum and in the C2 bypass pathway.
AB - Complement activation plays an important role in human pathophysiology. The effect of classical pathway activation is largely dependent on alternative pathway (AP) amplification, whereas the role of AP for the down-stream effect of mannan-induced lectin pathway (LP) activation is poorly understood. In normal human serum specific activation of LP was obtained after exposure to a wide concentration range of mannan on the solid phase. Reaction mechanisms in this system were delineated in inhibition experiments with monoclonal antibodies. Direct mannose-binding lectin (MBL) independent activation of AP was not observed even at high mannan concentrations since addition of the inhibiting anti-MBL mAb 3F8 completely abolished generation of the terminal C5b-9 complex (TCC). However, selective blockade of AP by anti-factor D inhibited more than 80% of TCC release into the fluid phase after LP activation showing that AP amplification is quantitatively responsible for the final effect of initial specific LP activation. TCC generation on the solid phase was distinctly but less inhibited by anti-fD. C2 bypass of the LP pathway could be demonstrated, and AP amplification was also essential during C2 bypass in LP as shown by complete inhibition of TCC generation in C2-deficient serum by anti-fD and anti-properdin antibodies. In conclusion, the down-stream effect of LP activation depends strongly on AP amplification in normal human serum and in the C2 bypass pathway.
U2 - 10.1016/j.molimm.2009.09.005
DO - 10.1016/j.molimm.2009.09.005
M3 - Journal article
C2 - 19800125
VL - 47
SP - 373
EP - 380
JO - Molecular Immunology
JF - Molecular Immunology
SN - 0161-5890
IS - 2-3
ER -
ID: 19440209