TY - JOUR
T1 - The contribution of the alternative pathway in complement activation on cell surfaces depends on the strength of classical pathway initiation
AU - de Boer, Esther C. W.
AU - Thielen, Astrid J. F.
AU - Langereis, Jeroen D.
AU - Kamp, Angela
AU - Brouwer, Mieke C.
AU - Oskam, Nienke
AU - Jongsma, Marlieke L.
AU - Baral, April J.
AU - Spaapen, Robbert M.
AU - Zeerleder, Sacha
AU - Vidarsson, Gestur
AU - Rispens, Theo
AU - Wouters, Diana
AU - Pouw, Richard B.
AU - Jongerius, Ilse
N1 - Funding Information: This work was supported by internal grants of Sanquin (PPOC-12-038-PRG and PPOC-19-25/L2476) and part of the research programme Aspasia with project number 015.014.069, which is (partially) financed by the Netherlands Organisation for Scientific Research (NWO) to IJ. RMS was supported by an NWO-VENI personal grant (016.131.047). We kindly thank prof. Claire Harris for providing us with the FH62V. Funding Information: This work was supported by internal grants of Sanquin (PPOC‐12‐038‐PRG and PPOC‐19‐25/L2476) and part of the research programme Aspasia with project number 015.014.069, which is (partially) financed by the Netherlands Organisation for Scientific Research (NWO) to IJ. RMS was supported by an NWO‐VENI personal grant (016.131.047). We kindly thank prof. Claire Harris for providing us with the FH. 62V Publisher Copyright: © 2023 The Authors. Clinical & Translational Immunology published by John Wiley & Sons Australia, Ltd on behalf of Australian and New Zealand Society for Immunology, Inc.
PY - 2023
Y1 - 2023
N2 - Objectives: The complement system is an important component of?innate immunity. The alternative pathway (AP) amplification loop is considered an essential feed forward mechanism for complement activation. However, the role of the AP in classical pathway (CP) activation has only been studied in ELISA settings. Here, we investigated its contribution on physiologically relevant surfaces of human cells and bacterial pathogens and in antibody-mediated complement activation, including in autoimmune haemolytic anaemia (AIHA) setting with autoantibodies against red blood cells (RBCs). Methods: We evaluated the contribution of the AP to complement responses initiated through the CP on human RBCs by serum of AIHA patients and recombinant antibodies. Moreover, we studied complement activation on Neisseria meningitidis and Escherichia coli. The effect of the AP was examined using either AP-depleted sera or antibodies against factor B and factor D. Results: We show that the amplification loop is redundant when efficient CP activation takes place. This is independent of the presence of membrane-bound complement regulators. The role of the AP may become significant when insufficient CP complement activation occurs, but this depends on antibody levels and (sub)class. Our data indicate that therapeutic intervention in the amplification loop will most likely not be effective to treat antibody-mediated diseases. Conclusion: The AP can be bypassed through efficient CP activation. The AP amplification loop has a role in complement activation during conditions of modest activation via the CP, when it can allow for efficient complement-mediated killing.
AB - Objectives: The complement system is an important component of?innate immunity. The alternative pathway (AP) amplification loop is considered an essential feed forward mechanism for complement activation. However, the role of the AP in classical pathway (CP) activation has only been studied in ELISA settings. Here, we investigated its contribution on physiologically relevant surfaces of human cells and bacterial pathogens and in antibody-mediated complement activation, including in autoimmune haemolytic anaemia (AIHA) setting with autoantibodies against red blood cells (RBCs). Methods: We evaluated the contribution of the AP to complement responses initiated through the CP on human RBCs by serum of AIHA patients and recombinant antibodies. Moreover, we studied complement activation on Neisseria meningitidis and Escherichia coli. The effect of the AP was examined using either AP-depleted sera or antibodies against factor B and factor D. Results: We show that the amplification loop is redundant when efficient CP activation takes place. This is independent of the presence of membrane-bound complement regulators. The role of the AP may become significant when insufficient CP complement activation occurs, but this depends on antibody levels and (sub)class. Our data indicate that therapeutic intervention in the amplification loop will most likely not be effective to treat antibody-mediated diseases. Conclusion: The AP can be bypassed through efficient CP activation. The AP amplification loop has a role in complement activation during conditions of modest activation via the CP, when it can allow for efficient complement-mediated killing.
KW - alternative pathway
KW - amplification loop
KW - antibodies
KW - autoimmune haemolytic anaemia
KW - classical pathway
KW - complement activation
UR - http://www.scopus.com/inward/record.url?scp=85147099019&partnerID=8YFLogxK
U2 - https://doi.org/10.1002/cti2.1436
DO - https://doi.org/10.1002/cti2.1436
M3 - Article
C2 - 36721662
SN - 2050-0068
VL - 12
JO - Clinical & translational immunology
JF - Clinical & translational immunology
IS - 1
M1 - e1436
ER -