TY - JOUR
T1 - The Influence of Human IgG Subclass and Allotype on Complement Activation
AU - Damelang, Timon
AU - de Taeye, Steven W
AU - Rentenaar, Rosa
AU - Roya-Kouchaki, Kasra
AU - de Boer, Esther
AU - Derksen, Ninotska I L
AU - van Kessel, Kok
AU - Lissenberg-Thunnissen, Suzanne
AU - Rooijakkers, Suzan H M
AU - Jongerius, Ilse
AU - Mebius, Mirjam M
AU - Schuurman, Janine
AU - Labrijn, Aran F
AU - Vidarsson, Gestur
AU - Rispens, Theo
N1 - Funding Information: This work was supported by Genmab (to T.D. and S.W.d.T.). Publisher Copyright: © 2023 American Association of Immunologists. All rights reserved.
PY - 2023/12/1
Y1 - 2023/12/1
N2 - Complement activation via the classical pathway is initiated when oligomeric Igs on target surfaces are recognized by C1 of the complement cascade. The strength of this interaction and activation of the complement system are influenced by structural variation of the Ab, including Ab isotype, subclass, and glycosylation profile. Polymorphic variants of IgG have also been described to influence Fc-dependent effector functions. Therefore, we assessed complement binding, deposition, and complement-dependent cytotoxicity (CDC) of 27 known IgG allotypes with anti-trinitrophenyl specificity. Differences between allotypes within subclasses were minor for IgG1, IgG3, and IgG4 allotypes, and more substantial for IgG2. Allelic variant IGHG2*06, containing a unique serine at position 378 in the CH3 domain, showed less efficient complement activation and CDC compared with other IgG2 polymorphisms. We also observed variable cell lysis between IgG1 and IgG3, with IgG3 being superior in lysis of human RBCs and Ramos cells, and IgG1 being superior in lysis of Raji and Wien133 cells, demonstrating that a long-standing conundrum in the literature depends on cellular context. Furthermore, we compared IgG1 and IgG3 under different circumstances, showing that Ag density and Ab hinge length, but not complement regulators, define the context dependency of Ab-mediated CDC activity. Our results point toward a variation in the capacity of IgG subclasses to activate complement due to single amino acid changes and hinge length differences of allotypes to activate complement, which might give new insights on susceptibility to infectious, alloimmune, or autoimmune diseases and aid the design of Ab-based therapeutics. The Journal of Immunology, 2023, 211: 1725-1735.
AB - Complement activation via the classical pathway is initiated when oligomeric Igs on target surfaces are recognized by C1 of the complement cascade. The strength of this interaction and activation of the complement system are influenced by structural variation of the Ab, including Ab isotype, subclass, and glycosylation profile. Polymorphic variants of IgG have also been described to influence Fc-dependent effector functions. Therefore, we assessed complement binding, deposition, and complement-dependent cytotoxicity (CDC) of 27 known IgG allotypes with anti-trinitrophenyl specificity. Differences between allotypes within subclasses were minor for IgG1, IgG3, and IgG4 allotypes, and more substantial for IgG2. Allelic variant IGHG2*06, containing a unique serine at position 378 in the CH3 domain, showed less efficient complement activation and CDC compared with other IgG2 polymorphisms. We also observed variable cell lysis between IgG1 and IgG3, with IgG3 being superior in lysis of human RBCs and Ramos cells, and IgG1 being superior in lysis of Raji and Wien133 cells, demonstrating that a long-standing conundrum in the literature depends on cellular context. Furthermore, we compared IgG1 and IgG3 under different circumstances, showing that Ag density and Ab hinge length, but not complement regulators, define the context dependency of Ab-mediated CDC activity. Our results point toward a variation in the capacity of IgG subclasses to activate complement due to single amino acid changes and hinge length differences of allotypes to activate complement, which might give new insights on susceptibility to infectious, alloimmune, or autoimmune diseases and aid the design of Ab-based therapeutics. The Journal of Immunology, 2023, 211: 1725-1735.
KW - Complement Activation
KW - Glycosylation
KW - Humans
KW - Immunoglobulin G
UR - http://www.scopus.com/inward/record.url?scp=85178540057&partnerID=8YFLogxK
U2 - https://doi.org/10.4049/jimmunol.2300307
DO - https://doi.org/10.4049/jimmunol.2300307
M3 - Article
C2 - 37843500
SN - 0022-1767
VL - 211
SP - 1725
EP - 1735
JO - Journal of immunology (Baltimore, Md.
JF - Journal of immunology (Baltimore, Md.
IS - 11
ER -