Requirement for complement in antibody responses is not explained by the classic pathway activator IgM

Abstract

Animals lacking complement factors C1q, C2, C3, or C4 have severely impaired Ab responses, suggesting a major role for the classic pathway. The classic pathway is primarily initiated by antigen–Ab complexes. Therefore, its role for primary Ab responses seems paradoxical because only low amounts of specific Abs are present in naive animals. A possible explanation could be that the classic pathway is initiated by IgM from naive mice, binding with sufficient avidity to the antigen. To test this hypothesis, a knock-in mouse strain, Cμ13, with a point mutation in the gene encoding the third constant domain of the μ-heavy chain was constructed. These mice produce IgM in which proline in position 436 is substituted with serine, a mutation previously shown to abrogate the ability of mouse IgM to activate complement. Unexpectedly, the Ab response to sheep erythrocytes and keyhole limpet hemocyanin in Cμ13 mice was similar to that in WT mice. Thus, although secreted IgM and the classic pathway activation are both required for the normal primary Ab response, this does not require that IgM activate C. This led us to test Ab responses in animals lacking one of three other endogenous activators of the classic pathway: specific intracellular adhesion molecule-grabbing nonintegrin R1, serum amyloid P component, and C-reactive protein. Ab responses were also normal in these animals.

Innate Immunity Mediates Follicular Transport of Particulate but Not Soluble Protein Antigen

“…Mice lacking complement-activating IgM, owing to a point mutation in the m H chain, showed a normal Ab response to sheep RBCs (48). Upon injection of specific IgM Abs, other mechanisms besides classical pathway activation might therefore also play a role for IgM-mediated Ag trafficking despite the requirement for C1q.…”

Absence of surrogate light chain results in spontaneous autoreactive germinal centres expanding VH81X-expressing B cells

“…SRBCs in sterile Alsever's solution were purchased from the National Veterinary Institute (HåtunaLab, Bro, Sweden) and stored at 4°C. SRBCs were washed in PBS three times before immunizing control mice with 5 Â 10 8 cells in 0.2 ml PBS in the tail vein 65 .…”

Critical role of the IgM Fc receptor in IgM homeostasis, B-cell survival, and humoral immune responses

“…Earlier studies suggested that IgM-mediated enhancement of antibody production was dependent on activation of the classic complement pathway (5). However, a very recent report demonstrated that mice expressing IgM unable to activate complement (Cμ13 mice) had completely normal antibody production (9). Collectively, these observations suggest that much of the effector function of IgM, especially with regard to the enhancement of humoral immune responses and suppression of autoimmunity, is mediated through FcμR.…”

“…It was proposed that IgM-antigen immune complexes enhanced B-cell survival by interacting with both B-cell receptor (BCR) and the complement receptor (CR) on B cells (2,8). However, very recently, knock-in mice expressing mutant IgM unable to activate complement were found to have completely normal antibody responses (9). Therefore, IgM-mediated enhancement of antibody production cannot be solely explained by activation of the classic complement pathway, and additional mechanisms are likely involved.…”