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

Proc Natl Acad Sci U S A. 2011 Oct 25;108(43):E934-42. doi: 10.1073/pnas.1109831108. Epub 2011 Oct 10.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Monoclonal / immunology
  • Antibody Formation / immunology*
  • C-Reactive Protein / immunology
  • Chromatography, Agarose
  • Complement Pathway, Classical / immunology*
  • Complement System Proteins / immunology*
  • DNA Primers / genetics
  • Enzyme-Linked Immunosorbent Assay
  • Enzyme-Linked Immunospot Assay
  • Flow Cytometry
  • Gene Knock-In Techniques
  • Immunoglobulin mu-Chains / genetics
  • Immunoglobulin mu-Chains / immunology*
  • Mice
  • Mice, Inbred BALB C
  • Microscopy, Confocal
  • Mutation, Missense / genetics
  • Polymerase Chain Reaction
  • Serum Amyloid P-Component / immunology


  • Antibodies, Monoclonal
  • DNA Primers
  • Immunoglobulin mu-Chains
  • Serum Amyloid P-Component
  • Complement System Proteins
  • C-Reactive Protein