Complement C4 maintains peripheral B-cell tolerance in a myeloid cell dependent manner

Eur J Immunol. 2013 Sep;43(9):2441-2450. doi: 10.1002/eji.201343412. Epub 2013 Jul 3.


The factors that allow self-reactive B cells to escape negative selection and become activated remain poorly defined. Using a BCR knock-in mouse strain, we identify a pathway by which B-cell selection to nucleolar self-antigens is complement dependent. Deficiency in complement component C4 led to a breakdown in the elimination of autoreactive B-cell clones at the transitional stage, characterized by a relative increase in their response to a range of stimuli, entrance into follicles, and a greater propensity to form self-reactive GCs. Using mixed BM chimeras, we found that the myeloid compartment was sufficient to restore negative selection in the autoreactive mice. A model is proposed in which in the absence of complement C4, inappropriate clearance of apoptotic debris promotes chronic activation of myeloid cells, allowing the maturation and activation of self-reactive B-cell clones leading to increased spontaneous formation of GCs.

Keywords: Autoimmunity; Germinal center; Lupus nucleolar antigen; Negative selection.

Publication types

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

MeSH terms

  • Animals
  • Apoptosis
  • Autoantigens / immunology
  • Autoimmunity
  • B-Lymphocytes / immunology*
  • B-Lymphocytes / metabolism
  • Bone Marrow Cells / immunology
  • Complement C4 / deficiency
  • Complement C4 / genetics
  • Complement C4 / immunology*
  • Immune Tolerance*
  • Lupus Erythematosus, Systemic / immunology
  • Lymphocyte Activation
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Myeloid Cells / immunology
  • Nucleolus Organizer Region / immunology
  • Receptors, Antigen, B-Cell / genetics
  • Ribonucleoproteins / immunology*


  • Autoantigens
  • C4b protein, mouse
  • Complement C4
  • Receptors, Antigen, B-Cell
  • Ribonucleoproteins