Complement C4A Regulates Autoreactive B Cells in Murine Lupus
Léa Simoni,
Jessy Presumey,
Cees E. van der Poel,
Carlos Castrillon,
Sarah E. Chang,
Paul J. Utz,
Michael C. Carroll
Affiliations
Léa Simoni
Program in Cellular and Molecular Medicine, Boston Children’s Hospital, Boston, MA 02115, USA
Jessy Presumey
Program in Cellular and Molecular Medicine, Boston Children’s Hospital, Boston, MA 02115, USA
Cees E. van der Poel
Program in Cellular and Molecular Medicine, Boston Children’s Hospital, Boston, MA 02115, USA
Carlos Castrillon
Program in Cellular and Molecular Medicine, Boston Children’s Hospital, Boston, MA 02115, USA
Sarah E. Chang
Department of Medicine, Division of Immunology, and Institute for Immunity Transplantation and Infection, Stanford University School of Medicine, Stanford, CA 94305, USA
Paul J. Utz
Department of Medicine, Division of Immunology, and Institute for Immunity Transplantation and Infection, Stanford University School of Medicine, Stanford, CA 94305, USA
Michael C. Carroll
Program in Cellular and Molecular Medicine, Boston Children’s Hospital, Boston, MA 02115, USA; Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA; Corresponding author
Summary: Systemic lupus erythematosus (SLE) is a severe autoimmune disease mediated by pathogenic autoantibodies. While complement protein C4 is associated with SLE, its isoforms (C4A and C4B) are not equal in their impact. Despite being 99% homologous, genetic studies identified C4A as more protective than C4B. By generating gene-edited mouse strains expressing either human C4A or C4B and crossing these with the 564lgi lupus strain, we show that, overall, C4A-like 564Igi mice develop less humoral autoimmunity than C4B-like 564Igi mice. This includes a decrease in the number of GCs, autoreactive B cells, autoantibodies, and memory B cells. The higher efficiency of C4A in inducing self-antigen clearance is associated with the follicular exclusion of autoreactive B cells. These results explain how the C4A isoform is protective in lupus and suggest C4A as a possible replacement therapy in lupus.
