Complement C4A Regulates Autoreactive B Cells in Murine Lupus

• Main Authors: Léa Simoni, Jessy Presumey, Cees E. van der Poel, Carlos Castrillon, Sarah E. Chang, Paul J. Utz, Michael C. Carroll
• Format: Article
• Language: English
• Published: Elsevier 2020-11-01
• Series: Cell Reports
• Subjects: Complement C4; SLE; B cell tolerance; Murine model
• Online Access: http://www.sciencedirect.com/science/article/pii/S221112472031319X
• ISSN: 2211-1247

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.