NCF4 dependent intracellular reactive oxygen species regulate plasma cell formation
Chang He,
Huqiao Luo,
Ana Coelho,
Meng Liu,
Qijing Li,
Jing Xu,
Alexander Krämer,
Stephen Malin,
Zuyi Yuan,
Rikard Holmdahl
Affiliations
Chang He
Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, PR China; Division of Medical Inflammation Research, Department of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden; Department of Cardiovascular Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, PR China
Huqiao Luo
Division of Medical Inflammation Research, Department of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden
Ana Coelho
Division of Medical Inflammation Research, Department of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden
Meng Liu
Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, PR China; Division of Medical Inflammation Research, Department of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden; National Joint Engineering Research Center of Biodiagnostics and Biotherapy, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, PR China
Qijing Li
Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, PR China; Division of Medical Inflammation Research, Department of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden; Department of Hematology, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, PR China
Jing Xu
Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, PR China
Alexander Krämer
Division of Medical Inflammation Research, Department of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden
Stephen Malin
Department of Medicine Solna (MedS) Center for Molecular Medicine, Karolinska Institute, Stockholm, Sweden
Zuyi Yuan
Department of Cardiovascular Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, PR China
Rikard Holmdahl
Division of Medical Inflammation Research, Department of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden; National Joint Engineering Research Center of Biodiagnostics and Biotherapy, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, PR China; Corresponding author. Division of Medical Inflammation Research, Dept. of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden.
Defective reactive oxygen species (ROS) production by genetically determined variants of the NADPH oxidase 2 (NOX2) complex component, NCF4, leads to enhanced production of autoantibodies to collagen type II (COL2) and severe collagen-induced arthritis (CIA) in mice. To further understand this process, we used mice harboring a mutation in the lipid endosomal membrane binding site (R58A) of NCF4 subunit. This mutation did not affect the extracellular ROS responses but showed instead decreased intracellular responses following B cell stimulation. Immunization with COL2 led to severe arthritis with increased antibody levels in Ncf458A mutated animals without significant effects on antigen presentation, autoreactive T cell activation and germinal center formation. Instead, plasma cell formation was enhanced and had altered CXCR3/CXCR4 expression. This B cell intrinsic effect was further confirmed with chimeric B cell transfer experiments and in vitro LPS or CD40L with anti-IgM stimulation. We conclude that NCF4 regulates the terminal differentiation of B cells to plasma cells through intracellular ROS.
