Aberrant zonal recycling of germinal center B cells impairs appropriate selection in lupus
Gina M. Sanchez,
Eden S. Hirsch,
Arthur VanValkenburg,
Daniel P. Mayer,
Komi Gbedande,
Rebecca L. Francis,
Wenzhi Song,
Olivia Q. Antao,
Kyleigh E. Brimmer,
Alexander Lemenze,
Robin Stephens,
W. Evan Johnson,
Jason S. Weinstein
Affiliations
Gina M. Sanchez
Center for Immunity and Inflammation, Rutgers New Jersey Medical School, Newark, NJ 07103, USA
Eden S. Hirsch
Center for Immunity and Inflammation, Rutgers New Jersey Medical School, Newark, NJ 07103, USA
Arthur VanValkenburg
Division of Infectious Diseases, Department of Medicine, Rutgers New Jersey Medical School, Newark, NJ 07103, USA
Daniel P. Mayer
Center for Immunity and Inflammation, Rutgers New Jersey Medical School, Newark, NJ 07103, USA
Komi Gbedande
Center for Immunity and Inflammation, Rutgers New Jersey Medical School, Newark, NJ 07103, USA
Rebecca L. Francis
Center for Immunity and Inflammation, Rutgers New Jersey Medical School, Newark, NJ 07103, USA
Wenzhi Song
Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA; Robin Chemers Neustein Laboratory of Mammalian Cell Biology and Development, The Rockefeller University, New York, NY 10065, USA
Olivia Q. Antao
Center for Immunity and Inflammation, Rutgers New Jersey Medical School, Newark, NJ 07103, USA
Kyleigh E. Brimmer
Center for Immunity and Inflammation, Rutgers New Jersey Medical School, Newark, NJ 07103, USA
Alexander Lemenze
Center for Immunity and Inflammation, Rutgers New Jersey Medical School, Newark, NJ 07103, USA
Robin Stephens
Center for Immunity and Inflammation, Rutgers New Jersey Medical School, Newark, NJ 07103, USA
W. Evan Johnson
Division of Infectious Diseases, Department of Medicine, Rutgers New Jersey Medical School, Newark, NJ 07103, USA
Jason S. Weinstein
Center for Immunity and Inflammation, Rutgers New Jersey Medical School, Newark, NJ 07103, USA; Corresponding author
Summary: Autoimmune diseases such as lupus are characterized by polyclonal B cell activation, leading to the production of autoantibodies. The mechanism leading to B cell dysregulation is unclear; however, the defect may lie in selection within germinal centers (GCs). GC B cells cycle between proliferation and mutation in the dark zone and selection in the light zone (LZ). Temporal assessment of GCs from mice with either persistent infection or lupus showed an accumulation of LZ B cells. Yet, only in lupus, GC B cells exhibited reduced proliferation and progressive loss of MYC and FOXO1, which regulate zonal recycling and differentiation. As lupus progressed, decreased mutational frequency and repertoire diversity were associated with reduced responsiveness to CD40 signaling, despite accumulation of plasma cells. Collectively, these findings suggest that lupus disease progression coincides with an intrinsic defect in LZ B cell signaling, altering the zonal recycling, selection, and differentiation of autoreactive B cells.
