title: Defects in Germinal Center Selection in SLE.
abstract: Germinal centers (GCs) are the primary site at which clonal expansion and affinity maturation of B cells occur. B cells encounter antigen and receive T cell help in the GC light zone (LZ) and then migrate to the dark zone where they proliferate and undergo somatic mutation before cycling back to the LZ for further rounds of selection. Tolerance to autoantigens is frequently lost de novo as GC B cells undergo class switching and somatic mutation. This loss of tolerance is regulated by a variety of mechanisms including cell death, failure to compete for T cell help, and failure to differentiate into effector cells. Systemic lupus erythematosus (SLE) is characterized by loss of tolerance to nucleic acid antigens. While defects in tolerance occur in the naïve repertoire of SLE patients, pathogenic autoantibodies also arise in the GC by somatic mutation from non-autoreactive precursors. Several B cell defects contribute to the loss of GC tolerance in SLE, including polymorphisms of genes encoded by the Sle1 locus, excess TLR7 signaling, defects in FcRIIB expression, or defects of B cell apoptosis. Extrinsic soluble factors, such as Type-1 IFN and B cell-activating factor, or an increased number of T follicular helper cells in the GC also alter B cell-negative selection. Finally, defects in clearance of apoptotic debris within the GC result in BCR-mediated internalization of nucleic acid containing material and stimulation of autoantibody production by endosomal TLR-driven mechanisms.
authors: Center for Autoimmunity and Musculoskeletal Diseases, Feinstein Institute for Medical Research , New York, NY , USA.
authors: Megan
authors: M
authors: Woods
authors: Center for Autoimmunity and Musculoskeletal Diseases, Feinstein Institute for Medical Research , New York, NY , USA.
authors: Yong-Rui
authors: YR
authors: Zou
authors: Center for Autoimmunity and Musculoskeletal Diseases, Feinstein Institute for Medical Research , New York, NY , USA.
authors: Anne
authors: A
authors: Davidson
keywords: B cell; SLE; autoimmunity; germinal center; tolerance mechanisms