Germinal center exclusion of autoreactive B cells is defective in human systemic lupus erythematosus

J Clin Invest. 2005 Nov;115(11):3205-16. doi: 10.1172/JCI24179. Epub 2005 Oct 6.


Breach of B cell tolerance is central to the pathogenesis of systemic lupus erythematosus (SLE). However, how B cell tolerance is subverted in human SLE is poorly understood due to difficulties in identifying relevant autoreactive B cells and in obtaining lymphoid tissue. We have circumvented these limitations by using tonsil biopsies to study autoreactive B cells (9G4 B cells), whose regulation is abnormal in SLE. Here we show that 9G4 B cells are physiologically excluded during the early stages of the GC reaction before acquiring a centroblast phenotype. Furthermore, we provide evidence to indicate that an anergic response to B cell receptor stimulation may be responsible for such behavior. In contrast, in SLE, 9G4 B cells progressed unimpeded through this checkpoint, successfully participated in GC reactions, and expanded within the post-GC IgG memory and plasma cell compartments. The faulty regulation of 9G4 B cells was not shared by RA patients. To our knowledge, this work represents the first comparative analysis of the fate of a specific autoreactive human B cell population. The results identify a defective tolerance checkpoint that appears to be specific for human SLE.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Arthritis, Rheumatoid / immunology
  • Autoantibodies / biosynthesis
  • Autoantibodies / physiology
  • B-Lymphocyte Subsets / cytology
  • B-Lymphocyte Subsets / immunology*
  • B-Lymphocyte Subsets / pathology
  • Cell Line
  • Cell Proliferation
  • Child, Preschool
  • Clonal Anergy / immunology
  • Clonal Deletion / immunology*
  • Female
  • Germinal Center / cytology
  • Germinal Center / immunology*
  • Germinal Center / pathology
  • Humans
  • Immunoglobulin G / biosynthesis
  • Immunoglobulin G / physiology
  • Immunoglobulin M / biosynthesis
  • Immunologic Memory / physiology
  • Immunophenotyping
  • Lupus Erythematosus, Systemic / immunology*
  • Lupus Erythematosus, Systemic / pathology
  • Spleen / cytology
  • Spleen / immunology


  • Autoantibodies
  • Immunoglobulin G
  • Immunoglobulin M