The establishment of early B cell tolerance in humans: lessons from primary immunodeficiency diseases

Ann N Y Acad Sci. 2011 Dec;1246:1-10. doi: 10.1111/j.1749-6632.2011.06347.x.

Abstract

Patients with primary immunodeficiency (PID) provide rare opportunities to study the impact of specific gene mutations on the regulation of human B cell tolerance. Alterations in B cell receptor and Toll-like receptor signaling pathways result in a defective central checkpoint and a failure to counterselect developing autoreactive B cells in the bone marrow. In contrast, CD40L- and MHC class II-deficient patients only displayed peripheral B cell tolerance defects, suggesting that decreased numbers of regulatory T cells and increased concentration of B cell activating factor (BAFF) may interfere with the peripheral removal of autoreactive B cells. The pathways regulating B cell tolerance identified in PID patients are likely to be affected in patients with rheumatoid arthritis, systemic lupus erythematosus, and type 1 diabetes who display defective central and peripheral B cell tolerance checkpoints. Indeed, risk alleles encoding variants altering BCR signaling, such as PTPN22 alleles associated with the development of these diseases, interfere with the removal of developing autoreactive B cells. Hence, insights into B cell selection from PID patients are highly relevant to the understanding of the etiology of autoimmune conditions.

Publication types

  • Research Support, N.I.H., Extramural
  • Review

MeSH terms

  • Adult
  • Animals
  • Autoimmune Diseases / genetics
  • Autoimmune Diseases / immunology*
  • Autoimmune Diseases / metabolism
  • B-Cell Activating Factor / blood
  • B-Lymphocytes / immunology*
  • Cytidine Deaminase / metabolism
  • Humans
  • Immune Tolerance / immunology*
  • Interleukin-1 Receptor-Associated Kinases / metabolism
  • Protein Tyrosine Phosphatase, Non-Receptor Type 22 / genetics
  • Protein Tyrosine Phosphatase, Non-Receptor Type 22 / metabolism
  • Receptors, Antigen, B-Cell / immunology
  • Signal Transduction
  • Toll-Like Receptors / metabolism

Substances

  • B-Cell Activating Factor
  • Receptors, Antigen, B-Cell
  • Toll-Like Receptors
  • Interleukin-1 Receptor-Associated Kinases
  • Protein Tyrosine Phosphatase, Non-Receptor Type 22
  • Cytidine Deaminase