title: The establishment of early B cell tolerance in humans: lessons from primary immunodeficiency diseases.
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.
authors.affiliation: Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut 06511, USA. Eric.meffre@yale.edu
authors.forename: Eric
authors.initials: E
authors.lastname: Meffre
mesh_terms: D000328:Adult; D000818:Animals; D001327:Autoimmune Diseases / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D053264:B-Cell Activating Factor / Q000097:blood; D001402:B-Lymphocytes / Q000276:immunology*; D003564:Cytidine Deaminase / Q000378:metabolism; D006801:Humans; D007108:Immune Tolerance / Q000276:immunology*; D053592:Interleukin-1 Receptor-Associated Kinases / Q000378:metabolism; D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22 / Q000235:genetics / Q000378:metabolism; D011947:Receptors, Antigen, B-Cell / Q000276:immunology; D015398:Signal Transduction; D051193:Toll-Like Receptors / Q000378:metabolism
chemical_list: D053264:B-Cell Activating Factor; D011947:Receptors, Antigen, B-Cell; D051193:Toll-Like Receptors; D053592:Interleukin-1 Receptor-Associated Kinases; D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22; D003564:Cytidine Deaminase