Premium
The establishment of early B cell tolerance in humans: lessons from primary immunodeficiency diseases
Author(s) -
Meffre Eric
Publication year - 2011
Publication title -
annals of the new york academy of sciences
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.712
H-Index - 248
eISSN - 1749-6632
pISSN - 0077-8923
DOI - 10.1111/j.1749-6632.2011.06347.x
Subject(s) - peripheral tolerance , central tolerance , immunology , biology , primary immunodeficiency , b cell , immunodeficiency , immune tolerance , ptpn22 , b cell activating factor , major histocompatibility complex , breakpoint cluster region , receptor , genetics , immune system , gene , antibody , genotype , single nucleotide polymorphism
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.