title: Transcriptional and metabolic pre-B cell receptor-mediated checkpoints: implications for autoimmune diseases.
abstract: At the pre-B cell stage of lymphocyte development, immunoglobulin light-chains are not yet produced, and heavy-chains are covalently linked to surrogate light-chains composed of VpreB and λ5 to form the pre-B cell receptor (pre-BCR) in a non-covalent association with signal-transducing modules. Even tough the pre-BCR does not have the potential to bind conventional antigens, accumulating evidence indicates that pre-BCR-mediated checkpoints are important both for negative and positive selection of self-reactivity, and that defects in these regulatory nodes may be associated with autoimmune disease. Thus, the transcription factor BACH2, which represents a susceptibility locus for rheumatoid arthritis, has recently emerged as a crucial mediator of negative selection at a pre-BCR checkpoint. The lysosome-associated protein LAPTM5, which is highly expressed in an animal model of Sjögren's syndrome, plays a role in down-modulation of the pre-BCR. Studies of copy number variation in rheumatoid arthritis suggest that a reduced dosage of the VPREB1 gene is involved in disease pathogenesis. Notably, animal models of autoimmune disease exhibit defects in pre-B to naïve B cell checkpoints. Administration of a pre-BCR ligand, which also plays a role in anergy both in human and murine B lymphocytes, ameliorates disease in experimental models of autoimmunity. Further investigation is required to gain a better insight into the molecular mechanisms of pre-BCR-mediated checkpoints and to determine their relevance to autoimmune diseases.
authors.affiliation: Inserm, UMR 1132, F-75475 Paris, France; Université Paris Diderot, Sorbone Paris Cité, F-75475 Paris, France. Electronic address: moncef.zouali@wanadoo.fr.
authors.forename: Moncef
authors.initials: M
authors.lastname: Zouali
mesh_terms: D000818:Animals; D001327:Autoimmune Diseases / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D054420:Pre-B Cell Receptors / Q000235:genetics* / Q000378:metabolism*; D054448:Precursor Cells, B-Lymphoid / Q000378:metabolism*; D014158:Transcription, Genetic / Q000235:genetics*
chemical_list: D054420:Pre-B Cell Receptors
keywords: Anergy; Bach-2; Galectin-1; IRF4; IRF8; LAPTMS; Negative selection; Positive selection; Receptor editing; Tolerance