期刊
MOLECULAR IMMUNOLOGY
卷 62, 期 2, 页码 315-320出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.molimm.2014.01.009
关键词
Tolerance; Anergy; Receptor editing; LAPTMS; Bach-2; IRF4; IRF8; Positive selection; Negative selection; Galectin-1
资金
- Inserm
- University of Paris Diderot, Sorbone Paris Cite
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 lambda 5 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 Sjogren'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 nave 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. (C) 2014 Elsevier Ltd. All rights reserved.
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