title: Autoimmune bone marrow environment severely inhibits B cell development by inducing extensive cell death and inhibiting proliferation.
abstract: The spontaneous scurfy (sf) mutation in mice results in a complete loss of Tregs, leading to a lethal, multi-system autoimmune syndrome. We have carefully examined B lymphopoiesis in sf mice. Paradoxically, the B cell numbers at all developmental stages including pro-B, pre-B, immature and mature B cells are significantly decreased in the BM and spleen of sf mice, compared to that of wild-type littermate controls. The developing B cells in sf mice exhibit profoundly elevated cell death induced by down-regulation of Bcl-XL expression and up-regulation of Fas expression. In addition, the clonal expansion of pre-B and immature B cells in sf mice is significantly reduced compared to wild-type controls. Foxp3 expression is not detectable in all stages of developing B cells in wild-type mice, indicating that the defects are B-cell extrinsic, which is further supported by the recovery of B cell maturation in BM chimeric mice. Remarkably, IFN-γ production is significantly elevated in numerous cell types in the BM of sf mice. Taken together, these results indicate that the autoimmune inflammatory marrow environment has dramatic inhibitory effects on B cell development by inducing apoptosis and suppressing proliferation of developing B cells.
authors: Department of Pathology and Immunology, Baylor College of Medicine, Houston, Texas 77030, USA.
authors: Shih-En
authors: SE
authors: Chang
authors: Linjie
authors: L
authors: Guo
authors: Jun
authors: J
authors: Tian
authors: Yang
authors: Y
authors: Liu
authors: Zhuxiu
authors: Z
authors: Guo
authors: Biao
authors: B
authors: Zheng
authors: Shuhua
authors: S
authors: Han
mesh_terms: D000818:Animals; D015551:Autoimmunity / Q000235:genetics; D001402:B-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D001853:Bone Marrow / Q000276:immunology*; D016923:Cell Death / Q000235:genetics / Q000276:immunology; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D060833:Cellular Microenvironment / Q000276:immunology*; D005260:Female; D051858:Forkhead Transcription Factors / Q000235:genetics; D007371:Interferon-gamma / Q000096:biosynthesis; D038041:Lymphopoiesis / Q000235:genetics / Q000276:immunology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051020:bcl-X Protein / Q000378:metabolism; D019014:fas Receptor / Q000378:metabolism
chemical_list: D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D051020:bcl-X Protein; D019014:fas Receptor; D007371:Interferon-gamma