Regulation of the B cell receptor repertoire and self-reactivity by BAFF.
The TNF-family cytokine BAFF (BLyS) promotes B lymphocyte survival and is overexpressed in individuals with systemic lupus erythematosus and Sjögren's Syndrome. BAFF can rescue anergic autoreactive B cells from death, but only when competition from nonautoreactive B cells is lacking. Yet, high BAFF levels promote autoantibody formation in individuals possessing diverse B cells. To better understand how excess BAFF promotes autoimmunity in a polyclonal immune system, Ig L chain usage was analyzed in 3H9 site-directed IgH chain transgenic mice, whose B cells recognize DNA and chromatin when they express certain endogenous L chains. BAFF levels were manipulated in 3H9 mice by introducing transgenes expressing either BAFF or its natural inhibitor ΔBAFF. B cells in BAFF/3H9 mice were elevated in number, used a broad L chain repertoire, including L chains generating high-affinity autoreactivity, and produced abundant autoantibodies. Comparison of spleen and lymph node B cells suggested that highly autoreactive B cells were expanded. By contrast, ΔBAFF/3H9 mice had reduced B cell numbers with a repertoire similar to that of 3H9 mice, but lacking usage of a subset of Vκ genes. The results show that limiting BAFF signaling only slightly selects against higher affinity autoreactive B cells, whereas its overexpression leads to broad tolerance escape and positive selection of autoreactive cells. The results have positive implications for the clinical use of BAFF-depleting therapy.
Ota
Miyo
M
Department of Immunology and Microbial Science, Scripps Research Institute, La Jolla, CA 92037, USA.
Duong
Bao H
BH
Torkamani
Ali
A
Doyle
Colleen M
CM
Gavin
Amanda L
AL
Ota
Takayuki
T
Nemazee
David
D
D000818:Animals; D001323:Autoantibodies / Q000276:immunology; D015551:Autoimmunity / Q000276:immunology*; D053264:B-Cell Activating Factor / Q000276:immunology*; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D002469:Cell Separation; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D016133:Polymerase Chain Reaction; D011947:Receptors, Antigen, B-Cell / Q000276:immunology* / Q000378:metabolism; D017634:Self Tolerance / Q000276:immunology*
D001323:Autoantibodies; D053264:B-Cell Activating Factor; D011947:Receptors, Antigen, B-Cell; C505720:Tnfsf13b protein, mouse
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