title: Cellular competition independent of BAFF/B lymphocyte stimulator results in low frequency of an autoreactive clonotype in mature polyclonal B cell compartments.
abstract: The peripheral B cell prosurvival cytokine BAFF/B lymphocyte stimulator (BLyS) has been proposed to participate in the regulation of immunological tolerance. Selective elimination or reconstitution of B cells expressing transgene-encoded, autoreactive BCRs upon systemic BLyS depletion or supplementation, respectively, was observed in two separate studies. Such findings led to a model positing a higher dependency of autoreactive B cells on BLyS. We tested this model by exploiting two targeted IgH transgenic mice (H chain knock-in [HKI]) that produce large numbers of follicular (FO) B cells that are either weakly or strongly autoreactive with nuclear autoantigens. Even though HKI B cells do not exhibit classical features of anergy, we found that mature, naive, autoreactive HKI B cells are outcompeted for representation in the periphery by a polyclonal B cell population. However, this is not due to a higher dependency of HKI B cells on BLyS for survival. Additionally, excess BLyS does not rescue HKI B cells from selective elimination. These findings suggest that some autoreactive FO B cells can fully develop while in competition with non-autoreactive cells for BLyS, but remain at a competitive disadvantage for other trophic factors that regulate peripheral stability. As such, our data indicate the existence of peripheral tolerance mechanisms that regulate the frequency of autoreactive FO B cells independent of the BLyS pathway.
authors.affiliation: Department of Microbiology and Immunology, Thomas Jefferson University, Philadelphia, PA 19107, USA.
authors.forename: Neda
authors.initials: N
authors.lastname: Nikbakht
authors.forename: Thi-Sau
authors.initials: TS
authors.lastname: Migone
authors.forename: Chris P
authors.initials: CP
authors.lastname: Ward
authors.forename: Tim
authors.initials: T
authors.lastname: Manser
mesh_terms: D000818:Animals; D001324:Autoantigens / Q000276:immunology*; D053264:B-Cell Activating Factor / Q000378:metabolism / Q000502:physiology*; D016175:B-Lymphocyte Subsets / Q000276:immunology* / Q000473:pathology; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology*; D002478:Cells, Cultured; D017635:Clonal Anergy / Q000235:genetics / Q000276:immunology*; D055879:Gene Knock-In Techniques; D018655:Lymphocyte Count; D008231:Lymphopenia / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D051379:Mice; D008805:Mice, Inbred A; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011828:Radiation Chimera; D011994:Recombinant Proteins / Q000378:metabolism / Q000494:pharmacology
chemical_list: D001324:Autoantigens; D053264:B-Cell Activating Factor; D011994:Recombinant Proteins; C505719:TNFSF13B protein, human